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

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

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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.

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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)

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  • 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.

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