Drug Class 14: NSAIDs (Selective and Non-Selective) and Paracetamol

Drug class 14: NSAIDS (Non-steroidal anti-inflammatory drugs)

  • Non-selective NSAIDs (COX-1 and COX-2 inhibitors)

-Aspirin

-Diclofenac (Can be in combination with misoprostol)

-Ibuprofen, Indomethacin

-Ketoprofen, Keterolac

-Mefenamic acid, Naproxen

-Piroxicam, Sulindac, Tiaprofenic acid

Acronym: I sued Khoo Teck Puat for picking me an ass, dinosaur named ketorolac.

  • Selective NSAIDs (COX-2 selective)

Wrong assumption made: Scientists thought that PGI2 only came from COX-1 however COX-2 also produces PGI2.

-Absence of COX-2 in platelets. Thus, inhibition of COX-2 will lead to depressed PGI2 production, elevated blood pressure, accelerate atherosclerosis (Thromboxane A2 not balanced), Predispose patients to an exaggerated thrombotic effects

-Increased risk of rupture of atherosclerotic plaque.

-Celecoxib

-Etoricoxib

-Meloxicam

-Parecoxib

Acronym: So, they compensated me with a parrot and tori

 

14.1 Mechanism of action:

1. All inhibit the action of cyclo-oxygenase (COX 1 or 2). This enzyme produces prostaglandins from arachidonic acid which is cleaved from the phospholipid membrane by Phospholipase A2.

-Inhibition of COX will prevent production of COX as well as other mediators such as thromboxane.

2. *COX-1 is to produce PGE2 and PGI2 which has cyto-protective actions and prevents acid damage to the stomach.

Thus, Inhibition of COX-1 results in impaired gastric cytoprotection and anti-platelet effects.

3. Inhibition of COX-2 results in anti-inflammatory and analgesic action.

4. Reduction in glomerular filtration rate and renal blood flow occurs with both COX-1 and COX-2 inhibition.

Note: Most NSAIDs are non-selective, inhibiting both COX-1 and COX-2. COX-2 inhibitors however, have little or no effect on COX-1 at therapeutic doses but they are still associated with GIT adverse effects.

Major effects of NSAIDS:

-Anti-pyretic

-Anti-inflammatory

-Analgesic

-Anti-platelet (Aspirin, low dose)

-Anti-premature labour

14. 2 Clinical Indications:

(a) Rheumatoid arthritis-Including juvenile idiopathic arthritis

(b) Osteoarthritis

(c) Other inflammatory arthropathies-e.g. ankylosing spondylitis, Psoriatic arthritis, Reiter’s syndrome (Reactive arthritis)

(d) Acute gout

(e) Pain especially due to inflammation and tissue injury (e.g. menstrual pain, metastatic bone pain, renal colic, headache, migraine, post-operative pain)

(f) Fever

14.3 Precautions:

  • Allergic reactions to NSAIDs (including aspirin): Contraindicated
  • Asthma-Especially with rhinitis or nasal polyps-Contraindicated (May trigger bronchospasm/Aspirin induced asthma)
  • Coagulation disorders

-Increased risk of bleeding with NSAIDs (non-selective)àCOX-1 in platelets also inhibited, no thromboxane A2 [Especially at high doses]

-Selective NSAIDs (COX-2 inhibitors) and possibly diclofenac increase risk of thrombosis (Inhibits production of PGI2 in endothelial cells)

  • Bruising

-Increased risk of bleeding with topical NSAIDs.

  • Cardio/cerebrovascular disorders

-NSAIDs increase risk of cardiovascular events e.g. stroke and MI (Why? Because at high doses, PGI2 production also inhibited thus increased risk of thrombosis)

-Heart failure and hypertension may worsen due to sodium and fluid retention from NSAID-induced reduction in GFR and renal blood flow.

  • Gastrointestinal

-Contraindicated in active peptic ulcer disease/GI bleeding

-Avoid all NSAIDs if there is a history of GI bleeding (use with extreme caution and use prophylaxis)

-Inflammatory bowel disease (ulcerative colitis and Crohn’s disease) may worsen.

  • Renal impaired

-Pre-existing renal impairment increases the risk of NSAID-induced impairment

-Non-selective NSAIDs increase the risk of bleeding.

*Avoid use if Creatinine clearance CrCl <25ml/min (Celecoxib and Etoricoxib are contraindicated if CrCl<30ml/min)

-Avoid Ketorolac

  • Hepatic impaired

-Use with caution in severe impairment (coagulation factors production inhibited). Non-selective NSAIDs increase the risk of bleeding.

-Selective NSAIDs (COX-2 inhibitors) are not recommended.

  • Surgery

-Risk of renal impairment after surgery (Especially if dehydrated or renal hypoperfused-Reduced renal blood flow increases the importance of intra-renal prostaglandins in maintaining renal function-Compensatory vasodilation)

-Ensure adequate hydration before surgery, particularly when an NSAID is to be used for post-operative analgesia.

-Increased risk of bleeding with non-selective agents due to anti-platelet effects

-Consider stopping NSAID (2-3 days) before surgery, especially if there is a significant risk of post-operative bleeding.

*Note: Selective NSAIDs (COX-2) do not affect platelet aggregation but may increase risk of thrombotic events.

  • Elderly

-Increased risk of adverse effects, in particular heart failure, GIT ulceration and renal impairment.

  • Women

-Reconsider NSAID use if planning pregnancy

*May impair fertility by preventing or delaying ovulation (however, this is reversible)

  • Pregnancy/Breastfeeding

-Increased risk of miscarriage

-Risk appears highest when NSAIDs are taken around the time of conception

-Contraindicated during the latter part of pregnancy-

Closes the ductus arteriosus of fetus, leads to fetal renal impairment, decrease in the volume of amniotic fluid, inhibition of platelet aggregation, may delay labor and birth.

-CAT C-AUS

Breastfeeding: Safe to use, selective NSAIDs appear to be safe

14.4 Adverse effects/Side effects

-Common

1. Nausea

2. Gastrointestinal disturbances (dyspepsia, GI ulceration or bleeding)

3. Raised liver enzymes

4. Salt and fluid retention

5. Headache, dizziness

6. Hypertension

*Diarrhea-Mefenamic acid

-Infrequent

Oseophageal ulceration, rectal irritation (with suppositories), heart failure, hyperkalemia, renal impairment, confusion, bronchospasm, rash

Topical use: Skin irritation, erythema, itching and rash

Rare

MI, Stroke, photosensitivity (JIA-naproxen), acute renal failure, SJS, blurred vision, hypersensitivity, urticarial, nephrotic syndrome, interstitial nephritis, blood dyscrasias

Topical use: Dyspnea, nausea, dyspepsia, abdominal pain, gastritis, contact dermatitis, allergy, peripheral edema

Important information when choosing NSAIDs

  • Efficacy: Little difference in anti-inflammatory efficacy between NSAIDs, choice is dependent on individual response and tolerance.
  • Route of administration:

-Enteric coated and rectal formulations (do not reduce risk of GI ulceration, i.e. GI risk still present)

-Rectal administration may be useful alternative to oral route (Diclofenac, indomethacin, and ketoprofen are available as suppositories)-Acronym: suppositories for KID

-Topical NSAIDs achieve highest concentration in tissues under application site.

-Small amount absorbed into systemic circulation when topically applied.

-NSAIDs versus Paracetamol?

  • Toxicity

Note: Non-selective NSAIDs vary in their half-life and relative toxicity!

Selective COX-2 inhibitors have similar adverse effects to the non-selective agents

-Risk of GI complications and thrombotic events may differ.

  • Cardiovascular effects

-All NSAIDs can worsen existing cardiovascular disease (e.g. by increasing BP and reducing renal function)

-Selective NSAIDs (COX-2 Inhibitors) are associated with an increased risk of CV events (especially if low dose aspirin is not taken simultaneously)

*However, when low dose aspirin is taken with COX-2 inhibitor, the risk of GI adverse effects is the same as that with a non-selective NSAID.

-Increased risk of CV events for diclofenac and indomethacin whilst naproxen neither increased nor decreased risk.

  • Gastrointestinal effects

*All NSAIDs can cause serious GI adverse effects.

-Selective NSAIDs (COX-2 inhibitors) are generally associated with a lower risk of GI complications than non-selective agents

-Non-selective NSAIDs (especially Ketoprofen and piroxicam) appears to have highest risk of GI-complications. Diclofenac and ibuprofen appear to have the lowest.

-Advantage is lost for ibuprofen when used at full doses.

From the above, it is evident that not all NSAIDs are created equal (e.g. diclofenac and ibuprofen àLess GIT disturbances, diclofenac and indomethacinàLess CV risk)

14.5 Patient Counselling

-If patient develops swollen ankles, difficulty in breathing, black stools or dark-coffee-coloured vomit, stop taking medicine (suggests internal bleeding).

-Tell doctor immediately.

-Do not take aspirin for pain relief as it will increase the risk of side effects with NSAIDs.

14.6 Practice Points

-About 60% of patients will respond to any NSAID. Those who do not respond to one may respond to another.

Qn: Why would patients not respond to a particular NSAID?

Osteoarthritis: Maximal analgesic and anti-inflammatory effects are usually seen within 2 weeks. If appropriate responses are not observed within 3 weeks, try another NSAID.

Note: There is no rationale for using more than 1 NSAID at a time (excluding low dose aspirin for anti-platelet effects)

*For extra pain relief, NSAIDs may be used with paracetamol and if pain is severe use an opioid (e.g. morphine for tumour metastases in bone)

-Seek specialist advice if patient has aspirin induced asthma and great need for an NSAID (may be able to tolerate a selective COX-2 inhibitor, first dose should be given under medical supervision)

*Do not stop low-dose treatment when using an NSAID (NSAID has very weak anti-platelet effects)

*Measure blood count, creatinine and liver function before starting treatment. Repeat at least once a year during continued treatment.

*To reduce complications,

Use the lowest effective dose for the shortest period of time.

Use Paracetamol to enable lower doses of NSAID

-Use of the proton pump inhibitors (omeprazole) or misoprostol (PGE1 analogue) with an NSAID and in patients who are high risk of GI adverse effects

*14.7 Types of NSAIDs (Note NSAIDs are different in side effects, potency for COX-1 and COX-2, route of administrations etc.)

Non-selective NSAIDs

  1. 1.       Aspirin (Refer to drug class 12)
  • Diclofenac (Voltaren®)

2-(2,6-dichloranilino) phenylacetic acidàDiclofenac

  • Clinical indications:

(a) Rheumatoid arthritis*

(b) Osteoarthritis*

(c) Pain, especially due to inflammation (e.g. period pain)

(d) Local pain and inflammation in soft tissues (1% topical gel)

(e) Actinic keratosis- premalignant condition where thick, scaly, or crusty patches of skin are       present in people who are exposed to sun frequently

(f) Heavy menstrual bleeding (dysmenorrhea)

(g) Combination with misoprostolàIndication for Diclofenac and prevention of NSAID induced ulcers

  • Precautions

–          Proctitis (inflammation of anus)-Use of suppositories is contra-indicated

–          Increased cardiovascular risk-Avoid diclofenac (may increase risk of CV events)

  • Practice points

Combination with misoprostol

-Consider only for patients already stabilised on the same dose of single ingredient products because optimum dose of misoprostol to prevent NSAID-related gastric ulcers (800 mcg daily) prevents use of the lowest effective dose of diclofenac.

-Misoprostol is poorly tolerated due to adverse effects (diarrhea) and may lead to inadequate dosing of NSAID.

  • Ibuprofen

(Iso-butyl-propanoic-phenolic acid)

  • Clinical indications:

(a)    Rheumatoid arthritis*

(b)   Juvenile (child) idiopathic arthritis (JIA)-Common form of arthritis in children and adolescents

(c)    Pain, especially due to inflammation (e.g. period period, headache)

(d)   Fever

(e)   Heavy menstrual bleeding (dysmenorrhea)

*Combination with codeine-Mild to moderate pain

  • Precautions:

-Patients on low-dose aspirin (ibuprofen may reduce aspirin anti-platelet activity)

  • Counselling

-Take oral doses with or shortly after food

  • Practice points

Infants and children tolerate low grade fever (e.g. <38-38.5oC) well, often responds to fluids and comfort. May not need medication.

Recall: Fever is due IL-1 and IL-6 effects on the hypothalamus which causes an increase in set point for body temperature.

Note: Ibuprofen may reduce anti-platelet activity of low dose aspirin and potentially reduce or negate its cardio-protective effect.

*Never take ibuprofen and aspirin together.

-Unlikely, that an occasional dose of ibuprofen would have a clinically important effect.

-Choose an alternative NSAID if regular use is anticipated.

  • Indomethacin/Indometacin

(indole ring present, methoxy group present)

  • Clinical indications:

(a)    Rheumatoid arthritis*

(b)   Osteoarthritis*

(c)    Acute gout

(d)   Ankylosing spondylitis (Fusion of the vertebrae due to inflammation)

(e)   Pain, especially due to inflammation (e.g. period pain)

(f)     Closure of significant patent ductus arteriosus (seek specialist advice)

Precautions:

Proctitis-use of suppositories is contraindicated.

Adverse effects:

*Vertigo (Common)

Counselling points:

-Take capsules with or shortly after food

-This medication may affect patient alertness and coordination. Avoid tasks such as driving or operating equipment.

  • Ketoprofen

(RS)2-(3-benzoyl linked via ketone to phenyl)-propionic acid

  • Clinical indications:

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

(c)    Superficial sport injuries and similar injuries (topical)

  • Precautions:

-Procitis (Use of suppositories contraindicated)

  • Practice points:

-Capsules or suppositories may be used at bedtime to relieve nocturnal and morning symptoms

  • Ketorolac

(Dihydropyrrolizine carboxylic acid derivative structurally related to indomethacin)

(Isostere of ketoprofen)

  • Clinical Indications:

*Mild-to moderate post-operative pain

  • Precautions:

1.  Cautions where risk of bleeding is increased or hemostasis is critical (e.g. full anti-coagulation treatment, increased risk of haemorrhage, suspected intracranial bleeding, history of GI ulcer etc)

2. Dehydration or hypovolemia-Contraindicated

3. Treatment with probenacid-Contraindicated

4. Treatment with aspirin-Contraindicated

5. Treatment with lithium-Contraindicated

6. Treatment with oxpentifylline (treats peripheral vascular disease)-Contraindicated

*Note: DO NOT GIVE KETOROLAC WITH ASPIRIN OR PROBENACID.

 

7. Renal impaired-Contraindicated

-Contraindicated in moderate-to-severe impairment (renal impaired increases the half-life of ketorolac)

-Increases risk of adverse effects such as acute renal failure (Reduce dose in mild impairment)

8. Elderly

-Half-life of ketorolac may be prolonged, increasing risk of adverse effects. Reduce dose for elderly.

  • Adverse effects/Side effects

Common

  1. Pain at injection site
  2. Swelling
  3. Purpura

Infrequent

-Perioperative wound bleeding

Rare

-Brusing, hematoma or tingling at injection site

  • Administration advice/Practice points

IM INJECTION: Inject slowly and deeply into muscle. Apply pressure at injection site for 15-30 seconds (minimises local reactions)

IV: Inject over at least 30s

-Correct hypovolemia before administering ketorolac

-Higher than recommended doses increase risk of serious adverse effects without improving pain relief

-Risk of adverse effects may increase with prolonged treatment. Stop treatment ASAP.

 

  • Mefenamic acid (‘Me fend a mic’)
  • Clinical Indications:

(a)    Pain especially due to inflammation (e.g. period pain)

(b)   Heavy menstrual bleeding (dysmenorrhea)

  • Side effects/Adverse effects:

Common

-Diarrhea

  • Naproxen (naproxen sodium)

(+)-(S)-2-(6-methoxynaphthalen-2-yl) propanoic acid

  • Clinical indications:

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

(c)    Ankylosing spondylitis

(d)   Juvenile idiopathic arthritis (JIA)

(e)   Pain, especially due to inflammation (e.g. period pain, dysmenorrhea, migraine)

(f)     Heavy menstrual bleeding (Accepted)

  • Adverse effects/Side effects:

Pseudoporphyria (particulary in JIA) Common-Photosensitivity

  • Counselling:

*Take with or shortly after food

-JIA (juvenile idiopathic arthritis): Risk of skin reaction with naproxen (often with blisters and scars). Tell doctor if this occurs.

  • Practice Points:

-Naproxen can reduce the anti-platelet activity of low-dose aspirin

-Potentially negate or reduce aspirin’s cardio-protective effect

*Stop naproxen if pseudoporphyria occurs

-Controlled release products can be taken at night to relieve nocturnal and morning symptoms

-Oral liquid contains 8mg/ml of sodium

  • Piroxicam (Pirate oxi cam)

Contains pyridine ringàPiroxicam

  • Clinical indications: (a) Rheumatoid arthritis (b) Osteoarthritis (c) Ankylosing spondylitis (d) Superficial sports injuries and similar injuries
  • Precautions:

-Previous skin reaction with piroxicam-[Use of oral piroxicam is contraindicated, even if reaction was mild]

-Previous severe allergic reaction to any drug-[Use of oral piroxicam is contraindicated]

  • Counselling:

-Take tablets or capsules with or after food

-If patient develops a rash, stop taking piroxicam and tell the doctor.

  • Practice points:

-Serious skin reactions may be more frequent with piroxicam than with other NSAIDs.

  • Sulindac (arylalkanoic acid class)-Prodrug

{(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)benzylidene]-1H-indene-3-yl}acetic acidàSulindac

  • Clinical indications: (a) Rheumatoid arthritis (b) Osteoarthritis

 

  • Adverse effects:

-Renal stones (Rare)

 

  • Tiaprofenic acid (The ‘profanitic ‘acid) (Class: arylpropionic acid (profen) class)

(Contains Thienyl and propanoic acid)

  • Clinical indications

 

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

  • Precautions

-Urinary tract or prostatic disease (may worsen)

-Renal impaired: Reduces excretion

-Contraindicated in cystitis and Urinary Tract Infection

  • Adverse effects

Cystitis, bladder irritation (Rare)

  • Pharmacokinetics

Metabolism: Sparingly metabolised in the liver to two inactive metabolites.

-Excretion: Mostly excreted unchanged in the urine (Caution in Renal impaired)

 

  • Selective COX-2 inhibitors (Caution needed when used in patients with cardiovascular problems)

-Risk of allergies due to sulphonamide group present and contraindicated in hepatic impaired.

Ratio of Drug selectivity for COX-1 to COX-2= (IC 50 FOR COX-1)/(IC 50 FOR COX-2)

-Smaller ratio, more selective to COX-2

 

 

  • Celecoxib (COX-2 selective)

 

  • Clinical Indications

 

 

(a)    Rheumatoid arthritis

(b)   Osteoarthritis

(c)    Ankylosing Spondylitis

(d)   Pain due to dysmenorrhea or injury (soft tissue injury, musculoskeletal, post-operative)

  • Precautions

 

  1. Allergy to sulphonamides (may increase risk to celecoxib) [Contraindicated]
  2. Cardiovascular (Contraindicated in Heart failure)
  3. Contraindicated for pain due to Coronary Artery Bypass graft (CABG)
  4. Hepatic impaired. Contraindicated in severe hepatic impairment. Mild to moderate impairment reduces clearance and increases concentration. Reduce dose.

 

  • Practice points

-Same no. of gastric ulcerations in celecoxib and non-selective NSAIDs (so what is the advantage of COX-2 inhibitors?)

  • Etoricoxib (COX-2 selective) [E-tori coxib]

 

  • Clinical indications:

(a) Osteoarthritis

(b) Acute gout

(c) Acute pain (e.g. period pain)

  • Precautions:

Contraindicated in:

 

  1. Cardiovascular (contraindicated by manufacturer in patients with heart failure. NYHA II-IV)
  2. BP>140/90 mmHg (inadequately controlled hypertension)-Etoricoxib more likely to induce hypertension
  3. Coronary heart disease, cerebrovascular disease or peripheral arterial disease

Use cautiously in others at increased cardiovascular risk: May increase risk of thromboembolic events

*Hepatic impaired-Contraindicated in severe impaired.

 

  • Practice points:

Measure BP within 2 weeks, then repeat periodically, stop etoricoxib if BP rises significantly.

  • Meloxicam (Mel oxi cam)

 

  • Clinical Indications:

 

(a)    Osteoarthritis

(b)   Rheumatoid arthritis

  • Practice Points:

-Use the lowest effective dose, as the COX-2 selectivity of meloxicam is dose-dependent

-15mg dose provides greater pain relief than 7.5 mg dose but higher risk of GI adverse effects.

*Not indicated for relief of pain unrelated to arthritis (contraindicated for pain management in CABG)

-Although drug interactions involving CYP enzymes do not appear to be problematic, combination with CYP2C9 inhibitors is contraindicated in AUS product information.

  • Parecoxib (‘Parent coxib’)-Prodrug

-Water soluble and injectable prodrug of valdecoxib.

  • Clinical Indications:

*Post-operative pain (single dose)

  • Precautions:
  1. Increased risk of cardiovascular events (.e.g those with ischemic heart disease, peripheral arterial disease or cerebrovascular disease)-Contraindicated
  2. Major vascular surgery-Contraindicated
  3. Allergy to sulphonamides-Contraindcated
  4. Hepatic impaired (Contraindicated in severe impairment)
  5. Surgery

(Post CABG-Parecoxib is associated with increased risk of cardiovascular events and thrombolic events. Infection and poor wound healing complications)

  1. Elderly

-Reduce dose for elderly woman <50kg

  • Administration advice:

IM injection: Inject slowly and deeply into muscle.

IV injection: Give as a bolus directly into vein or into an IV line delivering sodium chloride 0.9% or glucose 5%

-Flush line before and after parecoxib injection to prevent precipitation when a second drug is given.

  • Practice points:

40mg is the maximum effective dose as higher doses do not have higher analgesic effect

-Onset of analgesia is approximately 15mins after injection. Duration of analgesia is 6-24 hours.

-Prodrug of valdecoxib (a selective COX-2 inhibitor associated with serious skin reactions)

*Has no effect on platelet function and thus does not promote bleeding during or after surgery.

————————————————Cox-3 Inhibitors (Analgesic)————————————————

  • Paracetamol/Acetaminophen (US) (NON-OPIOID ANALGESIC)

Analgesic efficacy is equivalent to aspirin but in therapeutic doses has only weak anti-inflammatory effects.

  • Mechanism of action: (Not fully determined)

-Inhibits prostaglandin synthesis in the brain but hardly at all in the periphery. No effect on platelet function.

-Modulation of inhibitory descending serotonergic pathways.

-Anti-pyretic effect is probably due to reduced production of prostaglandins in the hypothalamus

  • Clinical Indications:

 

(a)    Mild-moderate pain (including combination with dextropropoxyphene or codeine (OAA around 30 min after oral administration)

(b)   Fever

(c)    Migraine (with nausea and vomiting) *IN COMBINATION WITH metoclopramide

 

  • Precautions:

 

  1. Hepatic impaired (People with chronic liver disease may be at increased risk of liver damage following therapeutic overdose ie. 3x3000mg daily
  2. Pregnancy-Safe to use. CAT A-AUS. Breastfeeding: Safe to use.
  3. Sodium restriction-Soluble paracetamol products may contain large amounts of sodium
  4. Phenylketonuria: Soluble paracetamol products may contain aspartame.
  • Side effects/Unwanted effects

-Few and uncommon side effects.

*Common: Increased Aminotransferases

Toxic doses: 2-3 x therapeutic dose (Max adult recommended dose-3000mg per day)

(a)    Leads to renal and liver damage

àIt is normally inactivated in the liver by conjugation as glucorinide and sulphate

àHowever, at higher doses of paracetamol, enzymes for these pathways are exhausted and mixed function oxidases convert paracetamol to the toxic metabolite N-acetyl-b-benzoquinone imine.

àUsually it is further conjugated with glucorinide to prevent accumulation. At high doses, enzymes depleted.

àToxic intermediates accumulates and binds to macromolecules (causes cell death)

àAgents which stimulate glutathione production (e.g. acetylcysteine or methionine) can prevent liver damage if given early.

Rare side effects:

-Urticarial/Erythematous rash, drug fever and mucosal lesions

-Hypersensitivity reactions

-Neutropenia, Thrombocytopenia, Pancytopenia

-Acute hepatitis (only one case reported in AUS)

-Hypotension (IV)

  • Administration advice:

-Give IV infusion over 15 mins.

-Oral tablets (Before a meal)

  • Counselling:

-Many brands of paracetamol are available. Contained in many cough and cold products.

-Prevent overdosing by checking carefully which strength product is being used. Correct dose accordingly.

-Avoid using more than one product containing paracetamol at once. Too much paracetamol cause liver damage

Adult: Do not take more than 8 tablets or capsules (500mg strength) or 6 controlled release tablets each day.

Child: Give paracetamol strictly according to the dose and frequency instructions on the label and if pain and/or fever lasts for >48 hours, talk to the doctor.

 

  • Practice points:

-Paracetamol may be used in all age groups and is preferred over NSAIDs for mild-to moderate pain (fewer side effects)

-Can be used when NSAIDs are contraindicated (e.g. increased risk of bleeding, Gastric ulcers present)

-Can use in osteoarthritis of all grades, paracetamol alone is preferred but under used.

-Used with NSAID treatment for all painful conditions, although evidence is sparse for superiority of this combination compared with NSAID alone.

 

Children and infants:

-They can tolerate low grade fever relatively well. Often responds to fluids and comfort. May not require paracetamol.

-Lack of awareness of the strengths of different pediatric products (e.g. infant drops, liquid paracetamol and use of >1 product containing paracetamol). May lead to dosage errors and toxicity.

-Educate parents and caregivers appropriately

Onset of action:

-Approximately 30 min after oral administration.

-Erratic and delayed OAA after rectal administration.

-Approximately 5-10 min after IV administration.

 

 

 

 

——————————Drugs taken along with Diclofenac for GIT protective effects:

Anti-ulcer medications:

  • Misoprostol

(Prostaglandin E1 analogue)

  • Mechanism of action: (Protective effects)

*Increases secretion of mucus.

-Prostaglandin E1 analogue that protects GI mucosa by increasing the secretion of mucus when bound to prostaglandin receptors.

*Stimulates bicarbonate secretion in the duodenum

*Inhibits basal and stimulated acid secretion by a direct action on gastric parietal cells

 

  • Clinical Indications:

 

(a)    Peptic ulcer disease (PUD)

(b)   Prevention of NSAID-related ulcers

(c)    Obstetric indications (e.g. termination of second trimester pregnancy)

(d)   Intrauterine fetal death

(*Can be combined with diclofenac-Prevent NSAID-induced ulcers)

 

  • Precautions:

 

  1. Cerebrovascular or coronary artery disease (CAD)-Misoprostol-induced peripheral vasodilation may destabilise cardiac disease
  2. Predisposition to diarrhoea, dehydration

-Misoprostol induced diarrhea may worsen

3.    Surgery (Continue treatment during peri-operative period)

4.   Women (Ensure effective contraception during treatment)

5.   Pregnancy-CONTRAINDICATED. May induce labour by ripening cervix and increasing uterine

tone and contractility. CAT X-AUS

6.  Breastfeeding-Appears safe. Possibility of diarrhoea in child.

  • Adverse effects/Side effects:

Common

*GIT effects: Diarrhoea, Abdominal pain, Nausea, Flatulence, Dyspepsia, Vomitting

Infrequent

  1. Rash
  2. Headache
  3. Dizziness
  4. Constipation
  5. Uterine cramps
  6. Bleeding: Heavy menstrual bleeding, Post-menopausal bleeding, Intermenstrual bleeding

 

  • Counselling:

*Take with meals to reduce risk of diarrhoea. Tell the doctor if patient has symptoms such as black stools or vomit that looks like coffee grounds.

  • Practice Points:

-Misoprostol 800mg daily is the optimum dose for preventing ulcers due to NSAIDs. Consider the combination product only for patients already stabilised on the same doses of single ingredient products.

Drug Class 14: Thrombolytics/Fibrolytics, Anti-coagulants and other hemostatic agents

Drug Class 14: Thrombolytics and other hemostatic agents (Protamine, Tranexamic acid, Vitamin K)

Part 1———————————————————————————————–Thrombolytics—————————————————————————————————————————-

What are thrombolytics?

-Drugs that activate the natural anticlotting system, conversion of plasminogen to plasmin. Activation of this system breaks down fibrin threads and dissolves any formed clot. Effective only if pt. has plasminogen in the plasma.

14.1 Mechanism of action:

-They convert plasminogen to plasmin, which catalyses the breakdown of fibrin.

14.2 Clinical Indications

(a) Acute STEMI (ST-segment elevation myocardial infarction)

(b) Acute massive VTE (venous thromboembolism)/DVT in patients who are hemodynamically unstable

(c) Peripheral arterial thromboemolism

(d) Thrombosed IV cannulae, central venous catheters and hemodialysis shunts

14.3 Precautions

1. Risk of bleeding

CONTRAINDICATED in severe active bleeding disorders or disease states with an increased risk of bleeding e.g. severe uncontrolled hypertension, severe hepatic disease, bleeding orders, severe thrombocytopenia.

-Other drugs that can affect the clotting process may increase the risk of bleeding.

*Low dose aspirin (up to 150mg daily) or heparin may be used where indicated.

2. Spinal injection or puncture

-Seek specialist advice before considering intra-thecal or epidural analgesia or anesthesia or lumbar puncture

-Risk of epidural hematoma, which may cause paralysis

3. Pregnancy

-Only minimal amounts of streptokinase cross the placenta.

Streptokinase specific antibodies are found in fetal blood.

Alteplase: CAT B-AUS

Reteplase, Tenecteplase and Streptokinase: CAT C-AUS

4. Breastfeeding

-No data unavailable but unlikely to be absorbed by infant

14.4 Adverse effects/Side effects

Common

1. Bleeding, including bleeding at injection sites

2. Intracranial bleeding

3. Internal bleeding (e.g. Gastrointestinal, genitourinary)

4. Transient Hypotension

Infrequent

-Allergic reactions including fever, chills, rash, nausea, headache, bronchospasm, anaphylaxis, vasculitis, nephritis

Rare

-Cholesterol embolism

14.5 Practice points

-Avoid Intra-muscular injections and other invasive procedures during thrombolytic treatment.

-In the case of severe bleeding not controlled by local pressure, stop infusion of thrombolytic, fibrinogen, platelets, coagulation factors, tranexamic acid may be used (or protamine if herparin has been used).

-In acte MI, give aspirin in antiplatelet dose at least until discharge.

14.6 Types of thrombolytics

1. Alteplase (rt-PA) [Fibrin specific]

-Plasminogen activators produced by recombinant DNA technology.

-More fibrin specific than streptokinase because they activate plasminogen associated with thrombi in preference to circulating plasminogen.

  • Clinical Indications: (a) Acute STEMI (b) Massive pulmonary embolism (c) Acute ischemic stroke

2. Reteplase [Fibrin specific]

-Plasminogen activators produced by recombinant DNA technology.

-More fibrin specific than streptokinase because they activate plasminogen associated with thrombi in preference to circulating plasminogen.

  • Clinical Indications: Acute STEMI
  • Administration advice: No other medication, including heparin, should be injected through the line reserved for reteplase because of the risk of precipitation. 

3. Tenecteplase [Fibrin specific]

-Plasminogen activators produced by recombinant DNA technology.

-More fibrin specific than streptokinase because they activate plasminogen associated with thrombi in preference to circulating plasminogen.

  • Clinical Indications: Acute STEMI

4. Streptokinase (Contraindicated if previously exposured)

-Streptokinase: Produced by beta-hemolytic streptococci.

-Production of anti-bodies towards streptokinase occurs after streptokinase treatment or streptococcal infection.

-Streptokinase is likely to be ineffective if given between 5 days and 1 months or more after previous streptokinase treatment or acute severe streptococcal infection (e.g. glomerulonephritis, rheumatic fever, pancreatitis)

  • Clinical indications: (a) Acute STEMI (b) Acute massive VTE/DVT in patients who are hemodynamically unstable (c) Peripheral arterial thromboembolism (d) Trombosed hemodialysis solution
  • Precautions:

1. Previous treatments with streptokinase (take note if patient had previous MI)

*Previous streptokinase treatment or severe streptococcal infections (e.g. acute rheumatic fever, glomerulonephritis).

-Anti-streptokinase antibodies are likely to be present. Efficacy of streptokinase is likely to be reduced.

*If this occured between 5 days and 12 months ago, streptokinase contraindicated (risk of anaphylaxis)

*If used more than 12 months ago, consider alternative agents.

  • Adverse effects/Side effects:

Common

*Hypotension (related to infusion rate)

  • Practice points

-Stop heparin before giving streptokinase. *Check APTT (should be less than twice the normal control value before beginning thrombolytic treatment and before reinstituting heparin)

-Give patients a record of use so the information is available in the event of future need for streptokinase.

-Hypotension usually responds to fluids and temporarily stopping streptokinase infusion.

5. Urokinase [Drug is not marketed in Australia but may be available through the SAS]

-Enzyme isolated from human urine

  • Clinical indications: (a) Thrombosed IV cannulae (b) Central venous catheters (c) Hemodialysis shunts (d) Peripheral arterial thromboembolis
  • Practice points:

*Stop heparin before giving urokinase.

*Check APTT (activated partial thromboplastin time should be less than twice the normal control value before beginning thrombolytic treatment and before reinstituting heparin)

*Comparative information

  • ACUTE STEMI

-Streptokinase, alteplase, reteplase and tenecteplase are used in ACUTE STEMI within 12 hours of onset of chest pain

-Earlier administration is of greater clinical benefit

-Weight-adjusted heparin is given routinely with alteplase, reteplase and tenecteplase.

-Heparin may be given with streptokinase in selected patients.

*Alteplase given as an accelerated infusion appears to be associated with a slightly greater reduction in mortality but slightly higher risk of cerebral hemorrhage than streptokinase in STEMI patients presenting within 6 hours of symptom onset.

*Reteplase and tenecteplase reduce mortality to a similar extent as alteplase with a similar incidence of adverse effects. Both are given as a bolus injection and are considered the preferred thrombolytics.

-Streptokinase should be avoided in ATSI (aboriginal and torres strait islander) people because of their frequent high levels of anti-streptococcal antibodies.

  • Venous thromboembolism/Deep Vein thrombosis

-Streptokinase is approved for treatment of deep vein thrombosis and pulmonary embolism

-Alteplase is approved for treatment of massive pulmonary embolism.

*Consider thrombolytics in patients with acute massive embolism who are hemodynamically unstable.

Note: Treatment always carries a high bleeding risk.

  • Peripheral arterial thrombosis

-Both streptokinase and urokinase have been used successfully.

However, there is little evidence to recommend thrombolysis over angioplasty or surgery.

  • Stroke

-Alteplase may be used for the treatment of acute ischemic stroke in selected patients within 4.5 hours of symptom onset (The earlier treatment is started, the greater the benefit)

It reduces disability at 3 months, despite an increased risk of symptomatic intracerebral hemorrhage.

 

Part 2———————————————————————————————————Anti-Coagulants (Very big class)————————————————————————————-

 

For treatment of venous thromboembolism (DVT):

 

Drug choice: Heparins or Low Molecular Weight Heparins (Enoxaparin)

Factor Xa Inhibitors

Warfarin (Discussed in detail here)

 

Prevention of venous thromboembolism (DVT):

Drug choice: Factor Xa inhibitors (Discussed in detail here)

-Low dose heparin

Direct Thrombin inhibitor (Discussed in detail here)

-Other preventive measures

 

Ischemic stroke and transient ischemic attack

Drug choice: Heparin (Discussed in detail here)

Alteplase

 

 

Part 3———————————————————————————————————Other drugs affected hemostasis——————————————————————————-

1. Protamine [Pro-coagulant due to inhibition of heparin]

Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential forsperm head condensation and DNA stabilization

  • Mechanism of action:

-Combines with heparin to form a stable inactive complex. Reversing its anticoagulant effect.

Thus, it is a drug that reverses the anticoagulant effects of heparin by binding to it.

  • Clinical Indications:

*Heparin, dalteparin or enoxaparin overdose in patients with/or at high risk of severe hemorrhage 

  • Precautions

-Consider the need for protamine and original reason for heparin as re-heparinisation may not be effective until the protamine has been eliminated

-Seek specialist hemorrhage advice or consult local protocols

*Give only when resuscitation facilities are available.

1. Fish Allergies-Increase risk of allergy

2. Previous protamine treatment (including protamine containing insulins)-Increases risk of allergy

3. Infertile men (including vasectomy)-May have protamine antibodies and an increased risk of allergy.

4. Pregnancy: CAT B2-AUS

5. Breastfeeding-Unlikely o be absorbed by child

  • Adverse effects/Side effects

Common

1. Sensation of warmth

2. Flushing

3. Nausea

4. Vomitting

5. Tiredness

6. Allergy

Infrequent

Hypotension, bradycardia, dyspnea (especially if given rapidly), allergy, rebound bleeding with excessive doses

*Allergy

-Urticaria/Hives and severe hypersensitivity reactions including cardiovascular collapse. Bronchospasm and death have occured.

  • Administration advice

-IV maximum rate 5 mg/minute (too rapid administration may cause severe hypotension and anaphylactoid reactions)

  • Practice Points

-Protamine has an onset of action (OAA) of 5 mins.

-Withdrawal of heparin is usually sufficient to treat minor bleeding.

-Protamine is not recommended for danaparoid overdose

-Protamine can have an anti-coagulant effect in overdose or in the absence of heparin

-Transfusions may still be needed for severe hemorrhage.

2. Tranexamic acid [Anti-fibrolytic]

  • Mechanism of action: Inhibits breakdown of clots by blocking binding of plasminogen and plasmin to fibrin
  • Clinical indications: (a) Hereditary angioedema (b) Reduction of bleeding in minor surgery (dental surgery, cervical conisation, prostatectomy) in patients with mild to moderate coagulopathy (c) Reduces bleeding in heavy menstrual bleeding, traumatic hyphema, cardiac surgery or knee/hip arthroplsaty

*Coagulopathy refers to a condition in which the blood’s ability to clot is impaired

  • Precautions: 

1. Active intravascular clotting-CONTRAINDICATED

2. Predisposition to thrombosis-Increases risk of thrombotic adverse effects

3. Subarachnoid hemorrhage-May increase cerebral ischemic complications

4. Renal impaired

-Reduce dose in renal impairment

-In hematuria due to renal parenchymal disease, thrombosis may lead to intra-renal obstructoin.

5. Pregnancy

-Contact one of the pregnancy drug information centres. CAT B1-AUS

6. Breastfeeding-Appears safe

  • Adverse effects/Side effects:

Common

1. Nausea

2. Vomitting

3. Diarrhea

Infrequent or rare

-Hypotension, thrombosis, allergic skin reactions, transient disturbance of colour vision

  • Practice points

-May be used as a mouthwash (e.g. in anti-coagulant treated or hemophiliac patients undergoing minor oral surgery)

-Recently marketing approval was given for IV tranexamic acid in cardiac surgery and knee or hip arthroplasty. However, there are shortcomings in the product information that AMH cannot provide

3. Vitamin K/ Pytomenadione [For coagulation]

  • Mechanism of action: Essential co-factor in the synthesis of blood clotting factors II, VII, IX and X and proteins C and S. Reverses effect of Vitamin K antagonists.

Image

  • Clinical Indications: (a) Hemorrhage or threatened hemorrhage due to severe hypoprothrombinemia e.g. from excessive dose of vitamin K antagonist (b) Hypovitaminosis K (c) Prevention and treatment of hemorrhagic disease of the newborn
  • Precautions

1. Fat malabsorption syndromes, Biliary atresia, Pancreatic insufficiency-Impaired oral absorption

2. Elderly

Due to greater response to Vitamin K, dosage should be at the lower end of the recommended range.

3. Pregnancy

-Use if required, does not readily cross the placenta

-May be used from 36 weeks gestation in women taking liver enzyme inducing anti-epileptics (e.g. phenytoin and carbamazepine)

4. Breastfeeding-Safe to use

  • Adverse effects/Side effects

Common

1. Pain

2. Tenderness

3. Erythema (IM injection)

Infrequent

-Allergic reactions including anaphylaxis (especially with rapid IV injection)

Rare

-Hemolytic anemia, Hyperbilirubinemia, Kernicterus (in neonates, especially if preterm)

  • Administration advice

-Give injection orally or by slow IV injection over 30s.

  • Practice Points

-Vitamin K may not be required in all cases of excessive anti-coagulation due to vitamin K antagonists

-Temporarily stopping the drug and re-adjustment of vitamin K antagonists dose may be all that is necessary

-Anti-coagulant of Vitamin K antagonist may be difficult to re-establish for several days to weeks after large doses of Vitamin K. *If intending to restart Vitamin K antagonist, use lowest possible dose of Vitamin K.

-IM administration is the preferred route for prevention of hemorrhagic disease of the newborn because of reliability of administration and level of compliance.

-Oral administration may be as effective as IM administration if there is full compliance with dosage schedule.

  • Extra information

-Sources of Vitamin K: Green leafy vegetables (supplies Vitamin K1-phylloquinone) and bacterial synthesis in the colon (supplies vitamin K2-menaquinone)

-After absorption into the bowel, Vitamin K is oxidized to form an inactive epoxide.

-Most Vitamin K comes from bacterial synthesis by colonic bacteria.

*To be catalytically active, Vitamin K synthesized must be reduced by epoxide reductase in the liver.

  • Vitamin K γ-carboxylates glutamate residues in the Vitamin K-dependent coagulation factors (Factor II/Prothrombin, VII, IX, and X + Protein C and S)
  • Vitamin K-dependent coagulation factors are synthesized in theliver in a non-functional state.
  • *When carboxylated in the liver by Vitamin K, these coagulation factors are able to bind to calcium which is essential to the formation of a fibrin clot.

Prothrombin time (PT)- This is a coagulation test that evaluates all of the vitamin K-dependent factors except factor IX and proteins C and S

Coumarin derivatives act as anti-coagulants by inhibiting the activity of epoxide reductase, hence the vitamin K-dependent coagulation factors are useless (cannot bind to calcium)

Summary of Vitamin K functions:

1. Assist in carboxylating Vit-K dependent coagulation factors which allows them to bind to calcium for the formation of clot.

2. Bone calcification: γ-carboxylatse glutamate residues in osteocalcin.

Vitamin K deficiency: Bleeding diathesis (GIT bleeding, ecchymoses-Subcutaneous purpura), prolonged PTT

  1. Rare but can be caused by use of broad-spectrum antibiotics, which destroys colonic bacterial synthesis of vitamin.
  2. Also caused by therapy with Coumarin (Warfarin) derivatives: Inhibits hepatic epoxide reductase.
  3. Fat malabsorption: Cannot reabsorb fat-soluble vitamins (e.g. Celiac disease)
  4. Newborns: Lack bacterial colonisation of the bowel and must receive an intra-muscular vitamin K injection at birth to prevent hemorrhagic disease

Vitamin K toxicity: Uncommon even due to excessive intake

Drug Class 13: Corticosteroids/Glucocorticoids

13.1: Inhaled corticosteroids (ICS) [For Asthma]

-Beclomethasone, Budesonide, Ciclesonide (Active metabolite-Des-ciclesonide), Fluticasone, Prednisolone (Solo-Active metabolite of Prednisone)

*Most potent and consistently effective class of medications for long-term control of asthma in both adults and children.

  • Mechanism of Action (Corticosteroids)

1. Glucorticoids readily cross cell membranes and bind with high affinity to specific nuclear receptors. Following binding, transcription  and protein synthesis altered.

-May inhibit leukocyte infiltration at the site of inflammation.

-Reduce/Inhibit mediators of inflammation

-Suppression of the humoral immune responses.

2. Regulate gene expression which results in glucocorticoid effects

-Glucocorticoid effects: Gluconeogenesis, proteolysis (breaks down proteins), lipolysis (breaks down fats), Suppression of inflammation and immune responses (useful in asthma)

-Unwanted mineralocorticoid effects:  Hypertension, sodium and water retention, potassium loss

3. Inhibits Phospholipase A2 which prevents downstream production of inflammatory mediators (e.g. Prostaglandins-PGI2, PGE2, PGD2, Thromboxane A2, Leukotrienes such as LTE4, LTC4, LTD4)

-Reduces inflammation which is evident in asthma.

Note: Corticosteroids may have predominantly glucocorticoid effects but tend to have some/minimal mineralocorticoid effects as well (becomes side effects when treating asthma)

For ICS Mechanism of action,

1. Decreased IgE synthesis (triggers mast cell degranulation)

2. Increased number of b-adrenergic receptors on leukocytes

3. Decreased Arachidonic acid metabolism (Decreases PGs and LTE released)

  • Precautions (ICS has a predominant systemic action so these precautions are less crucial)

1. Latent TB– May be reactivated. Consider treatment with isoniazid

2. Peptic ulcer disease-Corticosteroids may increase the risk of peptic ulcers

***3. Diabetes-Corticosteroids worsen diabetes control and may cause hyperglycemia in non-diabetics.

4. Hypertension, Heart failure

-May be worsened due to sodium and water retention side effects (mineralocorticoid effects)

5. Psychiatric disorders-May be exacerbated

6. Glaucoma-Intraocular pressure may be increased

7. Osteoporosis

8. Myasthenia gravis

-Increased muscle weakness may occur during the first few weeks of treatment with corticosteroids, seek specialist advice.

9. Infections (Corticosteroids are immunosuppressive)

-Increase the risk and severity of infection.

*Use with caution if patient has a history of recurrent infections. 

-The decision to start or continue corticosteroids in a patient depends on various factors e.g. type of infection (active or latent), its severity, whether the infection can be treated or controlled and the indication for the drug.

*Seek specialist advice if unsure.

10. Intra-articular injection (Not applicable here-ICS)

Contraindicated in patients with infective arthritis, skin or soft tissue infections near joint (risk of introducing bacteria into joint) or a prosthetic joint.

11. Surgery

-Patients with hypothalamic-pituitary adrenal (HPA) suppression due to corticosteroids or taking replacement doses of corticosteroids for adrenal insufficiency should be given corticosteroids for protection against adrenal crisis during surgery and for 24-48 hours afterwards. 

-Wound healing may be delayed by pharmacological doses of corticosteroids.

12. Children (Effects do not apply to ICS)

-Chronic use of corticosteroids (at pharmacological doses) may retard growth (Effects do not apply to ICS).

-Follow growth and development carefully.

-Catch-up growth may occur after corticosteroid withdrawal

13. Pregnancy

*Use the lowest safest dose for the shortest possible time. Budesonide is the preferred ICS for pregnancy (Most gestational data available)

-No treatment is more serious for fetus and ongoing pregnancy.

-Corticosteroid use in early pregnancy (before 12 weeks) may slightly increase risk of orofacial clefts.

-ICS-(CAT A-AUS)

*Hydrocortisone, prednisone, prednisolone, methylprednisolone are preferred for maternal disorders as placental transfer is limited.

*Betamethasone and dexamethasone are preferred for fetal disorders as placental transfer is greater.

  • Adverse effects/Side effects (ICS related)

-These adverse effects occur when corticosteroids are used at pharmacological doses.

Note: *Inhaled corticosteroids only have systemic actions when given in high doses.

-Short courses of high dose systemic treatment cause fever adverse effects than prolonged courses of lower doses.

Practice points: Reduction of systemic absorption can be achieved by using Metered dose inhaler with a spacer. Then, rinse mouth with water and gargle. Spit out water to reduce oral side effects.

Practice points:  Monitor Dosage and side effects.

(a) Systemic Side effects (Common):

1. Mineralocorticoid effects (Na+ reabsorption and K+ excretion, Increases BP). Sodium and water retention.

-Prednisolone, Prednisone, Methylprednisolone, Hydrocortisone (most significant) and cortisone has mineralocorticoid effects.

2. Adrenal suppression (adrenal cortex does not see the need for adrenal production of corticosteroids)

3. Increased susceptibly to infections, Masking of signs of infection

4. Edema (relatd to mineralocorticoid effects)

5. Hypertension (related to mineralocorticoid effects)

6. Hypokalemia (related to mineralocorticoid effects)

7. Hyperglycemia (Increased gluconeogenesis)

8. Dyslipidemia (Increased lipolysis)

9. Osteoporosis (Inhibition of collagen/cartilage formation), Fractures

10. Increased appetite

11. Delayed wound healing (Immunosuppression), Skin atrophy

12. Bruising

13. Acne

14. Hirsutism

15. Growth retardation in children

16. Myopathy

17. Muscle weakness and wasting

18. Fat redistribution (Cushing’s syndrome-Fat distributes around waist/abdomen area). Classical moon face appearance. Buffalo hump.

19. Weight gain

20. Amneorrhea- absence of a menstrual period in a woman of reproductive age

21. Psychiatric effects-Euphoria, hypomania, depression, disturbances of mood, cognition, sleep and behaviour. Delirium and psychosis are less common.

22. Posterior subcapsular cataracts-Cataracts that affect the back of the lens

*Amenorrhea-Absence of menstruation in women of reproductive age.

(b) Systemic side effects (Infrequent):

-Osteonecrosis (particularly of the femoral and humeral heads, Ocular hypertension, glaucoma

-For intra-articular injection: Refer to AMH 2012.

(c) Systemic side effects (Rare):

-Peptic ulceration, hypersensitivity reactions, tendon rupture (especially of Archilles tendon), Central serous chorioretinopathy

***Specific side effects for ICS: Important for asthma

1. Dysphonia (Hoarseness)

-Caused by deposition of ICS on vocal cords and myopathy of laryngeal muscles (occurs up to 1/3 of those using ICS)-Very common

-Less occurance with breath-activated delivery (BAI)

-Method of inhalation leads to protection of vocal cords by false cords.

2. Oral candidasis (Opportunistic Fungal infection due to Candida Albicans)

-Can be prevented by using spacer device or by gargling after use of the inhaler.

  • Comparative information

-Corticosteroids with minimal mineralocorticoid properties (e.g. Prednisolone and prednisone) or no mineralocorticoid properties (e.g. Beclomethasone, Dexamethasone and triamcinolone) are generally preferred for use as immunosuppressants or anti-inflammatory agents.

Acronym: TBe De But-To be debuted (no mineralocorticoid effects). P and P-Partially (some mineralocorticoid effects)

*Higher levels of fluticasone causes significant reduction in adrenal cortisol production

  • Counselling points

-Take the tablets or oral liquid with food to help reduce stomach upset.

-Tell the doctor immediately if patient has any signs of infection.

-This medication may affect patient’s mood (psychiatric effects). Cause problems with sleeping. Talk to the doctor if patients have any concerns.

*Do not stop taking this medication suddenly unless doctor tells patient otherwise. The doctor may need to be reduce dose gradually when intending to stop treatment (avoid withdrawal symptoms-Fatigue, Weakness, body aches, Joint pain)

-Tell all health professionals (doctors, dentists, surgeons, pharmacists, nurses etc) that the patient is treated with corticosteroids (or have taken them in the past). If patient becomes ill or intending to have surgery, the dose of medicine may need to be increased.

-Consider wearing a Medic Alert (r) Bracelet/ Steroid card detailing treatment (Only required when treated with high doses of corticosteroids)

*Warn patient that medication of ICS is not instantaneous. Time is required (since transcription is altered). Tell patient it will take days to see maximal response. 

  • Practice points

-Measure blood glucose, weight, BP acid and electrolytes at baseline. Then do so each week for the first month of treatment

-Watch for signs/symptoms of infection. Signs of infection may be masked.

-Measure BMD at baseline if likely to require chronic treatment (>3 months) or repeat courses. Evaluate and manage other risk factors for osteoporosis and consider need for drug treatment to prevent bone loss.

-Monitor for cataracts and glaucoma in patients on long term corticosteroids.

-Adrenal suppression (MINIMISE RISK OF ADRENAL SUPPRESSION BY GIVING CORTICOSTEROIDS IN THE MORNING)

-Under periods of stress (e.g. trauma, surgery, infection, blood loss), dose of corticosteroids may need to be increased.

*Refer to AMH 2012 for specific points on Intra-articular injection (used for joints-RA)

  • Types of ICS (In alphabetical order)

1. Beclomethasone

-Synthetic halogenated inhaled glucocorticoid (has Cl)

Beclomethasone structure (Contains Cl halogen so beClomethasone)

  •  Clinical Indications:

(a) Treatment of steroid-dependent asthma (unusually hard to control type of asthma)

(b) For relieving symptoms associated with allergic or non-allergic rhinitis

(c) Preventing recurrent nasal polyps following surgical removal

(d) Prevention of neo-natal respiratory distress syndrome

(e) Intradermal administration of dermatological disease [not relevant for ICS form]

(f) Adjunctive treatment for inflammatory arthritis (e.g. rheumatoid, osteoarthritis, acute gout, tendonitis [not relevant for ICS form]

  • Precautions

-Breast feeding: Safe to use

-Pregnant women: Safe to use (CAT A-AUS)

  • Pharmacokinetics

-Nasal inhalation absorption (minimal absorption systemically)

-Oral inhalation absorption (Drug is absorbed rapidly from lungs and GIT). Some of the oral inhaled dose is absorbed systemically, but usually not sufficient to exert therapeutic effects.

-OAA: typically occurs in a few days but full effects can take as long as 1-4 weeks to be apparent.

Note: Without a spacer, approximately 10-25% of a spacer device, approx 10-25% of the orally inhaled dose will enter the respiratory tract. The rest will be deposited in the mouth or oropharynx and swallowed.

∴ Use a spacer to maximise percentage of medication delivered into lungs.

  • Practice Points

-Can be injected directly into affected soft tissue (e.g. bursitis, myostitis)

-Symptom relief usually occurs 2-4 hours for intra-articular injection, and is maintained for at least 4 weeks.

2. Budesonide (Not found in AMH 2012)

Budesonide structure(Budesonide)

-May be Administered via intranasal inhalation (once a day dosing), oral inhalation or orally for various conditions

-Potent glucorticoid with weak mineralocorticoid activity.

-Less desirable side effect profile when compared to other Intranasal steroids.

-Inhaled budesonide (via oral or nasal) possess high topical anti-inflammatory activity but low systemic activity.

  • Clinical indications: (a) Allergic rhinitis (Intranasal inhalation) (b) Asthma (oral inhalation) (c) Crohn’s disease (orally)
  • Pharmacokinetics: 

1. First pass metabolism after oral absorption (oral inhalation/nebulisers). Inactivated extensively in the liver.

-Very low systemic effects (6% of the dose reaches systemic circulation)

∴ Preferred for children or when high doses of ICS are required.

2. Only 20% of the dose reaches the systemic circulation (nasal inhalation)

3. Ciclesonide (Modern and recent version)———Prodrug

Ciclesonide structure (ciclesonide-Notice the ester group present, it is a pro-drug)

-Non-halogenated glucocorticoid which is beneficial in treating inflammatory conditions such as allergic rhinitis and asthma.

Clinical indications: (a) Asthma (b) Allergic rhinitis

+Drug has a low systemic bioavailability following intranasal or oral inhalational administration which limits systemic side effects such as adrenal suppression.

The active metabolite of ciclesonide, des-ciclesonide is 100-120x more potent than ciclesonide.

  • Pharmacokinetics:

1. Lung/Mucosal Metabolism: Esterases in the nasal and lung mucosa hydrolyse ciclesonide to a biologically active metabolite, des-ciclesonide (100-120x more potent than parent)

2. Hepatic Metabolism (Liver): CYP3A4 and CYP2D6 metabolises des-ciclosonide furthur.

3. Administered by intranasal inhalation or oral inhalation.

4. Oral bioavailability is negligible.

5. OAA: following intranasal administration is 24-48 hours. Desired effects observed after 1-2 weeks in those with seasonal allergic rhinitis and 5 weeks in those with perennial allergic rhinitis. 

4. Dexamethasone (Indications not specific)-Not for asthma or COPD

Dexamethasone structure

-Halogenated corticosteroid

  • Clinical indications: (a) Multiple myeloma (b Lymphoma (c) Some leukemias (Need to research on this) (d) Post-operative or chemotherapy induced nausea and vomitting (d) CROUP (e) Cerebral edema due to malignancy
  • Precautions: 

1. Breastfeeding-Limited data avilable. Consider using alternative corticosteroid (e.g., prednisolone or budesonide)

  • Adverse effects/Side effects

Common

1. Transient itching

2. Burning or tingling in perineal area (after IV bolus)

*Perineal- region of the body and surrounding structures

  • Administration advice

-Give IV injection over 1-3 minutes

  • Practice points

-Can be given by intra-articular or soft tissue injection for local effect.

-Use of adjuvant IV dexamethasone (starting for bacterial meningitis is controversial). Recommended if S.pneumoniae is suspected in adults or H.influenza in children

-When treating penicillin-resistant pneumococcal meningitis, consider reduced CSP penetration of vancomycin due to corticosteroids.

5. Fluticasone (for asthma, COPD treatment and other conditions)

Fluticasone structure

-Contains fluorine (so Fluticasone). Synthetic Steroid with medium potency.

  • Clinical indications:

(a) Relieve inflammatory and puritic manifestations of dermatoses (skin diseases) and psoriasis. [TOPICAL]

(b) Allergic and non-allergic rhinitis [Intranasal inhalation-Fluticasone furoate]

(c) Asthma [Oral Inhalation]

(d) Used clinically for certain patients with COPD.

fluticasone furoate (Intranasal inhalation-Allergic Rhinitis)

  • Pharmacokinetics

-Most of a dose following intranasal adminstration of fluticasone is swallowed with metabolism in the gut and partial absorption with extensive first pass metabolism (CYP3A4)

*First pass metabolism eliminates all/most of the systemic effects. 

-Absorption following topical administration to the skin is usually minimal and depends on such factors as the vehicle and integrity of the epidermis.

-Due to primary absorption from the lungs, the oral inhalation aerosol usually results in systemic bioavailability of about 30%  of the delivered dose.

-Bioavailability of the oral inhalation powder is approx 14%

6.  Hydrocortisone/cortisol —(Indications not specific but can be used for Asthma)

Hydrocortisone.Cortisol structure

  • Clinical Indications: (a) Autoimmune or inflammatory conditions (b) Adrenal insufficiency (Glucocorticoid replacement) (c) Anaphylaxis (as an adjunct to management) (c) Asthma
  • Precautions: Breast feeding (safe to use). Pregnancy-Safe to use (May cause maternal disorders so avoid use over long periods of time) 

7. Methylprednisolone (given as methylprednisolone sodium succinate or methylprednisolone acetate)-For severe asthma and other conditions

Methylprednisolone (Additional methyl group attached at C6)

  • Clinical indications (for MTP sodium succinate): (a) Anaphylaxis (as an adjunct to management) (b) Acute severe asthma (c) Autoimmune or inflammatory disease (d) Acute transplant rejection (e) Acute exacerbation of multiple sclerosis (MS)
  • Clinical indications (for MTP acetate): (a) Autoimmune or anti-inflammatory conditions (Intramuscular) (b) Adjunctive treatment for inflammatory arthritis (e.g. osteoarthritis, rheumatoid) (c) Gout (d) Tendonitis (intra-or peri articular injection)
  • Precautions:

– IV administration of methylprednisolone acetate-CONTRAINDICATED       WHY? Release acetate ions?

-Breastfeeding (safe to use). *Give dose immediately after a feed and wait 4 hours before the next feed.

  • Administration advice

Methylprednisolone sodium succinate

-Rapid IV administration of high doses may cause arrhythmia, cardiovascular collapse or cardiac ARREST.

-Infuse IV doses of >250 mg over at least 30 mins and doses of <250 mg over at least 5 mins.

  • Practice points 

-Improves rate of recovery from exacerbation of MS.

Methylprednisolone acetate can also be given by intradermal injection for local effect.

8. Prednisolone/Prednisone (Can be used for acute asthma and various other conditions)

*Need to know which is the active metabolite and which is the prodrug

Prednisolone vs Prednisone

(Notice that prednisone has the ketone group at C11 whereas prednisolone has an OH/hydroxyl group at C11)

*Prednisone is the prodrug (needs to be reduced to OH in the liver). Prednisolone is the active metabolite (Has the OH group)

Prenisolone (Solo steroid-Active-metabolite).  Prednisone (Still a son, needs to grow up-Prodrug)

-Hepatically activated prodrug.

  • Clinical indications:

(a) Severe, persistant, Acute asthma  (b) Autoimmune and inflammatory diseases (c) Acute transplant rejection (d) Acute gout (e) CROUP (f) Inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe-[OPTHALMIC SOLUTIONS] (g) May be used for multiple myeloma, lymphoma, some leukemias [CHECK TREATMENT PROTOCOL]

Note: Systemic corticosteroids may be added to other long-term maintenance medications in the managment of uncontrolled severe persistent asthma.

  • Precautions:

-Breastfeeding: Safe to use. Take dose immediately after a feed and wait 4 hours before the next feed. Doses up to 80mg have been studied.

  • Practice Points:

-Prednisone is converted to active prednisolone in the liver and vice versa (via CYP3A4 inducer)

Prednisolone (Active metabolite) is used for CROUP when dexamethasone oral liquid is unavailable.

*CROUP-respiratory condition that is usually triggered by an acute viral infection of the upper airway. The infection leads to swelling inside the throat, which interferes with normal breathing and has symptoms of coughstridor, and hoarseness

Note: Systemic corticosteroids may be added to other long-term maintenance medications in the managment of uncontrolled severe persistent asthma.

-When asthma is stabilised, dose should be reduced or eliminated due to the side effects associated with chronic administration.

-Short courses of treatment may be used in moderate to severe exacerbations.

-If long term therapy is required, the lowest possible effective dose should be used.

9. Triamcinolone (can be used for asthma and other conditions)

Triamcinolone structure

-Long acting, synthetic corticosteroid given topically, orally, injection or by inhalation.

  • Clinical indications: 

(a) Autoimmune or Inflammatory diseases (Intramuscular injection) (b) Dermatological disease (Intradermal injection) (c) Adjunctive treatment for inflammatory arthritis (e.g. rheumatoid or osteoarthritis) (d) Acute Gout (e) Tendonitis (intra- or peri-articular injection)

  • Precautions

-Breastfeeding (data is limited). Diffusion into breast milk is low?

  • Adverse effects/Side effects

-Systemic adverse effects may arise from intra-articular and intra-dermal administration.

Common:

Local administration: Intra-articular pain, flare, hyperpigmentation

  • Practice Points

-Use triamcinolone 10mg/ml for intra-articular injection of doses <5 mg and for intradermal injection

-Intravitreal (injection into eye) triamcinolone is used to treat conditions such as diabetic macular edema, indication is not recommended by manufacturer!

Risk of adverse effects such as: Increased intraocular pressure, cataract formation, endophthalmitis and visual disturbances

*Endophthalmitis-is an inflammation of the internal coats of the eye

*Drug Class 12: New CHF Drugs-Tolvaptan, Niseritide, Candoxatril and Omapatrilat

Drug Class 12: New Drugs For Congestive Heart Failure (Nesiritide, Tolvaptan, Candoxatril, Omapatrilat)

ALL THESE DRUGS ARE PREDOMINANTLY FOR SYMPTOMATIC MANAGEMENT (FATIGUE, PULMONARY EDEMA, DYSPNEA, CARDIOMEGALY etc)

12.1 Tolvaptan (ADH/Anti-diuretic hormone antagonist)

Image Tolvaptan structure

Image

-Vasopressin structure (ADH is another name: It prevents diuresis, thus reabsorbs water)

  • Mechanism of action:

*It is an anti-diuretic hormone/ADH antagonist (Promotes water loss without increasing Na+ excretion)

-Fluid overload in heart failure gives rise to hyponatremia (Defined as serum concentration <135 mmol/L)

*Recall the story where the woman drank too much water in a radio contest and died (Hyponatremia <135 mmol/L)

-Hyponatremia Occurs in chronic heart failure and liver cirrhosis as well.

*Promotes aquaresis (excretion of water without electrolyte excretion)——-VERY IMPORTANT!

-When water is lost via aquaresis, concentration of Na+ in serum increases (beneficial to hyponatremic patients)

***Beneficial drug for euvolemic or hypervolemic hyponatremia patients.

12.2 Nesiritide (Recombinant form of BNP)-BNP mimicking molecule

Image (32 amino acids)

BNP is not released by brain, but by cardiac myocytes in the ventricles of the heart in response to excessive stretching!!!

-recombinant form of the 32 amino acid human B-type (Brain) natriuretic peptide

-Structurally identical to BNP

-The release of BNP is modulated by calcium ions.

*Misnomer: BNP is named as such because it was originally identified in extracts of porcine/pigs brain, although in humans it is produced mainly in the cardiac ventricles.

-Note: BNP and ANP have similar functions. They are both released in response to

-Both BNP and NT-proBNP (N-terminal fragment-Biologically active) levels are found to be raised in left ventricular dysfunction.

  • Mechanism of action of Nesiritide:

Image (ANP and BNP physiological actions-Counteracts RAAS system)

1. It binds to natriuretic peptide receptors present in the heart, kidneys, vasculature and other organs. cGMP levels increase.

***2. Natriuretic peptides (both BNP and ANP) binds to guanylyl cyclase coupled membrane receptors. This increases cGMP which is similar to organic nitrates and NO. 

3. Mimicks the functions of ANP (ANP promotes Na+ excretion). Thus, this would lead to promotion of Na+ excretion. Leading to water lost as alongside Na+.

4. Dilation of afferent renal arterioles and constricting of the efferent arterioles occur. Thus, GFR increases and more sodium is lost.

5. Relaxation of vascular smooth muscle. Vasodilation occcurs.

6. Decreased release and actions of aldosterone, Angiotensin II, Endothelin and ADH.

7. Increase diuresis and natriuresis while maintaining renal blood flow.

8. May reduce ventricular remodelling (Animal studies)

-Exert an anti-fibrotic effect on cardiac fibroblasts

-Reduce deposition of collagen and fibronectin in extracellular matrix (Reduce Angiotensin II production which has a profound effect on cardiac remodelling)

-Reduction production of inflammatory mediators.

Overall Benefits: Improves dyspnea (shortness of breathness-exertional) and rapidly reduces pulmonary pressure in patients with decompensated HF. 

  • Nesiritide vs Dobutamine (B1 selective inotropic agent for CHF)

Both Improves symptoms in patients with acutely decompensated HF (symptomatic control) [Symptomatic control]

-Appears to be safer than dobutamine

-Nesiritide may increase mortality (increased risk of death) compared to common, conventional, non-inotropic drugs (e.g. ACE-inhibitors, Organic nitrates, Calcium channel blockers)

12.3 Candoxatril-Orally active Prodrug (Treats CHF in men-‘Sexist drug’)

Candoxatril (‘Can do sex trail’)

Image (Candoxatril structure)

Orally active prodrug of candoxatril

Image (Notice that the two rings at the side is cleaved off to form COOH)

Candoxatrilat: A Metabolite which is a potent neutral endopeptidase (NEP) inhibitor

What is neutral endopeptidase (NEP or Neprilysin)?

Background information: Neutral endopeptidase (NEP) (a.k.a Neprilysin) degrades vasoactive peptides, including the natriuretic peptides, angiotensin II, and endothelin-1

-particularly highly expressed in kidney and lung tissues

  •  Mechanism of action (Candoxatril): Neutral endopeptidase (NEP) inhibitor.

-Inhibits neprilysin/NEP’s activity against signalling peptides (e.g. Atrial natriuretic factor, Substance P, endothelin and enkephalins)

-Potentiates ANP activity in the heart, endothelin activity in blood vessels (constricts Blood pressure and increases blood pressure) and substance P activity in the brain (Neuromodulator)

-So this inhibition may have a beneficial effect against cardiac impairment.

*Chronic administration of NEP inhibitors reduces both cardiac mass and amount of fibrotic tissues in the left ventricle in spontaneously hypertensive rats 

–>Indicates that NEP inhibitors may regulate cardiac fibroblasts’ synthesis of collagen.

***Treats CHF IN MEN (not women)!!!

12.4 Omapatrilat (NEP inhibitor and ACE-inhibitor combined)

-New anti-hypertensive agent which combines ACE-inhibitor and NEP inhibitor

Image (Notice the Thiazepine ring and carboxylic acid portion-Belongs to ACE-inhibitors)

  • Mechanism of action:

-Combination of ACE-inhibitor effects (Inhibits production of Angiotensin II-Effects inhibited)

-Combination of NEP-inhibitor (Inhibits activity of NEP against signalling molecules)

*Dramatic effect on Blood pressure and improves HF symptoms. Possible pharmacogenetic issues.

  • Side effects/Adverse effects

1. Angioedema

-Pharmacogenetic issues

-Some races may experience more angioedema (especially African-American races)

-Smokers also more susceptible to angioedema

Drug Class 11 (includes 5 groups): Anti-platelet drugs

Class 11 (Group 1,2,3,4,5) Anti-platelet drugs

Image

General Mechanism of action: Blocks/Inhibits protein aggregation by blocking various mediators (e.g. glycoprotein IIb/IIIa, ADP etc) which activates platelets or inhibiting enzymes such as COX-enzymes.

Image

Classes of anti-platelets:

1. Glycoprotein IIb/IIIa inhibitors

2. Thienopyridines (ADP inhibitors)

3. Aspirin/NSAIDs

***Class 11 Group 1——————————11.1 Glycoprotein IIb/IIIa inhibitors———————————————————————————————–

11.1.1 Mechanism of action:

-Prevents binding of fibrinogen to platelet by occupying and blocking glycoprotein IIb/IIIa receptor. Thus, platelet aggregation is inhibited.

-3 Drugs in this class. Abciximab (chimeric monoclonal antibody). Tirofiban (Non-peptide antagonist). Eptifibatide (cyclic heptapeptide)

Image Eptifibatide (cyclic heptapeptide)

11.1.2 Clinical Indications: (a) Unstable Angina (b) non-STEMI (non-ST elevating myocardial infarction) in high-risk patients (c) PCI (percutaneous coronary intervention)

-Non-STEMI (does not cause an elevation in ST segment of an ECG.

-STEMI is when there is a transmural infarction of the myocardium – which just means that the entire thickness of the myocardium has undergone necrosis – resulting in ST elevation. Usually due to a complete block of a coronary artery (occlusive thrombus). This requires the use of thrombolytics like Streptokinase to lyse the thrombus. Evidence has proven that it is very effective and not as risky (Benefits > Risk)

UA or NSTEMI is when there is a partial dynamic block to coronary arteries (non-occlusive thrombus). There will be no ST elevation or Q waves on ECG, as transmural infarction is not seen. The main difference between NSTEMI and unstable angina is that in NSTEMI the severity of ischemia is sufficient to cause cardiac enzyme elevation.
-PCI-non-surgical procedure used to treat the stenotic (narrowed) coronary arteries of the heart found in coronary heart disease

11.1.3 Precautions

1. Contraindicated in those with a history of intra-cranial disease (neoplasm, arteriovenous malformation, aneurysm)

2. Contraindicated in people with acute pericarditis, history of vasculitis, aortic dissection

3. Contraindicated in people with severe active bleeding, or disease states with an increased risk of severe bleeding (e.g. severe uncontrolled hypertension, severe thrombocytopenia, bleeding disorders, history of stroke-Within a month for tirofiban and eptifibatide, within two years for abciximab) or any history of hemorrhagic stroke.

-Other drugs that may affect the clotting process e.g. Heparin and low dose aspirin is should be avoided. 

4. Spinal injection or puncture. Seek specialist advice before considering intra-thecal puncture or epidural analgesia or anestheisa or lumbar puncture. Increased risk of epidural hematoma, may lead to paralysis.

5. Surgery. Stop treatment immediately if emergency CABG (coronary artery bypass graft) is required.

6. Pregnancy. LImited data available.

-Abciximab, eptifibatide (Both CAT C-AUS). Tirofiban (CAT B1-AUS)

7. Breastfeeding. Avoid since limited data available.

11.1.4 Side Effects/Adverse effects

1. Bleeding, thrombocytopenia (common)

2. Allergic reactions, thrombocytopenic purpura (rare)

***11.1.5 Practice points

-Glycoprotein IIb/IIIa inhibitors are used with herapin (part of the coagulation pathway), LMWHs (Low molecular weight heparin-anticoagulant class) or bivalirudin (reversible inhibitor of thrombin) and low dose-aspirin.

-Stop heparin, aspirin and glycoprotein IIb/IIIa inhibitor if platelet count drops below 100×10^9/L or drops below 25% of baseline platelet count.

11.1.6 Types of Glycoprotein IIb/IIIa inhibitors

1. Abciximab (Chimeric Monoclonal Antibody-MAB)-Platelets recover in 2 days (Affects dosing frequency?)

  • Clinical Indications: (a) Percutaneous transluminal coronary angioplasty (PTCA) and intracoronary stenting (b) Unstable angina refractory to conventional treatment where PCI is planned
  • Precautions

1. Use of IV dextran (iron deficiency treatment) before or during PTCA-contraindicated

2. Abciximab infusion within 30 days-Increases risk and severity of thrombocytopenia

3. Thrombocytopenia from previous dose of abciximab-Increases risk of recurrence.

  • Pharmacokinetics

1. Biphasic. Initial phase t1/2 of less than 10 mins and a second phase half life of about 30 mins (due to rapid binding to platelet IIb/IIIa receptors)

2. DOA-short around 2 days (platelets recover in about 2 days)

  • Side Effects/Adverse effects

1. Bleeding, thrombocytopenia (common)

2. Allergic reactions, thrombocytopenic purpura (rare)

2. Eptifibatide (Cyclic heptapeptide)

Eptifibatide structure

  • Mechanism of action: Eptifibatide is a reversible inhibitor of platelet aggregation. It works by inhibiting adhesion of several substances
    (including von Willebrand factor and fibrinogen) to the glycoprotein IIb/IIIa receptor on platelets
  • Clinical indications: (a) Unstable angina and non-STEMI in high-risk patients. (b) Elective PCI with stenting
  • Precautions (Take extra precaution in renal and hepatic dysfunction):

1. Hepatic impaired patients. Avoid use in patients with clinically significant hepatic disease (increased risk of bleeding)

2. Renal impaired patients. Reduce dose in renal impairment. Contraindicated in dialysis patients. Why?

  • Practice points:

-Give low dose aspirin and heparin infusion with eptifibatide

-Monitor PT (Prothrombin time/INR, APTT, Creatinine Clearance, Platelet count, hemoglobin and hematocrit (packed cell volume or erythrocyte volume fraction) before treatment. Monitor hemoglobin, hematocrit and platelet count within 6 hours after the start of treatment and at least once daily thereafter.

  • Pharmacokinetics

1. Low protein binding. Protein binding around 25%

2. Metabolism. No major metabolites detected in blood, but deamination takes place in urine.

3. For patients with coronary artery disease, the mean clearance of eptifibatide is around 55-80 ml/kg/hour

4. Half life of approx 2.5 hours

  • Side Effects/Adverse effects

1. Bleeding, thrombocytopenia (common)

2. Allergic reactions, thrombocytopenic purpura (rare)

3. Tirofiban (Non-peptide, synthetic drug)

Image

  • Mechanism of action: Binds/Blocks glycoprotein IIb/IIIa receptor and so prevents fibrinogen binding to platelet. Thus, there is decreased platelet aggregation.
  • Clinical Indications: (a) Unstable angina and non-STEMI in high risk patients
  • Precautions:

*Renal impaired. Reduce dose if Creatinine Clearance is <30ml/min. (Drug is Urinary and bile excreted)

  • Pharmacokinetics:

1. Excretion. Urinary and bile excreted

2. Half life-1.5 hours

  • Adverse effects/Side effects

1. Bleeding, thrombocytopenia (common)

2. Allergic reactions, thrombocytopenic purpura (rare)

  • Practice points:

-Give low-dose aspirin and heparin infusion with tirofiban

-Monitor PT, APTT, Creatinine Clearance, platelet count, hemoglobin and hematocrit before treatment. Monitor all these within 6 hours upon commencement of treatment and at least once a day thereafter.

*APTT-Activated partial thromboplastin time (Part of the blood clotting pathway)

*Comparative information between the 3 agents

-Abciximab has a longer duration of action than tirofiban and eptifibatide and is less suitable for patients who need CABGs.

***Group 2: 12.1 Thienopyridines (class 2 P2Y12/ADP receptor blockers) + Ticagrelor——————————————————————

Thienopyridine

Note: All these drugs have a thiophene ring attached to a pyridine ring. Hence the name thienopyridines. [Clopidogrel, Ticlopidine, Prasugrel]

The only drug that does not have this thienopyridine ring is ticagrelor. However, the mechanism of action is the same (inhibits ADP receptors of subtype P2Y12). It binds to an allosteric site which is different from ADP making it an allosteric antagonist, thus the inhibition is reversible.  NOTE: THE MECHANISM OF ACTION, etc is not for Ticagrelor.

12.1.1 General Mechanism of action:

-The active metabolite irreversibly binds to the platelet ADP (P2Y12 subtype) receptor. Since ADP is an activating factor for platelet aggregation, the inhibition of the receptor prevents this process.

12.1.2 General Precautions

1. Hypersensitivity to thienopyridine (due to sulphur group present in thiophene ring)-CONTRAINDICATED!

2. Risk of bleeding-Contraindicated in severe active bleeding or disease states with an increased risk of severe bleeding (e.g. bleeding disorders, severe hepatic disease)

3. Other drugs that may affect clotting process may increase the risk of bleeding. Avoid combinations or monitor closely. Low dose aspirin may be used where indicated with clopidogrel and prasugrel.

4. Spinal injection or puncture

-Seek specialist advice before considering intrathecal or epidural injection (analegesia or anesthesia). Use in patients with Lumbar puncture also requires specialist advice.

5. Surgery

May be necessary to reduce the anti-platelet effect before surgery (e.g. CABG, dental surgery). ***Stop clopidogrel at least 6 days before, stop prasugrel at least 8 days before and stop ticlopidine at lesat 10-14 days before planned surgery.

6. Pregnancy-CAT B1-AUS

7. Breastfeeding-Use of clopidogrel is acceptable. Avoid breastfeeding with clopidogrel or ticlopidine. 

12.1.3 General Adverse effects/Side effects

Common

1. Bleeding (may be severe and may cause anemia)

2. Hypersensitivity.

-Skin reactions (e.g. rash, urticaria/hives) are common with clopidogrel and ticlopidine. Infrequent with prasugrel.

-Reports of Stevens-Johnson-Syndrome (SJS) and exfoliative dermatitis (clopidogrel, ticlopidine). Cross-reactivity can occur.

*Comparative information for the 3 agents above (clopidogrel, ticlopidine, prasugrel)

-Rsk of neutropenia (lack of neutrophils) is greatest with ticlopidine. Should be used if other anti-platelet agents are unsuitable.

-When comparing prasugrel with clopidogrel in ACS (acute coronary syndrome) after PCI (percutaneous Coronary intervention), prasugrel was superior in primary outcomes (e.g. death, stroke or MI) and in secondary outcomes (e.g. stent thrombosis).

-However there is an increased risk of major bleeding and fatal bleeding risk associated with prasugrel. Overall mortality is similar.

4. Clopidogrel-Prodrug (usually in combination with aspirin) [Brand name: Plavix–Very commonly used]

ClopidogrelContains Cl so Clopidogrel. Note the thienopyridine ring and the ester bond (PRODRUG)

  • Mechanism of action:

-Blocks ADP binding to platelet ADP subtype P2Y12 receptor. Reduces ADP mediated activation of GIIb/IIIa complex, thus inhibits activation of platelets, thus reducing platelet aggregation.

  • Clinical indications:

(a) Prevention of vascular ischemic events in patients with symptomatic atherosclerosis (recent ischemic stroke, recent MI or peripheral arterial disease with intermittent claudication)

(b) Non-ST segment elevation acute coronary syndrome (with aspirin)

(c) Adjuvant to reperfusion for STEMI (with aspirin) unless acute CABG is likely

(d) Acute coronary syndrome (ACS) in those already taking clopidogrel and aspirin

(e) Prevention of thromboembolism after placement of intracoronary stent (with aspirin)

-Adjuvant: Pharmacological agent used in conjunction to boost/modify the effects of the other drug.

  • Precautions

1. Administration with CYP2C19 inhibitors, inducers or substrates. CYP2C19 metabolises clopidogrel (prodrug) to its active metabolite.

*Combining clopidogrel with inhibitors of CYP2C19 or genetic lack of CYP2C19 activity may decrease clopidogrel’s effectiveness in reducing the risk of cardiovascular events.

2. Surgery

-For patients with coronary stents, assess bleeding risk if clopidorel continued versus risk of stent thrombosis if it is stopped prematurely.

-Consider delaying elective surgery until dual anti-platelet treatment (aspirin and clopidogrel) is no longer required.

  • Adverse/Side effects

1. Diarrhea (Common)

2. Bleeding (Common)

2. Gastrointestinal ulcer (Infrequent)

3. Thrombotic thrombocytopenia purpura, aplastic anemia, thrombocytopenia, neutropenia, Intracranial hemorrhage (rare)

  • Pharmacokinetics

1. Half life-8 hours

2. Extensive protein binding (~96%)

3. Hepatic metabolism. Prodrug-Has to be converted to active metabolite via CYP2C19 enzyme in the liver.

  • Practice points

*Optimal duration of treatment in ACS and after placement of coronary stent is debated. Longer treatment is recommended with a drug-eluting stent than with a bare-metal stent.

  • Drug Interactions (Clopidogrel)

CYP2C19 metabolises clopidogrel to active metabolite. Thus, CYP2C19 inhibitors or substrates can affect efficacy.

1. Proton pump inhibitors/PPIs

-PPIs (including omeprazole and esomeprazole) may decrease clopidogrel’s antiplatelet activity by reducing formation of its active metabolite (R-130964)

-Low concentrations of active metabolite, through either genetic lack of CYP2C19 activity or by inhibition of CYP2C19 enzyme may decrease clopidogrel’s effectiveness in reducing risk of cardiovascular events.

*Avoid combination

5. Prasugrel (Thienopyridine ring present)-Also an inactive PRODRUG 

Prasugrel (Notice the ester group present-Inactive prodrug)

Note: ***Needs to be hydrolysed by intestinal carboxylesterases and hepatic conversion to produce active metabolite.

-Mainly by CYP3A4 and CYP2B6. Lesser extent CYP2C9 and CYP2C19.

  • Mechanism of action:

-Active metabolite irreversibly binds and antagonises platelet P2Y12 receptor for the life of the platelet.

Prevents ADP binding and activation of glycoprotein IIb/IIIa (GIIb/IIIa complex)

  • Clinical Indications: (a) Prevention of atherothrombotic events (with aspirin) in Acute coronary Syndrome (including both STEMI and NSTEMI) to be managed with PCI.
  • Precautions

1. History of stroke or TIA (transient ischemic attack)-Contraindicated due to an increased risk of bleeding and stroke in trials

***2. Asian ethnicity-May be at increased risk of bleeding

3. People less than 60 kg

-Due to a higher concentration of prasugrel’s active metabolite and increased risk of bleeding, lower maintenance dose has been recommended. Use cautiously.

4. Elderly

-Generally not recommended for those >75 years old.

-May be used with caution in those at lower risk of bleeding.

-Due to a higher concentration of prasugrel’s active metabolite and increased risk of bleeding, a lower maintenance dose has been recommended. Use cautiously.

  • Pharmacokinetics

1. Prodrug. Thus, needs to be hydrolysed by intestinal carboxylesterases and hepatic conversion to produce active metabolite.

-Mainly by CYP3A4 and CYP2B6. Lesser extent CYP2C9 and CYP2C19.

2. Highly protein bound. 98% bound

3. Metabolite is an Irreversible inhibitor of ADP.

4. Half life ~7 hours (for active metabolite)

6. Ticlopidine (Thienopyridine class which inhibits P2Y12 ADP receptor)-Prodrug 

Ticlopidine

*Active metabolite is 10x more potent than parent drug.

  • Mechanism of action: Both ticlopidine and active metabolite (10x more potent) Blocks ADP binding to P2Y12 receptor. Thus, prevents platelet-fibrinogen binding.
  • Clinical Indications: (a) Secondary prevention of ischemic stroke and TIA in patients intolerant of or unresponsive to other anti-platelet drugs.
  • Precautions

*Hepatic-Contraindicated in severe impairment or cholestatic jaundice. Use cautiously in mild-to moderate impairment. Stop treatment if hepatitis or jaundice occurs.

  • Adverse/Side effects

Common

1. Diarrhea, Nausea, Anorexia, Vomitting, Upper abdominal pain (tolerance may develop), mild to severe neutropenia

Infrequent

2. Hepatitis, mild increases in ALP, total cholesterol and triglycerides

*ALP-Alkaline phosphatase (found in many tissues e.g. liver, bile ducts and blood)

Rare

-Thrombocytopenia, aplastic anemia, thrombotic thrombocytopenic purpura, eosinophilia, Diarrhea with severe colitis

  • Pharmacokinetics

-Needs to be metabolised to active metabolite (10x potency)

-98% plasma protein bound.

  • Counselling Points

*Take with food to reduce stomach upset

*Tell the doctor if patient develops fevers, chills, sore throat,  mouth ulcers, bleeding or bruising

  • Practice points

-Risk of neutropenia is greatest in the first 12 weeks of treatment. ***Obtain full blood count at baseline, then every 2 weeks for 4 months then as indicated.

Stop ticlopidine if neutrophil count is below 1.2X10^9/L or platelet count is <80X10^9/L. Neutropenia is usually reversible on stopping ticlopidine.

  • Drug Interactions

1. Phenytoin

-Ticlopidine increases phenytoin concentration and risk of toxicity.

*Monitor phenytoin concentration and for adverse effects.  Decrease dose of phenytoin as required.

7. Ticagrelor (Non-Thienopyridine)

Ticagrelor-Notice that the thiophene ring and the pyridine ring is gone. *NOT A PRODRUG

  • Mechanism of action: Similar to the others but binds reversibly due to the lack of thienopyridine ring. Reversibly Binds to P2Y12 receptor, inhibits platelet aggregation. Antagonises ADP and prevents platelet activation.
  • Clinical Indications: Acute coronary syndrome (with aspirin)
  • Precautions:

1. Patients at risk of bradycardia (e.g. sick sinus syndrome without pacemaker, 2nd or 3rd degree atrioventricular block)

-Use with caution as such patients were excluded from trials. May cause asymptomatic ventricular pauses.

2. Asthma, COPD

-Ticagrelor may cause dyspnea (shortness of breath)

3. Weight <60kg. Increases risk of bleeding.

4. Hyperuricemia-Ticagrelor may increase uric acid concentration.

5. Treatment with strong inhibitors of CYP3A4 is contraindicated. Increases risk of bleeding as ticagrelor concentration.

6. Risk of bleeding-CONTRAINDICATED in severe active bleeding or disease states with an increased risk of severe bleeding (e.g. bleeding disorders, severe hepatic disease)

7. Other drugs that can affect the clotting process may also increase the risk of bleeding. *Avoid combinations and monitor closely. Low dose aspirin should be used with ticagrelor.

8. Spinal injection or puncture. Seek specialist advice before considering intra-thecal puncture or epidural analgesia or anestheisa or lumbar puncture. Increased risk of epidural hematoma, may lead to paralysis.

9. Hepatic impaired

-Contraindicated in moderate to severe impairment (Ticagrelor is mostly eliminated via liver-CYP3A4)

10. Surgery

-Stop ticagrelor 5 days before procedure if anti-platelet effect is not wanted.

11. Pregnancy (CAT B1-AUS) and AVOID breastfeeding.

  • Side effects/Adverse effects

Common:

1. Bleeding (Common)-May  be severe and cause anemia. Example include nose bleed

2. GI hemorrhage

3. Dyspnea (rarely severe)

4. Nausea

5. Diarrhea

6. Non-cardiac chest pain

7. Raised uric acid concentration

8. Raised creatinine concentration (reduced renal clearance)

Infrequent:

Rash, Itch (due to Sulphur groups present)

Rare:

Hyperuricemia

  • Pharmacokinetics

1. Highly Plasma bound. Ticagrelor and active are 99% plasma bound

2. Hepatic metabolism. Ticagrelor is a substrate and inhibitor of CYP3A4.

  • Practice points

-Ticagrelor with aspirin is more effective than clopidogrel with aspirin in preventing cardiovascular events in patients with ACS.

-Significant reduction in MI (ticagrelor + aspirin combination) but non-significant increase in stroke.

-Incidence of total major bleeding was similar. The rate of major intracranial hemorrhage was higher with ticagrelor

-The risk benefit of ticagrelor was less favourable when used with aspirin doses.

***Group 3– 13.1: Aspirin (In low doses-For anti-platelet effects)—————————————————————–

Aspirin (prodrug)/Acetylsalicylic acid

Very important: Only low doses of aspirin required to inhibit thromboxane A2 in platelets (150mg).

Why? Platelets are exposed to aspirin in the portal blood (after absorption via small intestine and before reaching liver) so they are already inactivated. After passing through the liver, it is converted into salicylate. Thus, the systemic endothelium/vessels is protected (PGI2 synthesis reduced but still occurs) 🙂

∴ Low Dose Aspirin (150mg) required for the anti-platelet effect. 

aspirin(Prodrug-Converted to salicylic acid in the liver. Avoid exposure to moisture/air)

  • Mechanism of action: 

*Note: Aspirin (prodrug) is the one with the anti-platelet effects not salicylate (metabolite)

1. Inhibits platelet aggregation by irreversibly inhibiting cyclo-oxygenase.

2. Thus, reducing the synthesis of Thromboxane A2/TXA2 (an inducer of platelet aggregation) for the entire lifetime of the platelet (irreversibly binds)

***Aspirin is unique among NSAIDs because it irreversibly inhibits COX by acylating the active site (a serine residue) of the enzyme.

-By inhibiting COX-1, it prevents the formation of products including thromboxane, prostacyclin and other prostaglandins (for the entire lifetime of platelet)

-Reduces TXA2 production in platelets and PGI2 in endothelium (platelets do not have prostacyclin synthesase/PGI2 synthase to make PGI2)

Note: Inhibition of PGI2 (normally inhibits platelet aggregation) is not intended. Thus, we use low doses of aspirin (Higher doses will inhibit PGI2 production in endothelium-Undesirable effect)

  • Clinical Indications

1. Acute Myocardial Infarction (including combination with pravastatin)

2. Unstable Angina (including combination with pravastatin)

3. Primary prevention of stroke and acute MI in patients with risk factors

4. Secondary prevention of stroke and Transient ischemic attack (including combination with dipyridamole)

5. Secondary prevention in ischemic heart disease (angina, MI, after CABG and PCI)

6. Prevention of thromboembolism in non-rheumatic AF in low risk patients

7. Relief of pain, inflammation and fever

*Can be combined with clopidogrel- 8. For acute coronary syndrome (ACS). For those already taking aspirin and clopidogrel.

In summary:

It is used primarily to decrease the risk of arterial thrombosis in patients who had suffered myocardial infarction or severe artherosclerosis.

It is also used in  post-coronary artery bypass, angioplasty or stenting (life time use) and in patients with a tendency to suffer thrombotic stroke.

  • Precautions

1. Allergy to aspirin or NSAIDs-Contraindicated                         Why are people allergic to NSAIDs?

2. Aspirin-sensitive asthma-Contraindicated

*Aspirin sensitive asthma/Samter’s triad-Samter’s triad is a medical condition consisting of asthma, aspirin and NSAID sensitivity, and nasal/ethmoidal polyposis. It usually begins in young adulthood (twenties and thirties are the most common onset times) and may not include any other allergies.

3. Increased risk of bleeding

Contraindicated in severe active bleeding or disease states with increased risk (e.g. bleeding disorders, erosive gastritis, peptic ulcer disease, severe hepatic disease)

4. Other drugs that can affect the clotting process

*Avoid combinations or monitor closely. Other anti-platelet or anti-coagulant drugs may be used with low-dose aspirin (up to 150mg daily) where indicated.

5. Spinal Injection or puncture

-Seek specialist advice before considering intrathecal or epidural injection (analegesia or anesthesia). Use in patients with Lumbar puncture also requires specialist advice.

6. Renal impaired

*USE WITH CAUTION in severe impairment because of reduced excretion (Aspirin is excreted via renal route)

-Leads to accumulation of aspirin in the body and thus increased risk of bleeding. Further deteriorates renal function (Inhibits Prostaglandin production, compensatory dilation of afferent or efferent arterioles)

People with kidney diseasehyperuricemia, or gout should not take aspirin because it inhibits the kidneys’ ability to excrete uric acid, and thus may exacerbate these conditions.

7. Surgery

-Weight risk of cardiovascular events versus bleeding risk. Aspirin may be stopped 7 days before surgery to decrease risk of bleeding. However, its withdrawal may increase risk of cardiac events. 

Dental procedures: Safe to continue aspirin

CABG (coronary artery bypass graft): Low dose aspirin may be beneficial if taken before procedure.

-Patients with coronary stents: Aspirin should not be stopped in peri-operative period. 

8. Pregnancy

-Low dose aspirin (up to 150mg daily) is considered to be safe.

*Avoid higher doses in the last trimester due to risk of premature closure of the fetal ductus arteriosus

-Leads to delay of labour and birth. Increased bleeding time in newborn. (Higher doses of aspirin in last trimester-CAT C)

Ductus_Arteriosus image

9.  Breastfeeding-Low dose aspirin (up to 150mg daily) is considered safe. Avoid using higher doses.

***10. Children below 12 years old

-Contraindicated due to increased risk of Reye’s syndrome (especially with influenza infection)

  • Pharmacokinetics

1. Protein bound. Highly protein bound (95%)

2. Metabolism.

-Metabolism of salicylate normally follows first-order kinetics. However, after very large doses, the metabolic pathways become saturated (zero-order kinetics)

Note: After administration of large doses, enzyme is saturated, thus small dose increments thus increases aspirin levels.

3. Excreted (Renal)

-Excreted predominantly by kidneys (Hence, take extra precaution in kidney/renal impaired)

4. Plasma elimination and therapeutic half life

-Plasma elimination half life is 30 mins

-Therapeutic half life is 7 days! (Long duration of action)-New platelets have to be synthesised. Affected platelets take 7-10 days to be removed from circulation and for new platelets to replace them.

  • Counselling points

-Take tablets or capsules from packaging just before use. Aspirin can be hydrolysed rapidly if not protected by packaging.

-Mix dispersible tablets in half a glass of water immediately before use.

  • Practice Points

-No evidence that enteric coated products decrease risk of GI bleeding

-In patients with a history of aspirin-induced ulcer bleeding, clopidogrel causes more recurrent ulcer bleeding than aspirin combined with a PPI (proton pump inhibitor)

  • Aspirin resistance

-Aspirin cannot prevent all thrombotic events.

-There is no consensus on the definition or treatment of aspirin resistance.

-Poor compliance is common (up to 40%). Aspirin resistance is rare when compliance occurs.

  • Adverse effects/Side effects

-Local effects

1. Gastrointestinal effect (Focal erosive gastritis-gastric mucosal erosion caused by damage to mucosal defenses).

-Bleedings also occur which is worsened by anti-platelet effects.

-Systemic effects

2. Salicylism (Aspirin poisoning) can occur due to repeated ingestion of large doses. This syndrome consists of tinnitus, vertigo, decreased hearing and sometimes nausea and vomitting.

3. Skin rashes

4. Worsening of asthma in aspirin-sensitive individuals (inhibition of vasodilating prostaglandins)

5. Reye’s Syndrome

-Aspirin is contraindicated in children below 12 years of age.

-Brain (severe encephalitis occurs) and liver (fatty liver) affected.

-Usually occurs after a viral infection (Influenza) and has a mortality of 20% to 40%.

6. Altered Acid-Base and Electrolyte balance

-Lead to compensated respiratory alkalosis, uncompensated respiratory acidosis and metabolic acidosis (aspirin dessociates in blood to release H+)

*Definitions:

Metabolic acidosis: occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body

Respiratory alkalosis:  increased respiration (hyperventilation) elevates the blood pH

Compensation: Drop in Bicarbonate ion concentration due to the need to neutralise excess H+

  • Drug interactions

-Analgesic doses of aspirin can decrease blood glucose concentrations. This occurs even at low doses (anti-platelet effect) which can be a concern. Why?

1. *Potentially hazardous increase in effect of warfarinAspirin displaces it from plasma proteins and partly because of its anti-platelet effect.

2. Aspirin on its own reduces urate secretion. It interferes with uricosuric agents such as probenacid.

-Should not be used in gout.

3. Valproate (Anti-convulsant for epilepsy)-Only at high doses of aspirin!

-Aspirin increases valproate concentration. Increases the therapeutic and adverse effects. Combination also increases effects on blood coagulation and platelet function.

-Avoid large doses of aspirin or monitor clinical effects. Adjust valproate dose as required.

***Low dose aspirin does not interact. 

4. NSAIDs with aspirin

5. Corticosteroids

-Corticosteroids may decrease salicylate concentration when high-dose aspirin is used (e.g. kawasaki’s disease). Monitor salicylate concentration and clinical effect.

-Increase aspirin dose if necessary. Be particularly careful to reduce aspirin dose when withdrawing corticosteroids.

6. Anagrelide-May increase risk of bleeding. Seek specalist advice.

7. Acetazolamide (Anti-convulsant for seizures)

-Increased risk of acetazolamide toxicity (e.g. metabolic acidosis, if high dose aspirin is used, development of toxicity may be slow)

-If possible avoid this combination, use paracetamol or an alternative NSAID instead.

*Low dose aspirin is safe to use. Thus, we can use it in this case (Low dose aspirin for anti-platelet effects)

***Group 4: Dipyridamole (PDE 5 inhibitor)——————————————————————————————————————————————————————

Dipyridamole (Phosphodiesterase-5-inhibitor)

Dipyridamole (Two pyrimidine rings attached with two piperidine rings)

  • Mechanism of action

-Phosphodiesterase 5 inhibitor. Increases cAMP levels (since phoshodiesterase’s function is to convert cAMP back to AMP)

-Dipyridamole inhibits PDE-5 and increases cAMP levels which induces platelet inhibition.

-Increased cAMP levels will activate protein kinase A and thus decrease levels of calcium in the cytosol. Inhibits release of granules and thus activation of platelets.

  • Clinical Indications

1. Prevention of thromboembolism in patients with prosthetic heart valves (with warfarin)

2. Secondary prevention of ischemic stroke and Transient ischemic attacks (TIA) [In combination with aspirin]

3. Cardiac stress testing (IV)

*Mainly for prevention. *Similar to aspirin indications but NOT FOR UNSTABLE ANGINA. Roughly as effective as aspirin but with less bleeding problems.

  • Precautions

1. Aortic stenosis (Dipyridamole-induced vasodilation may increase pressure gradient across aortic valve and worsen organ perfusion)

2. Unstable angina, recent MI-*Use with caution. Vasodilation may induce myocardial ischemia.

Why?

-Collateral vessels are not dilated. Vasodilation occurs in other non-ischemic areas. Thus, blood flow directed towards normal areas. Blood flow in ischemic area is reduced (Worsen myocardial ischemia)

3. Treatment with other drugs that can affect clotting process

-May increase risk of bleeding, monitor closely.

4. Spinal injection or puncture. Seek specialist advice before considering intra-thecal puncture or epidural analgesia or anestheisa or lumbar puncture. Increased risk of epidural hematoma, may lead to paralysis.

 

5. IV use

-Contraindicated in: Acute MI, unstable angina, severe aortic stenosis, pulmonary embolus or infarction

Contraindicated in: Uncontrolled arrhythmias (with symptoms of hemodynamic compromise)

-Contraindicated in: Uncontrolled heart failure

-Contraindicated in : Acute myocarditis, pericarditis or active endocarditis

-Contraindicated in: Acute aortic dissection

-Contraindicated in: Systolic BP <90 mmHg. Recent Unexplained fainting or Transient ischemic attack.

-Contraindicated in: Oral dipyridamole treatment

6. Pregnancy

-CAT B1 OR C (combination with aspirin)-AUS

7. Breastfeeding

-Limited data available.

  • Adverse effects/Side effects

Common:

1. Headche (VERY COMMON SIDE EFFECT)

2. Diarrhea

3. Nausea

4. Vomitting

5. Hot flushes

6. Hypotension

7. Tachycardia (Due to worsening of blood perfusion to ischemic areas)

Infrequent:

1. Rash, urticaria (hives)

Rare:

Dyspnea (shortness of breath), Bronchospasm (with IV administration)

  • Administration advice

-Dilute before IV administration. Use antecubital vein to minimise irritation

  • Counselling

-This medicine is best absorbed (p.o) on an empty stomach 1 hour before or 2 hours after food. If it upsets patient’s stomach, it can be taken with food or milk to minimise upset of stomach.

-Severe Headache. Severe headache can occur when taking this medication especially at the start of treatment. Tell the doctor if this occurs to patient.

  • Practice Points

-Used as a pharmacological stress for cardiac stress testing in patients unable to exercise.

*Group 5: Prostacyclin Analogue-Illoprost————————————————————————————————————————————————————–

Illoprost (Prostacyclin analogue) (Iloprost resembles prostacyclin I2/PGI2)–>Prostacyclin pgi2(Prostacyclin I2)

Illoprost-Synthetic analogue of Prostacyclin I2.

  • Mechanism of action:

-Inhibits all pathways to platelet activation (by increasing cAMP). However, it has a short half-life. 

-Iloprost dilates systemic and pulmonary arterial vascular beds. It also affects platelet aggregation but the relevance of this effect to the treatment of pulmonary hypertension is unknown. 

  • Clinical Indications:

1. Moderate to severe pulmonary hypertension (idiopathic or secondary to drugs e.g. phenylephrine which increases vascular resistance in lungs)

2, Connective tissue disease

3. Chronic pulmonary thromboembolism (where surgery is not possible)

  • Precautions:

1. Conditions with an increased risk of hemorrhage

2. Cerebrovascular event within the last 3 months-Contraindicated

3. Acute pulmonary infections, COPD and asthma-may worsen   Why?

4. Cardiac

Contraindicated in severe coronary heart disease, Unstable angina, MI within the last 6 months, severe arrhythmias, valvular defects with clinically relevant myocardial function disorders unrelated to pulmonary hypertension.

-Unstable pulmonary hypertension with advanced right heart failure may worsen.

-Systemic hypotension may worsen (due to excessive dilation of pulmonary arterial beds). Do not begin treatment if systolic BP <85 mmHg.

5. Renal impaired

-Reduce dosage in impairment during dialysis. Iloprost is predominantly renally excreted.

6. Hepatic impaired

-Reduce dosage in impairment

  • Adverse/Side effects

Common:

1. Syncope

2. Cough

3. Trismus (Unable to open mouth/jaw completely due to muscle spasm or trigeminal nerve damage)

4. Flushing

5. Headache

*Trismus-Unable to open mouth/jaw completely due to muscle spasm or trigeminal nerve damage

  • Pharmacokinetics

-Biphasic renal elimination (excreted via urine). Also excreted via feces.

-Half life of approx 2 hour

  • Administration advice (via nebuliser)

-Check suitability of nebuliser before use. Use only a mouthpiece. Avoid contact of solution with skin and eyes.

Drug Class 11: Organic and Inorganic Nitrates

Class 11: Nitrates

Glyceryl trinitrate (Nitroglycerin-Not preferred) (not a nitro compound)-Volatile, oily liquids with low molecular mass

Isosorbide dinitrate-High molecular mass nitrate esters, exist as solids at rtp

Isosorbide mononitrate-High molecular mass esters, exists as solids at rtp

Note: ***To have a pharmacological effect, the compounds above MUST BE REDUCED to form reactive free radical nitric oxide (NO), an active component (similar to a prodrug).

11.1 Mechanism of action:

-NO produced by reduction of these compounds. NO increases the cellular level of cGMP. Activates PKG and modulates activities of PDEs 2,3,5 (phosphodiesterases), responsible for the breakdown/hydrolysis of cGMP and cAMP.

-In smooth muscles, NO mediates increase in intracellular cGMP and activates PKG. This leads to reduced phosphorylation of myosin light chain and reduced calcium concentration in the cytosol causing vasodilation.

1.Provide exogenous source of nitric oxide (which mediates vasodilator effects). Predominantly venodilators. 

2. Reduce venous return and preload to the heart, thus reducing myocardial oxygen requirement.

3. Reduces afterload as arteriole resistance decreases.

  • AT LOW DOSES OF GTN, 

-preferential dilation of veins over arterioles (Venodilation occurs).

-Venodilation results in a decrease of both left and right ventricular size and end diastolic pressures. Little change in systemic vascular resistance.

-Systemic arterial pressure may fall slightly, heart rate is unchanged or may increase slightly in response to a decrease in BP (baroreceptor reflex). 

  • AT HIGH DOSES OF GTN,

-Causes venous pooling and also may decrease arteriolar resistance. Thus, systolic and diastolic blood pressure and cardiac output decreases.

-Causes pallor, weakness, dizziness, activation of compensatory sympathetic reflexes (baroreceptor reflex).

-Reflex tachycardia and peripheral arteriolar vasoconstriction tends to restore systemic vascular resistance.

-Coronary blood flow may increase transiently due to coronary vasodilation. However, it may decrease after due to cardiac output and blood pressure reduction of NO.

4. Cardiovascular effects (Effects on total and regional coronary blood flow)

-Ischemia is a powerful stimulus to coronary vasodilation and regional blood flow is adjusted by auto-regulatory mechanisms (i.e. if a region has low blood flow, body tries to compensate)

-In the presence of atherosclerotic coronary artery narrowing, ischemia distal to the lesion stimulates vasodilation.

-Significant coronary stenoses disproportionately reduce blood flow to the subendocardial regions of the heart which are subjected to compression during systole.

Effects of Organic Nitrate: Tend to restore blood flow in these ischemic regions. The hemodynamic mechanisms responsible for effects on coronary blood flow appear to be due to ability of organic nitrates to cause dilation.

-It also prevents vasoconstriction of the large epicardial vessels (outer layer of the heart wall) without impairing autoregulation in small vessels.

-Results in an increase in blood flow distributed preferentially to ischemic myocardial regions as a consequence of vasodilation induced by autoregulation.

Vascular stealVascular steal

5. Cardiovascular effects: Effects on Myocardial Oxygen requirements

-Has Effects on systemic circulation. Thus, nitrates reduce myocardial oxygen demand.

Preload: Increasing venous capacitance with nitrates decreases venous return to the heart. It also decreases ventricular end-diastolic volume and pressure (preload). Thus, decreasing oxygen consumption.

Afterload: Decreases arteriolar resistance by vasodilating systemic vessels. Thus, myocardial work and oxygen consumption decreases.

∴ Organic nitrates decreases both preload and afterload as a result of dilation of venous capacitance and ateriolar vessels.

-Decrease in cardiac workload aids greatly.

Summary of the effects:

1. Decreases cardiac workload (Decreases both afterload and preload) (Increased venous capacitance, Decreased arteriolar resistance-Minor)

2. Decreases systemic arterial pressure (High doses)

3. Dilation of epicardial coronary arteries (aids in regional blood flow to ischemic regions)

4. Deterimental effects:

-At high doses of organic nitrates, blood pressure/cardiac output may be reduced to an extent where coronary flow is compromised.

-Reflex tachycardia and increased sympathetic tone may override the beneficial effect of organic nitrates on myocardial oxygen demand and aggrevate ischemia.

 

11.2 Possible Indications 

(a) Prevention and treatment of (stable) angina

(b) Chronic heart failure (isosorbide dinitrate with hydralazine)

(c) Acute heart failure associated with myocardial infarction and unstable angina (Glyceral trinitrate/GTN infusion)

-Can be used prophylatically if used immediately prior to exercise or stress.

***Sublingual tablets: Place one under tongue, do not swallow. May spit out or swallow what is left of the tablet to avoid adverse effects such as headache. Wait for 5mins. If angina persists put another under tongue and call ambulance.

11.3 Precautions

1. Hypovolemia-Contraindicated  [Hypotension might occur?]

2. Reduced intracranial pressure-Contraindicated

3. Treatment with sildenafil, tadalafil or vardenafil (PDE inhibitors) –Contraindicated

4. Anemia-Contraindicated if significant

***5. G6PD (Glucose 6 Phosphate dehydrogenase) deficiency-Risk of hemolytic anemia

6. Cardiovascular-Contraindicated in hypotension, hypertrophic obstructive cardiomyopathy, cardiac tamponade, aortic or mitral stenosis or cor pulmonale

7. Surgery-Remove nitrate patches before diathermy, defibrillation or cardioversion.

*Diathermy-The use of high frequency electric current to produce heat (Used to either cut or destroy tissue or to produce coagulation)

*Cardioversion-A medical procedure by which abnormal heart rates or cardiac arrhythmia is converted to normal rhythm using electricity or drugs.

8. Pregnancy-No data available. Assume Not safe

9. Breastfeeding-No data available

11.4 Adverse effects/Side effects

-Most are due to vasodilator effects.

Common:

1. Orthostatic/Postural Hypotension (Worsened by alcohol and/or if patient is standing), Headache, Flushing

2. Syncope/Fainting (Position head low to facilitate venous return)

3. Palpitations

4. Peripheral edema

5. Rashes (occasional)

Infrequent:

*Contact dermatitis (topical), rebound angina

 

11.5 Crucial Points for counselling

*This medicine may make patient feel dizzy upon standing (postural hypertension). Get up gradually from sitting or lying to minimise this effect. Sit or lie down if necessary.

Note: Tolerance to nitrates occurs with frequent and continuous exposure (may occur within 24 horus).

*Avoid tolerance by ensuring a nitrate free period of at least 10-12 hours a day (AMH 2012).

11.6 Drug interactions

-Nitrates including sodium nitroprusside as well as amyl nitrite causes hypotension.

-If given with drugs that reduce BP (e.g. thiazides), additional hypertensive effects may occur.

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

-PDE 5 breaks down cGMP which itself causes smooth muscle relaxation and increased blood flow to the penis to assist erection.

-In the presence of a PDE 5 inhibitor, nitrates can drastically increase cGMP levels and reduce blood pressure greatly.

-Thus all 3 PDE 5 inhibitors are contraindicated.

 

 

11.7 Types of Nitrate agents

1. Glyceral trinitrate/GTN

Image

  • Clinical Indications

***(a) Stable Angina

(b) Heart failure associated with acute Myocardial Infarction (USE as infusion!!!)

(c) Unstable angina [Accepted indication]  (USE as infusion!!!)

(d) Acute pulmonary edema (USE as infusion!!!)

  • Precautions

* Pregnancy-Safety is not established. CAT B2-AUS

  • Administration advice

Infusion: GTN adsorbs to plastics (PVC). Use glass infusion bottle and polyethylene giving set.

*******Counselling

1. Patch administration -Apply to clean, dry skin on the chest area or upper arm. Fold the patch to prevent reuse.

2. Sublingual tablets/spray-Use during episodes of angina or before and activity expected to bring on angina

-Sit down or lie down before use as it may cause dizziness.

***CALL AN AMBULANCE IF SYMPTOMS ARE SEVERE, GET WORSE QUICKLY OR LAST FOR 10 MINS.

Sublingual tablets: Place one under tongue, do not swallow. May spit out or swallow what is left of the tablet to avoid adverse effects such as headache. Wait for 5mins. If angina persists put another under tongue and call ambulance.

-Store the tablets properly. Keep them in the original glass bottle away from moisture, heat and light. Do not carry tablets close to patient’s body (body temperature will affect degradation of tablets?)

-Write the date on the bottle when patient opens it. Discard any unused tablets 3 months later.

Sublingual sprays: Prime the spray before using it for the first time by pressing the nozzle 5 times, spraying it into the air. Prime it with 1 spray if it hasn’t been used for 7 days. Prime it with 5 sprays if it hasn’t been used for more than 4 months.

-When ready to use, aim the spray under the tongue and press the nozzle once, do not inhale the spray.

  • Pharmacokinetics of GTN 

    Absorption: Peak concentrations of GTN are found in plasma within 4 mins of sublingual administration of tablet.

    DOA: t1/2 of 1-3 mins.

    Metabolism: Avoids 1st pass metabolism/rapid entry

    OAA: More rapid if delivered sublingually.

     

  • Practice Points

-Sublingual GTN spray has a longer shelf life than tablets. It is useful for patients with infrequent angina.

-Ensure a nitrate free period of 10-12 hours each day when using a long acting glyceryl trinitrate patch (avoid tolerance)

-Do not stop IV infusion abruptly because of the potential for rebound symptoms.

  • Drug interactions

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

2. Isosorbide dinitrate (ISORDIL)

  • Clinical indications: 

(a) Prevention and treatment of angina

(b) Heart Failure (with hydralazine)

  • Precautions

-Pregnancy (CAT B1-AUS)

*****Counselling

1. Sublingual tablets

-Use during episodes of angina or before an activity expected to bring about angina (exercise)

-Sit or lie down before use of the drug as it may cause dizziness

-Place the tablet under the tongue, do not swallow. After angina has been relieved, patient may spit out what is left of the tablet to avoid adverse effects such as headache.

***CALL AN AMBULANCE IF SYMPTOMS ARE SEVERE, GET WORSE QUICKLY OR LAST FOR 10 MINS.

  • Drug interactions

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

3. Isosorbide-5-mononitrate (IMDUR)

  • Clinical Indications: Prevention of angina
  • Precautions: CAT B2 (No data available)

****Counselling: Swallow whole, do not crush or chew tablet. Tolerance may develop, Advise patients to have a IMDUR free period. Twice daily dosing schedule permitted and maintains efficacy.

  • Practice points: 

-Take at the time of the day when angina is most frequent (e.g. at night for nocturnal angina or in the morning for daytime angina)

-Twice daily dosing with isosorbide mononitrate is NOT RECOMMENDED (no ISM free period-Tolerance may occur).

-Treatment with isosorbide mononitrate for treatment of acute episodes of angina is NOT RECOMMENDED because of its slow onset of action.

  • Pharmacokinetics

-Does not undergo significant first pass metabolism. Has good oral bioavailability after oral administation.

-Mononitrate has significantly longer half life than isosorbide dinitrate.

-Can be formulated as a plain tablet and sustained release preparation (both dosage forms have a longer DOA than the corresponding dosage forms)

Absorption: Sublingual administration produces maximal plasma concentations of the drug by 6 mins.

DOA: t1/2 of approx 45 mins

Metbaolism: Enzymatic denitration followed by glucoronide conjugation.

-Initial metabolites produced: isosorbide 2 mononitrate and isosorbide 5 mononitrate. Both metabolites have longer half lives (3-6 hours) and contribute to therapeutic efficacy.

 

 

  • Drug interactions

*Phosphodiesterase 5 inhibitors-Sildenafil, tadalafil, vardeafil is CONTRAINDICATED.

 

 

*Developing Tolerance to organic nitrates

1. Transdermal patches of GTN (slow onset of action, continuous plasma nitrate concentration, peak effects occurring at 1-2 hours)

2. Sublingual organic nitrates (Continuous exposure to high doses to high doses of organic nitrates leads to decreased response)

Why does tolerance occur? Proposed mechanisms:

(a) Reduced capacity of the vascular smooth muscle to convert GTN to NO (active form)–>TRUE TOLERANCE

(b) Activation of mechanisms extraneous to the vessel wall–>PSEUDOTOLERANCE

(c) Inactivation of aldehyde dehydrogenase (involved in GTN biotransformation)

(d) Reactive intermediate formed during generation of NO from organic nitrates may damage and inactivate enzymes needed to form NO.

*Interrupt therapy for 8-12 hours a day to restore efficacy.

-Omit dosing at night in patients with exertional/stable angina. Adjust dosing intervals of oral/buccal preparations or by removing patches during ‘quiet’ periods.

-For patients who have paroxysmal nocturnal dyspnea (the sudden onset of shortness of breath at night), advise them to have have a organic nitrate free period during the ‘quiet’ periods of the day (i.e. not exercising)

 

 

 

*Comparison between the agents listed above:

-Nitrates vary in oral bioavailability. Formulations available, routes of administration and duration of effect.

This influences the choice of agent used to treat specific conditions.

Short acting nitrates:

  • Obviously, rapid onset but short-acting nitrates (sublingual GTN, sublingual isosorbide dinitrate) are useful in acute attacks of agina or preventing them when given immediately before an activity likely to induce angina.
  • Once sublingual tablets are opened, GTN tablets have a short shelf life of 3 months. Spray has a much longer shelf-life (2 years).
  • The spray may be particuarly useful for patients with infrequent symptoms.
  • Effects may be easier to adjust with sublingual tablets.

Long acting nitrates:

  • Long acting nitrates taken orally (isosorbide dinitrate, isosorbide mononitrate) and transdermal (GTN) are indicated for prevention of chronic angina.

IV Infusion of GTN:

  • IV infusion of GTN is appropriate/suitable in early management of acute MI and associated conditions (e.g. heart failure or persistent angina). Also, IV GTN can be used for unstable angina and acute pulmonary edema.
  • Isosorbide dinitrate is indicated for use in heart failure, in combination with hydralazine reduces mortality.

Image

4. Sodium Nitroprusside (Refer to Drug Class 8: Vasodilators)

8.4 Sodium nitroprusside

240px-Sodium-nitroprusside-2DSodium Nitroprusside/SNP/Sodium nitroferricyanide

Mechanism of action:

1. Non-selective arteriolar and venous dilator

2.  SNP breaks down in circulation to release nitric oxide (NO)

3. NO activates guanylate cyclase in vascular smooth muscle and increases intracellular production of cGMP. cGMP activates Protein Kinase G which activates phosphatases which inactivate Myosin light chains. Myosin light chains are involved in muscle contraction.

4. The end result is vascular smooth muscle relaxation, which allow vessels to dilate

5. In the human heart, nitric oxide reduces both total peripheral resistance as well as venous return, thus decreasing both preload and afterload.

*Due to this, it can be used in severe cardiogenic heart failure where it acts to increase cardiac output.

Clinical Indications: (a) Hypertensive emergency (b) Controlled hypotension during surgery to reduce bleeding (c) Acute Heart Failure

Precautions (All of them are contradicated for sodium nitroprusside use)

1. Compensatory hypertension (e.g. atrioventricular shunt or coarctation of the aorta- congenital condition whereby the aorta narrows in the area where the ductus arteriosus insets)

CONTRAINDICATED!!!

2. Vitamin B12 deficiency-CONTRAINDICATED!!! Refer to Vitamin Metabolic Biochemistry Lecture (Increased plasma homocysteine levels and increases damage to vessels. Adding nitroprusside will increase risk of thrombosis.)

3. Cerebral or coronary artery disease-CONTRAINDICATED!!!

4.  Congenital (Leber’s) optic atrophy-CONTRAINDICATED!!!

5. Tobacco amblyopia-CONTRAINDICATED!!!

6. Hypovolemia-CONTRAINDICATED!!!

7. Uncorrected anemia-CONTRAINDICATED!!!

Not contradicated but take extra caution

8. Increased intra-cranial pressure, encephalopathy-Risk of aggration

9. Hypothyroidism-Thiocyanate (degradation product of sodium nitroprusside). Inhibits both uptake and binding of iodine.

10. Hypothermia-Risk of aggravation

11. Pulmonary mpairment-May worsen hypoxemia

12. Renal impaired-Reduced excretion of thiocyanate concentrations during prolonged treatment.

13. Hepatic-Avoid use in severe impairment

14. Elderly-May require lower doses

15. Pregnant-Reserve for use in patients with hypertension not controlled by other agents. Short-term use for control of hypertensive crises may be safe provided that the pH and thiocyanate concentrations in maternal blood are monitored. Cat C-AUS

  • Side effects/Adverse effects

-Excessive hypotension or excessive cyanide accumulation

-Thiocyanate toxicity may also occur, especially with renal impairment

Common:

1. Nausea, Vomiting, Headache

2. Sweating, apprehension (Fear)

3, Restlessness

4. Muscle twitching

5. Retrosternal discomfort

6. Palpitations

7. Dizziness

8. Abdominal pain (with too rapid reduction in BP)

Infrequent:

-Postural hypotension, Hypothyroidism, Paraesthesia, feeling of warmth, rash, flushing, increased intracranial pressure

Rare:

-Thrombocytopenia, Methaemoglobinemia, Phlebitis (inflammation of veins usually in legs)

Toxicity:

-Toxicity may occur, particularly with prolonged infusion or higher than recommended maximum dose. Toxicity is due to accumulation of thiocyanate or cyanide.

*Sodium nitroprusside slowly breaks down to release 5 cyanide ions, especially upon exposure to UV light

*In normal renal function, cyanide accumulates with infusion rate of >2 micrograms/kg/min.

-Risk of toxicity is greater in renal impairment because of reduced excretion of thiocyanate.

-Thiocyanate toxicity causes confusion, psychosis, tinnitus, blurred vision, nausea, dyspnea, hypothyroidism and ataxia (lack of voluntary coordination of muscle movements)

Cyanide toxicity causes tachycardia, sweating, hyperventilation, headache, arrhythmias, metabolic acidosis, areflexia, coma, hypotension, pink colour of skin and mucous memranes, shallow breathing, dilated pupils and death.

  • Administration advice

-Dilute with glucose 5%, do not administer by direct injection!

-Infusion solution should be protected from light, e.g. with aluminium foil

-Final infusion concentration should be 50-100micrograms/ml (i.e. 50mg of sodium nitroprusside in 500-1000ml glucose 5%)

  • Practice points

-Monitor intra-arterial BP continuously during infusion and titrate infusion rate carefully to avoid excessive hypotension

-Abrupt withdrawl of sodium nitroprusside may cause rebound hypertension. Withdraw over at lesat 10-30 mins to avoid rebound.

-Usual duration of treatment should not exceed 72 hours because of cumulative thiocyanate toxicity and the possibility of cyanide toxicity; monitor thiocyanate concentrations.

  • Drug Interactions

-Nitrates (including sodium nitroprusside) as well as amyl nitrite causes hypotension. *Additional hypotensive effects may occur if administered with other anti-hypertensive agents.

*Administration with phosphodiesterase-5-inhibitors and nitrates is contraindicated.

Drug Class 10: Adrenergic agents (Blockers and Agonists)

PART 1———————————————–10.1 Alpha 2 agonists——————————————————————————————————————————————

Mechanism of action:

-Reduces intraocular pressure by suppressing formation and increasing uveoscleral outflow of aqueous humour.

Clinial Indications

1. Glaucoma (Chronic open-angle glaucoma)

2. Prevention of ocular hypertension following laser surgery

3. Glaucoma (Acute closed-angle glaucoma before laser iridotomy)

*Iridotomy-making puncture-like openings through the iris without the removal of iris tissue

Precautions

1. Severe cardiovascular disease-may worsen. Use with caution.

2. Pregnancy-Avoid use of Apraclonidine (CAT B3-AUS). Use Brimonidine if necessary (CAT B1-AUS).

Types of alpha 2 agonist drugs

1. Apraclonidine

Indications: Short term (<3 months) reduction of intraocular pressure in patients on maximally tolerated treatment for glaucoma

Side effects: Local allergic reactions limit short term use.

Common: Ocular irritation, especially allergic blepharonjunctivitis (with >3 months use), dry mouth and nose, taste disturbance.

Infrequent: Mydriasis (Dilation of pupils), Conjunctival blanching, lid retraction

Rare: Syncope (Loss of consciousness), Chest tightness, Reduction in BP, Headache

Practice Points: Ineffective in 30% of people with glaucoma.

-Progressive loss of effect and increasing ocular adverse effects after 3 months of treatment.

2. Brimonidine

Indications: Chronic open-angle glaucoma or ocular hypertension when b-blockers are not tolerated or are contraindicated.

***Can be combined with Timmolol for glaucoma or ocular hypertension (Combination with 0.5% timolol is appropriate)

Precautions: Adverse effects in children (may be severe e.g. hypothermia, CNS depression) more likely to occur than in adults (especially if <6 years or <20kg, avoid use in children <12 years)

Adverse effects:

Common:

1. Ocular irritation

2. Ocular allergic reaction

3. Conjunctival blanching

4, Lid retraction

5. Blepharitis

6. Dry mouth and nose

7. Taste disturbance

8. Fatigue, Headache, Drowsiness and Dizziness

*Blepharitis-eye condition characterized by chronic inflammation of the eyelid, the severity can vary

Infrequent:

-Systemic allergic reactions, depression, palpitations, systemic hypotension

***Counselling: The eye drop may cause drowsiness or dizziness. Avoid operating heavy machinery if affected.

Comparison between the two agents above:

-Apraclonidine reducse introocular pressure by 25% and Brimonidine reduces by 20%. However, the effect of apraclonidine reduces/declines after a month. Thus it is indicated for short term use (up to 3 months)

-Brimonidine is effective and well-tolerated when used long term

-May be used by opthalmologists in acute closed angle glaucoma or to prevent ocular hypertension following surgery

-Apraclonidine should only be used short term for acute pressure lowering as it is associated with a high incidence of allergic blepharoconjunctivits with chronic use.

*Allergic blepharoconjunctivits-Blepharoconjunctivitis is a condition in which the outer eyelids and mucous layer. Commonly referred to as pink eye, can occur by itself and be caused by allergies.

———————Alpha2 and imidazoline agonists (Clonidine and dexmedetomidine)————————————————–

Mechanism of action:

1. Have sedative, anxiolytic, analgesic and hemodynamic-stablising effects.

2. Act on alpha 2receptors in the CNS to reduce Noradrenergic activity. Also acts on receptors in other tissues.

3. Main site of analgesic action is believed to be the spinal cord.

4. Stimulation of imidazoline receptors result in a central hypotensive and anti-arrhythmic action.

Precautions:

1. Cardiovascular problems

-Pre-existing bradycardia (Heart rate may decrease further)

-Dehydration or heart failure (Sympathetic tone may be reduced, decompensation with hypotension and reduced heart rate may occur).

Adverse effects:

*Common-Hypotension, bradycardia, dry mouth, nausea

Practice Points

-Clinical effects develop slowly (after approximately 5-15 mins). *Monitor carefully for adverse effects.

-Produce little, if any, respiratory depression

-Does not cause anterograde amnesia (forgets things after initiation of drug treatment)

-Cardiovascular stabilising effects and reduction of post-operative shivering anre particularly useful in patients at high risk of myocardial ischemia

3. Clonidine

Clonidine structure

Mechanism of action: Centrally acting agonist at alpha 2 adrenoreceptors and imidazoline receptors. Reduces BP by reducig sympathetic tone.

Clinical Indications:

(a) Hypertension (b) Treatment of menopausal flushing (Limited efficacy) (c) Pre-medication (d) Adjunct during induction, maintenance and recovery of anaesthesia (e) Post-operative analgesia (accepted) (f) Post-operative shivering (Accepted) (g) Sedation and anlgesia in intensive care (seek specialist advice) (h) ADHD

(i) Diagnosis of phaeochromocytoma (Accepted)—> Measure catecholamines levels before and 4-6 hours after. The normal response is a 50% decrease in noradrenaline if there is no phaechromocytoma.

(j) Managment of opoid withdrawl symptoms (accepted)

*Premedication refers to a drug treatment given to a patient before a (surgical or invasive) medical procedure. These drugs are typically sedative or analgesic.

Precautions:

1. Severe bradycardia due to sick sinus syndrome (SSS) or heart block-CONTRAINDICATED.

2. Coronary heart disease, cerebrovascular disease

3. Raynaud’s phenomenon or other vasospastic peripheral vascular disease-Worsened by clonidine

4. Depression-May be worsened by clonidine. Avoid use in patients with history of depression

5. Diabetes-May cause transient rise in blood glucose conentration in patients with established diabetes.

6. Renal impaired-May worsen chronic renal failure

7. Surgery-Stopping clonidine abruptly may cause severe withdrawal syndrome. Maintain treatment through perioperative period using parenteral dosing if necessary.

8. Pregnancy-Use with caution, check with drug information centres. CAT B3-AUS

9. Breastfeeding-Use with caution, clonidine may decrease prolactin secretion. Check with drug info centre.

Side effects/Adverse effects:

Common:

1. Dizziness, drowsiness, sedation, headache

2. Fatigue, Sleep, Disturbance

3. Depression

4. Nausea

5. Vomiting

6. Constipation

7. Dry mouth, Salivary gland pain

8. Hypotension

9. Orthostatic hypotension

10. Erectile dysfunction

Infrequent: Bradycardia, itching, rash, fluid retention (transient), disturbed mental state, nightmare

Rare: Gynaecomastic, urinary retention, dry eyes, Raynaud’s syndrome, thinning of hair, transient alterations of liver function

*Withdrawl syndrome: Rebound hypertension occur 18-72 hours after last dose when clonidine was stopped abruptly. Characterised by rapid rise in BP, headache, flushing, sweating, insomnia, agitation and tremor. Avoid by gradually tapering of dose over days or weeks. Maintain treatment through perioperative period using parenteral dosing if necessary.

Administration: Give IV Dose in 10 ml sodium chloride 0.9% over 5 mins.

*Counselling:

  • This drug may cause drowsiness and increase the effects of alcohol. Do not drive or operate heavy machinery if affected.
  • Patient may feel dizzy on standing after first dose or an increased dose. Get up gradually from sitting or lying to minimise this effect. Sit or lie down if dizziness occurs.
  • Do not stop taking this medicine suddenly unless told by doctor to do so.

Practice points:

-After IV administration, the OAA is approximately 5 mins and DOA is around 4-5 hours.

-Mild transient hypertension lasting approximately 5 mins may occur following IV use, particularly with high doses and faster rates of administration.

-Addition of clonidine to intra-thecal (spinal-cord) local anesthetics improves intra-operative analegesia, increasing duration of sensory and motor block. However, the risk of arterial hypotension is increased too.

-Withdraw clonidine over at least 7 days. Stopping abrupt may cause a severe withdrawal syndrome.

-Presence of b-blocker can worsen the withdrawl syndrome. Withdraw clonidine over at least 7 days  after having stopped the b-blocker several days before.

-Limited efficay for menopausal flushing

-NO LONGER INDICATED FOR PROPHYLAXIS OF MIGRAINE!!!

4. Dexmedetomidine

Indications:

(a) Sedation of intubated patients in intensive care for up to 24 hours. (b) Procedural sedation

*Procedural sedation-a technique of administering sedatives or dissociative agents with or without analgesics to induce a state that allows the patient to tolerate unpleasant procedures while maintaining cardiorespiratory function

Precautions:

1. Hepatic impaired

-Clearance decreases in impairment. Consider reducing the loading dose and titrating carefully.

2. Elderly

-Increased risk of bradycardia and hypotension. Consier reducing the loading dose and titrating carefully.

3. Pregnancy

-Inadequate data (CAT B1-AUS)

Practice points

-At high concentration (e.g. during the loading dose) transient hypertension may occur which decreases as the concentration declines. Reduce infusion rate if necessary.

-Bradycardia and sinus arrest have been associated with high vagal tone and with rapid IV administration.

-During the adminstration of the drug, if patients are rousable and alert when stimulated, it suggests that the patient is inadequately sedated.

-Since it has no respiratory depression effects, it is not necessary to stop dexmedetomidine before extubation

*Extubation refers to the removal of a breathing tube (also called an endotracheal tube).

Adverse effects/Side effects

*Common: Transient hypertension (while giving loading dose)

*Infrequent: Hypertension (after stopping infusion), fever, headache, confusion, dizziness, visual disturbance, arrhythmia, hyperkalemia, hypoventilation

Comparision between the agents: Dexmedetomidine is a more selective alpha2 agonist than clonidine. It has a shorter elimination half-life and thus easier to titrate and recovery is faster.

Dexmedetomidine (Text me the tom. dinner)

5. Methyldopa (Prodrug)

Mechanism of action: Centrally acting alpha 2 receptor agonist. Reduces BP by reducing sympathetic tone.

Indications: Hypertension

Precautions: 

1. Pheochromocytoma-Contraindicated

2. Depression-Worsened by methyldopa

3. Renal impaired

-People with renal impairment may respond to lower dosage. Usual initial dose but may be all that is required (no need to increase dose subsequently)

4. Hepatic impaired

-Contraindicated in active hepatic disease.

5. Pregnancy and Breastfeeding

– Safe to use. CAT A-AUS

Side effects/Adverse effects:

Common:

1. Sedation

2. Dizziness, Light-headedness, Tiredness, Weakness

3. Dry mouth

4. Fever

5. Headache

6. Nausea

7. Diarrhoea

8. Positive direct Coomb’s test

*An abnormal (positive) direct Coombs’ test means you have antibodies that act against your red blood cells

Infrequent: Hemolytic anemia, eosinophilia, orthostatic hypotension, bradycardia, edema, constipation, sore tongue, depression, rash, nasal congestion, sleep disturbance, impotence

Rare: Hepatotoxicity with acute or chronic active hepatitis or hepatic necrosis, Leukopenia, Thrombocytopenia, Pancreateitis, reduced libido, hyperprolactinaemia (causing galactorrhoea in women and gynaecomastia in men)

Counselling:

*This medicine may make you feel drowsy or light-headed especially at the start of the treatment or when the dose is increased.

*Do not drive or operate heavy machinery if affected.

*Get up gradually from sitting or lying down to minimise effect. Sit or lie down if affected.

Practice Points:

-Used to treat hypertension in pregnancy BUT CNS and hepatic adverse effects limits its use in other patients

-Sedating effect of methyldopa is exacerbated by dose increases.

-Increase dosage at night to minimise inconvenience of increased sedation

-Monitor blood count and liver function during 6-12 weeks of treatment.

10.2 Part 2: Non-selective alpha-blockers——————————————————————————————————————————————————————————————

Reversible a-blockers (Competitive) Imidazolines: Phentolamine

Irrevisble a-blockers (Non-competitive): Phenoxybenzamine

Mechanism of action:

1) Block the effects of NAdr and Adr at the alpha1 and alpha 2 receptors (non-selective).

2) Results in vasodilation due to blockage of post-synaptic alpha 1 receptors and inhibits catecholamine-induced vasoconstriction.

3) Blockage of alpha 2 receptors in the pre-synaptic neurons result in more NAdr release and enhances reflex tachycardia (BAD!)

Clinical uses for these two drugs: Phaechromocytoma (Tumour on the adrenal gland)

Precautions:

1. Conditions where a sudden reduction in BP is undesirable (e.g. stroke, coronary artery disease)–>CONTRAINDICATED

2. Heart Failure-May worsen due to reflex tachycardia

3. Renal impaired-Impairment may be worsened by excessive hypotension.

Side effects:

Note: In phaechromocytoma, clinically significant (but tolerable) orthostatic drop in BP is the desired effect (not a side effect)

Common:

1. Orthostatic Hypotension,

2. Reflex tachycardia

3. Dizziness

4. Drowsiness

5. Fatigue

6. Nasal congestion

Infrequent: Miosis, Inhibition of ejaculation, GI irritation, confusion, headache, urinary urgency, dry mouth.

Practice points

-Used mainly in the management of phaecochromocytoma to block the effects of excessive circulating catecholamines, often with b-blockers (which reduces tachycardia)

6. Phenoxybenzamine (Irreversible, non-competitive)

Indications: Pheochromocytoma

Precautions: Pregnancy (may be used after 24 weeks of gestation, seek specialist advice-CATB2-AUS)

***Counselling: Dizziness may occur. Get up gradually from sitting or lying to minimise this effect. Tell patient to sit down if dizziness occurs. Take the first dose before bedtime, but be careful when getting out of bed during the night due to possible dizziness.

-This medicine may also cause drowsiness, do not drive or operate heavy machinery if patient feels dizzy or drowsy!

7. Phentolamine (Reversible, Imidazoline class)

Clinical Indications: (a) Pheochromocytoma (b) Erectile dysfunction, with papaverine (Opoid alkaloid anti-spasm drug) and/or alprostadil (Prostaglandin E1 analogue) [administered orally, bucally or intracarvenously]

Precautions:

1. Peptic Ulcers: Phentolamine may stimulate GI motility and gastric acid secretion.

2. Pregnancy. Has been used. Contact pregnancy drug centres for more info. CAT B1-AUS

Side effects/Adverse effects:

Infrequent: Intracavernosal, penile pain, hematoma

Rare: Intracarvenosal, Dizziness, fibrosis, priapism

*Priapism:  potentially painful medical condition, in which the erect penis does not return to its flaccid state, despite the absence of both physical and physiological stimulation.

Practice points:

*Use with papverine and/or alpostadil injection for erectile dysfunction (ineffective alone)

-No commercial product for intracarvenosal injection. Seek advice from pharmacist.

*Comparsion betwen the two agents above: Phenoxybenazmine irreversibly blocks the alpha receptors resulting in a long DOA (3-4 days). Available orally, it is used in weeks before surgery to stablise BP or for prolonged treatment if pheochromocytoma is inoperable.

*Phentolamine on the other hand, competitively blocks alpha receptors. Available as injection. It is used to control surges in BP during surgery for phaeochromocytoma.

10.3 Part 3: Selective Alpha 1 blockers—————————————————————————————————————————————————————————–

Quinazoline: Prazosin and Terazosin

General mechanisms: Blockade of a1 receptors inhibits vasoconstriction induced by endogenous catecholamines (result is a fall in BP due to decreased peripheral resistance). 

-Magnitude of decrease depends on activity of the sympathetic nervous system.

-For most alpha receptor antagonists, decrease/fall in BP is opposed by baroreceptor reflexes (increase in heart rate and cardiac output, as well as fluid retention)

-These compensatory reflexes are enhanced, if the antagonist also blocks a2 receptors on peripheral sympathetic nerve endings (recall alpha 2 on post-synaptic inhibits NAdr release, so blockage means more NAdr and thus more sympathetic tone.

-Blockage of a1 inhibits vasoconstriction. So Adr may be transformed to vasodepressor (binds to B2–>Vasodilation.)

Clinical Indications: Hypertension

Precautions: 

1. Heart failure due to mechanical obstruction (e.g. aortic stenosis)- CONTRAINDICATED

2. Volume depletion-Risk of exacerbation of orthostatic hypotension

3. Treatment with diuretics, beta-blockers, CCBs-Increases risk of first dose hypotension

4. Cataract surgery

-Selective alpha-blockers (particularly tamsulosin) are associated with intra-operative floppy iris syndrome during cataract surgery

-Interrupting treatment does not appear to reduce this risk. It may be necessary to modify surgical technique. Increased rates of post-operative ocular complications have been associated with tamsulosin use..

-Consider use of these agents carefully if cataract surgery is contemplated as these complications have occured even after these drugs were ceased.

5. Renal impaired

-Begin treatment cautiously in impairment as there may be a profound first dose effect (Excessive hypotension)

6. Elderly

***Often cannot tolerate alpha blockers due to orthostatic hypotension. Avoid use in elderly

7. Pregnancy and Breastfeeding

-CAT B2-AUS. Use with caution when breastfeeding.

*Counselling Points:

*Dizziness on standing may occur especially when starting treatment or when dose is increased.

-Get up gradually from sitting or lying down to minimise this effect.

-Sit down or lie down if necessary. Take the first dose at bedtime but be careful when getting up at night.

*This medicine may cause drowsiness or dizziness. DO NOT OPERATE HEAVY MACHINERY OR DRIVE IF AFFECTED.

*Tell the ophthalmologist that the patient is on this drug if he/she is going to have cataract surgery.

Practice Points:  Start additional anti-hypertensives cautiously as BP may fall sharply.

*First dose hypertension: Most serious to the elderly, fluid depletion or people on diuretics.

Solution: Minimise this effect by starting with a small dose of selective alpha-blocker given before bedtime.

-Increase dose slowly over 2 week intervals

-Withold diuretic for a few days before starting on selective a1 blocker

-Reduce dose of CCB or B-blocker before starting with selective a1 blocker

8. Prazosin (Potent and selective a1 receptor antagonist)

-Indications: Hypertension

Prazosin structure(Quinozoline and furan rings)

-Affinity for a1 receptors 1000x that of a2.

Mechanism of action:

1. Major effects of prazosin- Blockage of a1 receptors in arterioles and veins, leading to a fall in TPR and decreased venous return to the heart (decreases cardiac preload)

-Little tendency to increase cardiac output and rate (in contrast to hydralazine-vasodilator that has minimal effect on veins)

2. May act in CNS to suppress sympathetic outflow

3. Depresses baroreceptor reflex in hypertensive patients

4. Favourable effects on lipid levels in humans

-Decreases LDL (bad) and triglycerides while increasing concentrations of HDL (good)

Pharmacokinetics:

-Well absorbed with an oral bioavailability of 50-70% and peak plasma concentration 1-3 hours after oral dose

-Binds avidly a1-acid glycoprotein (only 5% of the drug is free). Diseases that modify the concentration of this protein (e.g. inflammatory process) may affect free fraction

-Extensively metabolised in the liver. Plasma t1/2 (2-3 hours) and may be prolonged to 6-8 hrs in CHF.

-In treatment of hypertension, DOA of the drug is 7-10 hours.

Adverse effects (Associated with first-dose effect)

1. Marked postural hypertension and syncope

-Occurs within 30-90 mins after initial dose

Solution: Limiting initial dose (1 mg at bed time), Increasing the dose slowly, Introduce additional anti-hypertensive drugs cautiously

9. Terazosin

Terazosin structure (Quinozoline and dihydrofuran rings)

*Comparison of two agents above: Both seem equally effective in treating hypotension when used at equipotent doses. However, they should only be used as third line therapy as doxazosin (discontinued) increased the rate of CHF compared with chlorthalidone (thiazide diuretic)

10.4 Part 4: Beta-blockers———————————————————————————————————————————————————————————————————-

*Know the structure activity relationship of Beta-blockers (prototype: Dichloroisoproterenol)

Note: SOME of these agents have ISA/Intrinsic Sympathomimetic activity properties! (i.e. are able to partially agonist receptors even though they are antagonists)

General Mechanism:

-Inhibits endogenous catecholamines from binding to b1 or b2 receptors. Decrease cAMP, PKA production, Various effects depending on receptor type.

General beneficial effects of B-blockers in Heart Failure:

  • Improve heart failure symptoms
  • Exercise tolerance
  • Measures of ventricular function (over several months in patients with heart failure)
  • Improves ventricular structure and function (decrease in chamber size, increase in ejection fraction)
  • Systolic function recovers and improves beyond baseline levels (over 2-4 months)
  • Possibly decreasing malignant ventricular arrhythmias
  • Reduce Hypokalemia
  • Anti-Ischemic effects

General concerns about B-blockers in heart failure:

  • May cause decompensation when initiated. Cardiac function is reduced, causing dyspnoea, edema and venous pooling
  • Fluid retention (Renders the need for diuretic agents)
  • Should be started at low doses (1/10 of final dose), increased slowly over course of weeks until maximum dose reached. Supervise carefully.
  • Not all B-agonists will have same effects. Some have the potential to worsen both ventricular function and symptoms in patients with CHF, they should be used cautiously in the disease.

General drug interactions of B-blockers:

-Beta blockers reduce BP, cardiac contractility and conduction.

-Administration with other drugs that also have these effects increase risk of hypotension, heart failure and/or signifcant bradycardia.

-Monitor BP, cardiac function and heart rate.

***Avoid combing beta-blockers (including eye-drops) with VERAPAMIL unless under specialist supervision.

-Most beta-blockers are hepatically cleared except ATENOLOL (renally cleared) and PINDOLOL/BISOPROLOL (hepatically and renally cleared)

1. Adrenaline

2. Beta 2 agonists

3. Clonidine

4. Ergot alkaloids

5. Isoprenaline

6. NSAIDs

*Applicable to all B-blockers below.

10.4.1 Non-selective B-blockers

Carvedilol, Nebivolol (both selective and non-selective depending on drug’s concentration), Oxprenolol, Pindolol

10. Propranolol (Blocks both b1 and b2 receptors)

Propranolol structure aryl-oxy-propanol-amine

Clinical indications:  (a) Hypertension (b) Angina (c) Tachyarrhythmias (d) Control of symptoms (tachycardia, tremor) in axiety and hyperthyroidism (e) Fallot’s tetralogy (f) Myocardial infarction (g) Prevention of migraine (h) Essential tremor (i) Phaeochromocytoma (with an alpha-blocker) (j) Prevention of oseophageal  variceal bleeding (seek specialist advice) [Accepted indication]

*Fallot’s tetralogy- a congenital heart defect which is classically understood to involve four anatomical abnormalities of the heart (including blue baby syndrome, cyanotic heart defects)

Pharmacokinetics:

-Hepatic eliminated!

Drug interactions:

1. Chlorpromazine

2. Cimetidine (Reduces metabolism of propranolol and somtimes may increase therapeutic and adverse effects). Consider using an alternative H2 antagonist or use a renally cleared B-blocker

3. Lignocaine

4. Rifampicin-Increases metabolism of propranolol. Reduce propranolol dose if necessary or use a renally cleared beta-blocker.

5. Rizatriptan

Precautions: 

*Hepatic impairment

-May require a lower dosage in impairment

*CONTRAINDICATED IN DIABETES, ASTHMA AND BRONCHOSPASM

*Propranolol is proving to be a sucessful treatment for infantile hemangiomas (see also timolol)

11. Carvedilol (B1, B2, Alpha blocker)

Carvedilol structure(Non-selective due to fused aromatic rings attached to phenyl ring)

Clinical indications: (a) Hypertension (b) Stable mild-to-severe heart failure (as an adjunct to conventional treatments  (e.g. diuretics and ACE-inhibitors)

Pharmacokinetics: 

-Hepatic eliminated

Precautions:

***Hepatic impairment- Avoid use in severe impairment

***Counselling:

-Patient may feel dizzy upon standing when taking this medication. Get up gradually from sitting or lying to minimise this effect. Sit or lie down if patient becomes affected.

Practice Points:

Heart Failure

  • Before starting treatment, optimise conventional treatments (Loop diuretics etc). Ensure that patients with severe hart failure are well stabilised with sitting systolic BP >85 mmHg, without peripheral edema, new pulmonary crackles or ascites, recent unstable angina, cardiac surgery or ventricular arrhythmias.
  • Reduce dose if heart rate is <55 beats/min (bradycardia)
  • Treat transient worsening of heart failure with increased doses of diuretics (e.g. loop diuretics). Temporarily withdraw carvedilol if necessary.
  • Treat hypotension by reducing dose of diuretics and other vasodilating drugs first. Reduce carvedilol if necessary.

Side effects/Adverse effects:

1. Hypotension

2. Diarrhea

3. Asthenia  *Asthenia: A medical condition which describes the body lacking strength with malaise, dizziness or fatigue associated

4. Bradycardia (Due to partial or complete AV conduction defects) -Caution in patients taking other drugs: Verapamil or various anti-arrhythmic agents, which may impair sinus-node function or AV conduction.

5. Weight gain

6. Cold extremities while taking B-blockers/ Raynaud’s phenomenon

7. Enhanced sensitivity to Beta stimulation when B-blocker is withdrawn abruptly. Bark enzyme decreases after prolonged B-blockade and after abrupt withdrawal, there is an enhanced response–>Exacerbate angina and may increase risk of sudden death.

8. CNS-adverse effects (Fatigue, Sleep disturbances, Insomnia, Depression and depression)–>No correlation between lipophilicity and B-antagonists.

9. Blunt recognition of hypoglycemia and may delay recovery from insulin-induced hypoglycemia (B2 receptors blocked–>Gluconeogenesis reduced)

10. Bronchoconstriction (major adverse effect). B1-selective antagonist (with ISA) at B2 adrenergic receptors may be less likely to induce bronchospasm.

-However, selectivity of current B1 blockers is modest (depends on dosage), should be avoided if possible in patients with asthma.

11. Can exacerbate heart failure (In patients with heart failure, acute myocardial infarction or cardiomegaly)

-nonetheless, chronic administration of B-receptor antagonists is effective in prolonging mortality in heart failure in certain patients.

Pharmacokinetics of Carvedilol:

-Substrate and inhibitor of P-glycoprotein.

Drug interactions (P-glycoprotein substrates/inhibitors/inducers)

1. Cyclosporin

2. Digoxin

3. Rifampicin-Decreases carvedilol’s concentration and may reduce its therapeutic effect. Increase carvedilol dose if necessary. Use a renally cleared B-blocker.

12. Nebivolol (Non-selective and selective depending on concentration)

Nebivolol (non-selective blocker) structure (Fused rings makes its non-selective, Bulky substituent on N makes bind to b-receptors)

Clinical indications: (a) Hypertension (b) Stable Heart Failure (used as an adjunct to conventional treatments e.g. diuretics and ACE-inhibitors)

Precautions: 

1. Renal impaired

-Lower starting dose for hypertension if Creatine clearance<30ml/min

2. Hepatic impaired

-Reduce dose in moderate hepatic impairment (Child-Pugh Class B)-Manufacturer contraindicates use in hepatic impairment

Pharmacokinetics:

-Hepatic eliminated!

-Metabolised by CYP2D6. When given with drugs that affect this enzyme, its concentration may alter, leading to incresaed adverse effects or loss of efficacy. Avoid combinations or monitor carefully. Adjust dose accordingly.

Drug interactions–>Any drug that belongs to CYP2D6 group

*Fluoxetine-Increase nebivolol concentration. Possibly increasing risk of adverse effects. Choose an alternative SSRI or monitor for nebivolol’s adverse effects and reduce dose if needed.

Practice Points:

  • Metabolism. Nebivolol is metabolised by CYP2D6. Titrate dose carefully as there are slow and fast metabolisers of the drug due to differences in CYP2D6 genotype.

*Titrate-Titration is the process of gradually adjusting the dose of a medication until optimal results are reached

Heart Failure

  • Use in Heart Failure. Evidence of mortality is stronger for bisoprolol, arvedilol and controlled release metroprolol. There is no evidence that nebivolol is more effective in any age group than those beta-blockers
  • Before starting treatment, optimise conventional treatments, ensure that patients with severe heart failure are well-stabilised with sitting systolic BP>85mmHg, without peripheral edema, new ascites or pulmonary crackles, recent unstable angina, cardiac surgery or ventricular arrhythmia
  • Reduce dose if heart rate is <55 beats/min

-Treat hypotension by reducing the dose of diuretics and other vasodilating durgs first, reduce dose of nebivolol if necessary.

13. Oxprenolol (Some ISA activity)

Oxprenolol structure

Clinical indications: (a) Hypertension (b) Angina (c) Tachycardias

Pharmacokinetics:

-Hepatic eliminated!

Precautions: 

*Hepatic Impairment

-May require lower dosage in impairment

14. Pindolol (ISA activity is present-Can activate B receptors)

Pindolol structure (Pindolol has fused ring-Non-selective blocker)

Clinical Indications: (a) Hypertension (b) Angina (c) Tachycardias

Pharmacokinetics:

-Hepatic and renal eliminated!

Precautions:

*Hepatic impairment

-Hepatic metabolism by CYP2D6

-May require lower dosage in impairment.

 

  • Timolol (Non-selective blocker)

Timolol structure

 

Clinial Indications: (a) Glaucoma [Eye drops](b) Ocular Hypertension

*Combination with bimatoprost, brimonidine, brinzolamide, dorzolamide, latanoprost or travoprost

*Used for glaucoma or ocular hypertension, when treatment with timolol 0.5% and one of the above is appropriate

***Do not use timolol 0.5% with bimatoprost, latanoprost or travoprost to start treatment. Use each drug separately if twice daily timolol is needed.

  • Practice points:

-Combination products may be appropriate when monotherapy is insufficient.

-Topical timolol has been used to treat infantile cutaneous hemangiomas

***Counselling Points:

Gel: Store bottle upside down down after opening so that gel collects in the bottle neck and stops bubbles forming as it is applied.

 

 10.4.2 Selective B1 Blockers-————————————————————————————————————————————————————————————————–

Acebutolol

Atenolol

Bisoprolol

Metroprolol

Esmolol

Mechanism of action:

1. B-receptor antagonists generally do not reduce BP in patients with normal BP but will lower BP in patients with hypertension

2. Reduction of B1-stimulated renin release from the JGA cells is a contributing mechanism

3. Long term administration of these drugs in hypertensive patients decreases peripheral vascular resistance.

15. Acebutolol (Amide in side chain of phenyl ring)

Acebutolol structure (Contains amide in side chain of phenyl ring)

-Not listed found in AMH 2012.

16. Atenolol

Atenolol structureAmide group present in R ‘side chain’. Hence Atenolol. Single ring-B1 selective

Clinical Indications: (a) Hypertension (b) Angina (c) Tachycardia (d) Myocardial Infarction (e) Prevention of migraine (accepted)

Pharmacokinetics:

-Renal excreted!!!

-Largely excreted by kidneys. Dosage should be reduced when Creatinine clearance is <35ml/min.

Precautions: 

Renal impaired-May accumulate in renal impaired. Lower dosage may be required.

17. Bisoprolol (Contains isopropyl group on the phenyl ring side chain)

Bisoprolol

Clinical Indications: (a) Stable moderate to severe heart failure in addition to ACE inhibitors, diuretics and optional digoxin

Pharmacokinetics:

-Hepatic and renal eliminated.

Precautions:

*Renal impaired-No dose reduction is required. Up to 10 mg daily. (Why? Does not accumulate in kidneys?)

Drug Interactions of Bisoprolol:

*Rifampicin

18. Metroprolol (Contains methyl group on phenyl side chain)

Metroprolol structure

Clinical Indications: (a) Hypertension (b) Angina (c) Tachycardia (d) Myocardial Infarction (e) Prevention of migraine (f) Stable heart failure with an ACE inhibitor, diuretics and optional digoxin

Precautions:

Hepatic impaired

-May require lower dosage in impairment

***Counselling points

Note: Controlled/Sustained release tablets may be broken in half or swallowed whole BUT DO NOT CRUSH OR CHEW THEM.

Pharmacokinetics

-Hepatic eliminated!

-Extensive first pass metabolism. Wide variability in half life based on genetic differences in CYP2D6 activity.

-Half life is usually 3-4 hours but can double in CYP2D6 metabolisers, who have 5x higher risk for adverse effects compared to normal metabolisers.

Practice points (Heart failure therapy)

-Before starting treatment in patients with CHF, optimise conventional treatments and ensure that patients with severe heart failure are well stabilised with sitting systolic BP>85 mmHg, no peripheral edema, no new pulmonary crackles or ascites or any recent unstable angina, cardiac surgery or ventricular arrhythmia

-Reduce dose if heart rate is <55 beats/min

-Treat transient worsening of CHF with increased dose of diuretics, temporarily withdraw controlled release metroprolol if necessary.

-Treat hypotension by reducing dose of diuretics and other vasodilating drugs first. Reduce dose of controlled release metroprolol if necessary.

Drug interactions:

1. Amiodarone-May increase metroprolol’s concentration. Increase the risk of severe bradycardia. Consider low dose to start metoprolol treatment.

2. Cimetidine-Reduces metabolism of metroprolol and sometimes may increase therapeutic and adverse effects. Consider using a renally cleared B-blocker.

3. Lercanidipine

4. Lignocaine

5. Paroxetine-Increases metroprolol concentration and may increase its adverse effects (including heart block). Use an alternative SSRI (e.g. citalopram) or a renally cleared b-blocker

6. Rifampicin-Increases metabolism of metoprolol and may reduce its therapeutic effect.  Increase metroprolol dose if necessary or use a renally cleared beta-blocker.

19. Esmolol (Contains Ester group in side chain of phenyl)

Esmolol structure

-Not found in AMH 2012.

Note: There is no B2 selective blockers mentioned here since B2 blockage leads vasoconstriction. 

10.5 Part 5: Selective B2 agonists——————————————————————————————————————————————————————————————-

(Note: B2 agonists loses selectivity when used in high doses)

Salbutamol/Atenolol, Terbutaline, Salmeterol, Eformoterol/Formoterol, Indacaterol

*Know the SAR of B2-agonists

*Know the difference in structures of SABAs and LABAs.

10.5.1 Mechanism of action in general: Relax bronchial smooth muscle by stimulating the B2 receptors

Clinical indications:

SABA INDICATIONS: (a) Acute asthma (SABA) (b) Symptomatic relief during Maintenance treatment of COPD and asthma  [SABA] (c) Prevention of exercise-induced asthma [SABA]

LABA INDICATIONS:  (a) Maintenance treatment of asthma (including nocturnal and exercise-induced asthma) in patients receiving ICS/oral corticosteroids. (b) Maintenance treatment of COPD

10.5.2. Precautions

-For oral and parenteral use consider:

1. Cardiovascular disorders (including hypertension, ischemic heart disease, heart failure, arrhythmias)

2. Hyperthyroidism-Risk of cardiovascular adverse effects

3. Diabetes-Risk of hyperglycemia (high dose)

4. Treatment with other sympathomimetic amines-May increase adverse effects (tremor, tachycardia, headache). *AVOID COMBINATION OR ADJUST DOSE AS NECESSARY!

5. Elderly-Start with a lower dose than the usual adult dose. Gradually increase if necessary.

10.5.3 Side Effects/Adverse effects

  • Incidence and severity of adverse effects depend on dosage and route of administration

Common

1. Tremor

2. Palpitations

3. Headache

***4. Serious hypokalemia may occur with high doses of B2 agonists. May be worsened by theophyllines, corticosteroids, diuretics and hypoxia.

Infrequent

-Hyperglycemia (high dose), tachycardia, muscle cramps, agitation, hyperactivity in children, insomnia

Rare

-Paradoxical bronchospasm, allergic reactions including urticaria (hives), angioedema and anaphylaxis, lactic acidosis

[Lactic acidosis]

-There are reports with high-dose IV and nebulised salbutamol.

-Respiratory compensation (increased respiratory rate and effort) due to increased lactate levels may be mistakened for worsening asthma.

  • Comparative information on the two types of b2 agonists

SABAs 

-Salbutamol and terbutaline have rapid OAA (5-15 mins)

-Short DOA (3-6 hours) and similar efficacy.

-They are useful for: Symptom relief in asthma and COPD and Prevention of exercise-induced asthma

LABAs

-Salmeterol, Eformoterol and Indacaterol seem to have similar efficacy.

-They are useful for COPD in those who remain symptomatic despite the use of SABA or have frequent exacerbations (2 or more a year). May be used without ICS.

-Salmeterol and Eformoterol are also useful for uncontrolled asthma (including nocturnal and exercise-induced asthma) in those already receiving inhaled or oral corticosteroids

-LABAs are not substitutes for ICS when treating asthma. The two must be used together.

-Products combining ICS and LABA ensure their concurrent use. But do not allow flexible dosing of each drug.

*Eformoterol has a quicker OAA than Salmeterol and is marketed for acute relief of symptoms in adults with asthma (already receiving ICS and regular eformoterol).

-The combination of budesonide  with 6 mcg eformoterol in a single inhaler is marketed for symptom relief in patients receiving maintenance treatment.

10.5.4 Practice Points

***Inhaled SABAs are the first line bronchodilators in acute asthma

***Consider preventive treatment if SABAs are needed more than 3 times a week

10.5.5 Pharmacokinetics of LABA

Drug (indication)                                                                Onset of Action (mins)                                                      Time to peak effect (hours)                                 Duration (hours)

1. Eformoterol (COPD, asthma)                                         1-3                                                                                                     1-2                                                                     >12

2. Indacaterol  (COPD)                                                        <5                                                                                                       2-4                                                                     up to 24 hours

3. Salmeterol (COPD, asthma)                                        10-30                                                                                                 3-4                                                                         >12

Note: Eformoterol has the most rapid OAA. DOA is the longest for Indacaterol.

-Concerns exists that inhaled B2 agonists may worsen asthma and increase mortality.

-Use SABAs as-needed and always use LABAs/ICS in asthma

-In patients taking ICS and LABAs, use lowest dose required to maintain control.

10.5.5 Routes of administration 

1. Inhaled route (preferred route). Preferred because of fewer systemic adverse effect and faster OAA.

2. Parenteral route. May be used in acute severe asthma but is associated with more adverse effects.

3. Nebuliser. NOT RECOMMENDED for maintenance treatment  or treatment of acute asthma in adults or children but may be used for treatment of severe or life-threatening acute asthma!

Advice/Counselling: Teach, check and reiew inhaler technique regularly, especially when asthma control is poor. Oral administration of salbutamol or terbutaline is rarely indicated.

20. Salbutamol/Albuterol (USA) [Short-acting Beta agonists/SABA]

Salbutamol(Notice that there is still a 4-OH and 3-OH is replaced by CH2-OH group)

*Not metabolised by COMT (since 3-OH is replaced) and not metabolised by MAO (t-butyl sterically hinders)–>But still short-acting…

Mechanism of action: Binds selective to B2 receptors to induce rapid bronchodilation

Clinical Indications: (a) Acute asthma (b) Symptom relief during maintenance treatment of asthma and COPD (c) Prevention of exercise-induced asthma (d) Management of pre-term labour (e) Relief of bronchospasm in anaphylaxis (Accepted)

Precautions:

1. Pregnancy-Safe to use (CAT A-AUS)

2. Breastfeeding-Safe to use

*Administration advice: Multidose solution for nebulisation may need dilution with sodium chloride (0.9%) to obtain a suitable final volume for the nebuliser.

***Counselling:

1. Make sure the doctor has given the patient a treatment plan!

2. Tell the doctor as soon as possible if patient needs to use this medicine in higher doses or more frequently than prescribed.

3. Regularly clean the plastic mouthpiece of the inhaler to prevent blockage of the nozzle.

Practice Points:

-Reserve nebuliser solution for life-threatening acute asthma

-IV route may be used in acute severe asthma but has a greater risk of adverse side effects (IM and SC injection rarely indicated)

-Oral administration also rarely used

21. Terbutaline [SABA]

Terbutaline image(Notice the same thing is present, 3-OH and 5-OH. No COMT)

Clinical indications: (a) Acute asthma (b) Symptom relief during maintenance treatment of asthma and COPD (c) Prevention of exercise-induced asthma (d) Tocolytic (Prevents premature labour)-Nina’s lectures)

Precautions: 

1. Pregnancy-Safe to use (CAT A-AUS)

2. Breastfeeding-Safe to use

*Acute asthma at home

1. Use Dry Powder Inhaler (4 puffs, 200 mcg). Repeat after 4 mins if no improvement.

2. If still no improvement, call an ambulance and continue giving 4 puffs every 4 mins until ambulance arrives.

*Adults may take up to 6-8 puffs every 5 mins while waiting for ambulance if attack is severe.

***Counselling

-Make sure doctor has given patient a treatment plan.

-Tell the doctor as soon as possible if patient needs to use this medication in higher doses or more frequently than prescribed.

***Practice points

-SC route may be used in acute severe asthma

–Oral administration is rarely used.

—————————————————————————————————————————————————————————————————————————————

22. Salmeterol [LABA]

Clinical indications:  (a) Maintenance treatment of asthma (including nocturnal and exercise induced asthma) in patients receiving inhaled or oral corticosteroids  (b) Maintenance treatment of COPD

Salmeterol structure(Long lipophilic side chain which can bind to the exosite-Dissociates and associates continuously thus DOA increases)

*Combination with fluticasone (Steroids-ICS)

-Maintenance treatment of asthma where use of combination product is appropriate (e.g. patients inadquately controlled with ICS or patients stabilised on salmeterol and fluticasone)

-Severe COPD with repeated exacerbations inadequetely controlled with regular B2 agonist therapy.

Precautions: 

1. Pregnancy (Limited experience but asthma control is paramount) (CAT B3-AUS)

2. Breastfeeding-Safe to use

*Counselling: DPI (dry powdered inhaler). 50 mcg twice daily.

-Combination with fluticasone

-DO NOT USE this drug to relieve symptoms of an asthma attack. Use short-acting reliever instead.

-Use this medicine everyday even if you are feeling better.

Practice points:

-In asthma, salmeterol is not a substitute for ICS treatment and they must be used together. 

-Should not be used for acute symptom relief or in the management of acute asthma

-Duration of protection against exercise-induced asthma may decline with regular use

-Consider using the lower recommended dose of salmeterol with fluticasone in those patients with COPD who are at greater risk of corticosteroid adverse effects

-Although the lowest strengths of the combination with fluticasone are marketed for starting maintenance treatment in patients with moderate persistent asthma, the more usual approach is to begin an inhaled corticosteroid. Add a LABA agonist later if necessary.

23. Eformoterol/Formoterol [LABA]

Clinical Indications: (a) Maintenance treatment of asthma (including nocturnal and exercise-induced asthma) in patients receiving inhaled or oral corticosteroids (b) Maintenance treatment of COPD (c) Symptom relief of asthma in adults already receiving ICS and regular eformoterol.

*Combination with budesonide (ICS)

-Used for Maintenance treatment of asthma especially when it is inadequately controlled with ICS or when stabiliised on regular eformoterol and budesonide.

-Symptom relief of asthma (combinations with 6 mcg eformoterol only) in those >12 years already receiving maintenance treatment

-Longest OAA

Precautions:

1. Pregnancy-Limited experience but asthma control is most important. CAT B3-AUS

2. Breastfeeding-Should be safe to use.

*Counselling

-Use this medicine everyday even if you feel better (OXIS-Turbuhaler, Symbicort 100/6, Symbicort 200/6)

-Tell the doctor asap if patient needs to use the medication in higher doses or more frequently than prescribed

-If patient is using it for symptom relief as well as regular use, make sure the doctor has given the patient an asthma plan.

*Practice points

-In asthma. eformoterol is not a substitute for ICS treatment and must be used together.

-Should not be used for symptom relief in asthma except in patients already receiving ICS and regular eformoterol

-Duration of protection against exercise-induced asthma may decline with regular use

*Combination with budesonide in asthma

-Combination products with 6 mcg eformoterol are marketed for symptom relief of asthma in patients >12 years maintained with eformoterol and budesonide

-This is a substantial change from the usual recommendations in asthma management (in clinical trials, severe exacerbations decreased compared with other relievers, however, experience outisde clinical trials is limited).

-This regimen should be used only in appropriately selected patients (e.g. some patients may overuse relievers, thus not suitable)

-Patients with well-controlled asthma should not switch to this new regimen

-Detailed patient education and careful monitoring is quired

-Consider potential for increased adverse effects

24. Indacaterol [LABA]

Indacaterol structure(Lipophilic side chains increases DOA)

Clinical Indications: Maintenance treatment of COPD

Precautions: 

1. Pregnancy (CAT B3-AUS)

2. Should be safe to use.

Adverse effects/Side effects:

Common: Post-inhalation cough (short duration)

*Counselling

-Use this medicine everyday even if you feel better.

-Tell the doctor as soon as possible if the patients need to use this medicine in higher frequency than prescribed or in higher doses.

*Indacaterol-Longest DOA

 

10.6 Part 6: Dobutamine [Beta-1 agonist]—————————————————————————————————————————————————————————————–

25. Dobutamine

Mechanism of action: Inotropic agent (Binds to B1 receptors-Stimulate cardiac myocytes B1-adrenergic receptors), vasodilator (weak B2 receptors).

*The prinicpal hemodynamic effect of dobutamine is increase in stroke volume due to its positive inotropic action. Thus cardiac output is increased (with little increase in heart rate-minimal chronotrophy)

*Does not activate dopaminergic receptors (increase in renal blood flow that occurs in assocation with dobutamine is proportional to the increase in cardiac output).

-At infusion rates that have positive inotropic effect in humans, the B1 adrenergic effect in the myocardium predominates.

-In the vasculature, the a-adrenergic agonist effect of the (-) enantiomer is negated by the partial agonism of the (+) enantiomer and vasodilator effects of B2 receptor stimulation.

Clinical Indications: Used for short-term support of circulation in advanced heart failure. Preferred B-agonist for management of patients with end-stage systolic dysfunction and CHF. 

(a) Inotropic support in acute Heart Failure (b) Cardiogenic and septic shock

*Cardiogenic shock-based upon an inadequate circulation of blood due to primary failure of the ventricles of the heart to function effectively.

(c) Pharmacological stress testing of myocardial function.

Precautions:

1. Phaechromocytoma-CONTRAINDICATED

2. Ventricular arrhythymias-CONTRAINDICATED

3. Atrial Filbrillation-CONTRAINDICATED IN ATRIAL FILBRILLATION. There is a risk of rapid ventricular response as dobutamine facilitates atrioventricular conduction.

4. Hypovolaemia-Correct before using dobutamine.

5. Children-Not marketed use in children. Limited information available, used in paediatric and neo-natal intensive care units.

6. Pregnancy (CAT B2-AUS)

7. Breastfeeding-Contact pregnancy drug information centres

Adverse effects/Side effects: 

Common:

1. Tachycardia

2. Excessive increase in BP

3. Ventricular ectopic activity

Infrequent:

Nausea, headache, angina, palpitations, ventricular tachycardia or filbrillation, Hypotension, Shortness of breath, rash, fever, eosinophilia, bronchospasm, urinary urgency, phlebitis and local inflammatory changes following extravasculation.

*Phlebitis- inflammation of a vein, usually in the legs

Rare:

-Allergic reaction (sodium metabisulfite in products)

*Administration advice

-Dilute before use in glucose 5% or sodium chloride 0.9%. DO NOT ADD TO SODIUM BICARBONATE OR OTHER STRONGLY ALKALINE SOLUTIONS.

-It is supplied as a racemic mixture that stimulates both B1 and B2 receptor (Weak) subtypes. The (-) enantiomer is an agonist for a-adrenergic receptors, whereas the (+) enantiomer is a very weak partial agonist.

10.7 Part 7: Mixed Agonists————————————————————————————————————————————————————————————————————-

10.7.1

26. Adrenaline (Non-selective adrenergic agonist-Depends on dose administered)

10.7.1 Mechanism of Action (Acts on alpha and beta receptors) 

1. Positive inotrope and chronotrope (B1 receptors)

2. Vasodilator at low dose (B2 receptors), Vasoconstrictor at high dose (alpha receptors)

3. Bronchial smooth muscle relaxant (B2 receptors)

4. Stabilises mast cells

5. Major effects are increased systolic blood pressure, reduced diastolic pressure, tachycardia, hyperglycemia and hypokalemia

10.7.2. Clinical Indications:

(a) Cardiac Arrest (b) Inotropic support in acute heart failure and cardiogenic shock, septic shock (seek specialist advice)

(b) Anaphylatic reactions

(c) Adjunct in local anesthesia

10.7.3. Precautions

1. Pheochromocytoma-CONTRAINDICATED

2. Use in local anesthesia of fingers, toes, ears, nose or genitalia-Contraindicated

3.  Hypervolemia-Correct before using adrenaline

4. Hyperthyroidism, Diabetes-Adverse reactions are more likely

5. Occlusive or cerebrovascular disease-Increases risk of peripheral ischemia or stroke.

6. Acidosis, Hypercapnia or hypoxia-May reduce the effectiveness and/or increase the incidence of adverse effects of adrenaline

7. Closed-angle glaucoma-Increases intraocular pressure due to pupillary dilation.

8. Cardiovascular

-Use cautiously in tachycardias. Reduce dose and monitor closely.

-Heart disease (ischemic heart disease, heart failure, other arrhythmias) increases risk of arrhythmias, angina and Myocardial ischemia

-Adrenaline may increase outflow obstruction in aortic stenosis and hypertrophic cardiomyopathy

-Pulmonary hypertension may worsen due to pulmonary vasoconstriction caused by adrenaline

-Adverse reactions are more likely in hypertension or other CV disease.

9. Pregnancy-CAT A-AUS (Joe’s notes: Adr crosses the placenta)

10. Breastfeeding-Not safe???? (Adrenaline excreted in breast milk)??????

10.7.4 Adverse effects

*Common

1. Anxiety

2. Headache

3. Fear

4. Palpitations

5. Tachycardia

6. Restlessness

7. Dizziness

8. Tremor

9. Dyspnoea

10. Weakness

11. Sweating

12. Pallor

13. Hyperglycemia

*Hypercapnia- refers to an increased amount of carbon dioxide, the waste product of respiration, in the blood

Infrequent:

-Excessive increase in BP, ventricular arhythmias, pulmonary edema, angina, peripheral ischemia and necrosis (at infusion site or in local anaesthesia of fingers, toes, ears, nose or genitals)

Rare:

-Allergic reaction (sodium metabisulfite is products)

***Overdose or rapid IV administration

-Arrhythmias (ventricular and supraventricular). Severe hypertension, cerebral hemorrhage, pulmonary edema.

10.7.5 Pharmacokinetics

-OAA is rapid and has DOA

-Rapidly distributed to the heart, spleen, several glandular tissues and adrenergic nerves.

-Approximately 50% of bound to plasma proteins, Rapidly metabolised in the liver and tissues.

-Up to 90% of the IV dose is excreted as metabolites in the urine.

NOTE: *Crosses the placenta and is excreted in breast milk.

*Noradrenaline is a vasoconstrictor with minimal cardiac action.

***Administration advice

-Give via central vein if possible. If using a peripheral vein, flush dose with at least 20ml IV fluid.

10.7.5 Drug interactions:

-Do not withhold adrenaline because of concerns regarding drug interactions!

-Adrenaline can cause arrhythmias, hypertension and vasoconstriction. Risk is increased when administered with other drugs that have these effects.

-Use combination cautiously, monitor ECG, BP, and hemodynamic parameters.

1. Beta-blockers-Vaso-constrictor effects (a1-receptor) predominates. Marked hypertension followed by Reflex Bradycardia may occur

2. Entacapone-Inhibits metabolism of adrenaline. Increase heart rate and potential for arrhythmias. Reduce dose of adrenaline if necessary.

3. Linezolid-Weak, reversible non-selective MAO inhibitor. Potentiate hypertension.

4. MAOIs-Irreversible, nonselective MAO inhibitor. Inhibits Adr metabolism . Potentiate hypertension.

5. Moclobemide-Reversible inhibitor of MAO-A. Thus inhibits metabolism of Adr, which increases hypertension effects.

6. Tricyclic antidepressants-Potentiate effects of Adr. Avoid combination if possible. Reduce initial dose and monitor carefully.

27. Noradrenaline

Mechanism for action: Binds to B1, B2 predominantly. Vasoconstrictor with few cardiac effects.

Clinical Indication: Acute hypertension

Precautions: 

1. Hypertension-CONTRAINDICATED

2. Hypovolemia-Correct before using NAdr

3. Hyperthyroidism, ischemic heart disease-Increases risk of cardiovascular adverse effects

4. Pregnancy-Use with caution if required, placental perfusion may be reduced.

Adverse effects/Side effects

Common:

1. Anxiety

2. Palpitations

3. Headache

Infrequent:

-Hypertension, Bradycardia (reflex consequence of increased BP), Extravasation may cause sloughing, Necrosis and Gangrene

Rare:

-Allergic Reaction (sodium metabisulfite in product)

***Administration advice

-Dilute in glucose 5% or glucose 5% in sodium chloride 0.9%. Give via central vein if possible, if using a peripheral vein, flush dose with at least 20ml IV fluid.

Drug Interactions:

-NAdr is a vasoconstrictor and can increase BP. There may be additional vasoconstriction or increase in BP if used with other drugs that have same actions.

1. Linezolid (Weak, reversible, non-selective MAOI)-Inhibits metabolism of NAdr. Increases its effects, rseulting in hypertension. *May need to reduce dose of NAdr. Use with caution

2. MAOIs (Irreversible, nonselective inhibitor MAO)-[Drugs that are MAOIs include phenelzine, tranylcypromine). Inhibits the metabolism of NAdr. May increase  NAdr effects resulting in hypertension. Use combinations with caution. May need to reduce dose of NAdr.

3. Moclobemide (Reversible inhibitor of MAO-A). Inhibits the metabolism of NAdr. *May increase its effects resulting in hypertension. Use combinations with caution. Reduce dose of NAdr if necessary.

4. Tricycle antidepressants (TCA)-Potentiate effects of NAdr. Avoid combination if possible. Otherwise, monitor closely for dysrhythmias and hypertension. Reduce dose of NAdr if necessary.

10.8.2 Labetalol (Mixed-Depends on isomer)-Alpha blocker and B2 agonist

Labetalol(Mixed effects) (NO ISA)

-Note the two chiral centres present (4 possible steroisomers: RR, RS, SR, SS)

-Only RR (mixed, non-selective, a1 selective blocker), SR (potent a1 blocker) active.

Clinical Indications: Hypertension

Pharmacokinetics:

-Hepatic eliminated

Precautions: 

-Hepatic impaired-May require a lower dosage in impairment

*Counselling points

*Patient may feel dizzy on standing when taking this medicine. Get up gradually from sitting or lying to minimise this effect. Sit or lie down if affected.