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.

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