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

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


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.


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)


  • 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——————————————————————


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


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 


*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


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


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

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


-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


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)


Rash, Itch (due to Sulphur groups present)



  • 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+)


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.


-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



2. Diarrhea

3. Nausea

4. Vomitting

5. Hot flushes

6. Hypotension

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


1. Rash, urticaria (hives)


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


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.


Pharmacology treatment of angina-Part III (Platelets and Primary Hemostasis)

Platelets and Primary Hemostasis

What is hemostasis?

-Arrest of blood loss from damaged vessels and is essential to life. It is the whole process of stopping bleeding while coagulation includes just the clotting of plasma with the formation of fibrin.

What is thrombosis?

-In contrast, thrombosis is the pathological formation of a hemostatic plug within the vasculature in the absence of bleeding.

  • Both hemostasis and thrombosis involve same mechanisms of platelet aggregation and blood coagulation.
  • Clot: Only used to refer to blood outside of the vasculature (i.e. should use thrombus in this case, within vessels)

Hemostasis: Divided into primary and secondary hemostasis

1. Primary hemostasis (concerns with the function of vascular endothelium and platelets)

-In a nutshell, platelets adhere to damaged areas of the circulation (which release collagen) by attaching to Von Willebrand Factor (VWF) and become activated, GP 1b receptors used to bind to VWF.

-Platelets change shape, exposing phospholipids and GP IIb/IIIa receptors. This produces thromboxane A2 and ADP to stimulate other platelets to aggregate.

-Calcium ions needed to calcify primary hemostatic plug. Fibrinogen trapped in the middle but requires secondary hemostasis to convert into fibrin.

Platelet aggregation (primary hemostasis)

Summary of Platelet aggregation (Primary hemostasis)

-Link to entire video lecture: http://www.youtube.com/watch?v=UiPP_ccFX3E

-Can be measured by Complete Blood Count (CBC)

2. Secondary Hemostasis (Concerns coagulation cascade)

Intrinsic Pathway 12–>11–>9–(8)–>10–>(5)–>2 (Prothrombin)–>1 (Fibrinogen)


Extrinsic Pathway (Requires Vitamin K)

Coagulation (Intrinsic and Extrinsic Pathway)Coagulation Cascade Version 2

-Intrinsic Pathway can be measured by PT (Prothrombin Time)

-Extrinsic Pathway can be measured by PTT/INR (Partial Thromboplastin Time/International Normalised Ratio)

What are platelets? [Not true cells but are circulating fragments of a cell]

-Platelets are small, non-nucleated, biconvex discs (1.5-3.5 microns in diameter)

-Normal lifespan is 7-10 days, made in bone marrow

-Forms plugs to occlude sites of vascular damage, promote clot formation by providing a surface for the activation of coagulation factors and secrete factors involved in vascular repair.

-Contains four granule types:

(a) Alpha granules: Contains host of adhesion molecules, coagulation factors and growth factors

(b) Dense granules: Very electron dense and contains serotonin

(c) Lysosomes: Contain lysosomal enzymes

(d) Microperoxisomes: Present in small numbers and contains catalase

  • They also contain a well developed cytoskeleton with a marginal band of microtubules which depolymerises at the onset of platelet aggregation.
  • Located deep to the marginal band is the dense tubular system (DTS) consisting of narrow membranous tubules (probably the site of prostaglandin synthesis)
  • Platelets also contain interconnected membrane channels continuous with the external environment via external pits. This is the open canalicular system (OCS) and is a channel for the secretion of alpha-granule contents.

  • Also contains glycoproteins (GP) on the platelet surface or inserted into alpha-granule membrane.

-They play a key role in normal platelet adhesion or aggregation.

-GP IIb/IIIa and GP 1b are examples.

Clinical deficiencies of GP:

1. Bernard-Soulier Syndrome-Congenital lack of GP 1b. Thus hemostatic plug/thrombus is poorly formed or absent in these patients.

2. Glanzmann’s thrombasthenia-GP IIb/IIIa is missing (cannot aggregate platelets)

Platelet activation and aggregation

-In response to a variety of agonists, platelets undergo a series of changes resulting in aggregation.

(a) Coagulation system: Thrombin. Generated via coagulation pathways.

-Thrombin is a powerful platelet agonist. Platelets have specific receptors for thrombin.

(b) Extravascular proteins: When the vasculature is damaged, the removal of the endothelial layer exposes vascular basement membrane rich in collagen.

(c) Also exposes large adhesive protein Von Willebrand Factor (VWF) which binds to GP 1b/GPIX (9)/GPV (5) complex

(d) Platelets themselves: Contains stores of ADP  in the dense granules. However, ADP is a weak agonist of platelets.

-Platelets have specific receptors for ADP.

When one of these agonist has bound to the platelet, internal signal are generated. Once activated:

1. Altered expression of surface glycoproteins and high affinity to glycoprotein.

-Leads to an altered expression of already constitutively expressed surface glycoproteins (GP IIb/IIIa complexes).

-Increased GP IIb/IIIa complexes and reduced number of GPIIb-IX complexes -This is due to bi-directional trafficking of these glycoproteins between the cell surface, the surface connected canlicular system and intracellular storage.

-The ‘inside-out’ signalling leads to conformational changes in GPIIb/IIIa complexes and they develop high affinity for their ligands (esp. fibrinogen)

Fibrinogen acts as a glue that ‘sticks’ platelets together during aggregation.

2. Platelets change shape

-Platelets normally circulate as flattened discs. However when activated, they undergo shape change.

-Cells become irregularly spherical with multiple pseudopodia

-At this time, the platelets become loosely associated with each other.

-This stage is called primary aggregation and is reversible. 

-If the agonist is strong enough (e.g. if thrombin was present), the shape change continues and pseudopodia becomes more apparent/pronounced.

3. Platelet secretion

-At this stage (after pseudopodia formed), platelet secretion is observed.

-Platelet secretion involves:

(a) Biosynthesis of labile mediators (Platelet activating factors (PAF) and thromboxane A2-From the Prostaglandin pathway)

-PAF causes platelet aggregation and dilation of blood vessels.

(b) Exposure of acidic phospholipid

-This occurs on the platelet plasma membrane and acts as a site of assembly for certain coagulation factor complexes.

-The result is enhanced thrombin formation and further platelet activation as well as fibrin formation. 

Link: http://www.ncbi.nlm.nih.gov/pubmed/21958383

(c) Secretion of platelet granules

Dense granules are released first (containing ADP, calcium and serotonin)

-Alpha granules (containing adhesion molecules e.g. fibrinogen, fibronectin and thrombospondin, coagulation factors) released second

-Lysososomal granules (containing lysosomal enzymes) released last

Function of these secretory substances:

-Accelerates aggregation and cements permanent attachments between platelets.

-The most important link between platelets is formed by reaction of GP IIb/IIIa  and fibrinogen.

Question: Where does fibrinogen come from?

Answer: Derived from plasma and from platelet internal stores.

.-This aggregation is now irreversible and is know as seccondary aggregation.

After primary aggregation and secondary aggregation, the individual platelets lose their integrity and fuse with each other.

Drugs that inhibit platelet aggregation (Anti-platelet drugs):

1. Aspirin (Metabolism)

-Aspirin (acetylsalicyliate) is a prodrug which is converted to salicylic acid (salicylate) in many tissues. Primarily in GIT mucosa and the liver.

-Salicylate is a highly protein bound (approx 90%)

  • Metabolism of salicylate normally follows first order kinetics.
  • However, when large doses of aspirin taken, metabolism pathways become saturated (zero-order kinetics) and small dosage increments result in large increases in aspirin levels.

-Salicylates are excreted predominantly by the kidneys.

Plasma aspirin, rather than salicylate is required for anti-platelet effects.

-Plasma elimination half-life is approx 30 mins. Therapeutic half life 7 days!!!

-Alters the balance between Thromboxane A2 which promotes aggregation and PGI2 which inhibits it.

Mechanism of Aspirin:

  • Alters the balance between Thromboxane A2 which promotes aggregation and PGI2 which inhibits it.
  • Aspirin inactivates COX-1 in platelets by irreversibly acetylating a serine residue in its active site.
  • Reduces Thromboxane A2 in platelets and PGI2 in endothelium (platelets do not possess prostacyclin synthase to produce PGI2)

Prostaglandin, Leukotriene pathway

2. NSAIDS (Refer to Pharmacology B lecture notes: NSAIDs)

-COX-1 enzyme inhibited by NSAIDs (COX-1 Functions–>Produces molecules that affect Platelet aggregation, GI-mucosa [Protective], kidneys and lungs.

-COX-2 enzyme also inhibited by NSAIDs (COX-2 Functions–>Produce PgE2 (inflmmation)

3. Paracetamol (Refer to Pharmacology B lecture notes: NSAIDs)

-Inhibits COX-3 enzyme which is has reversible inhibition. It has central anti-pyretic and analgesic effects.

-However, it has very little anti-inflammatory effect as COX-3 not primarily responsible for producing inflammation prostaglandins.

4. Dipyridamole

Mechanism of action: Phosphodiesterase inhibitor

-Phosphodiesterase convert cAMP to AMP. cAMP inhibits platelet function hence this inhibitor (dipyridamole) increases cAMP and induces platelet inhibition.

-Beneficial effects of dipyridamole and aspirin are additive.

Side effects: Headache

5. Prostacyclin (PgI2) Analogue

-Since prostacyclin (PgI2) inhibits all platelet activation pathways (by increasing cAMP and thus decreasing cytosolic calcium), the analogues can be used.

-However, prostacyclin itself has a short half life.

-Stable analogues such as Iioprost may be useful.

Side effects associated with Iioprost: Headache, flushing (due to vasodilation)

6. Thienopyridine derivatives

(a) Clopidogrel 

Mechanism of action: Blocks ADP binding to platelet P2Y12 receptor. This reduces ADP mediated platelet activation of glycoprotein IIb/IIIa sites. Thus reducing platelet aggregation.


-t1/2: 8 hours, hepatic metabolism, extensive protein binding (96%)

-Clopidogrel is a prodrug, thus needs CYP2C19 metabolism for active to be formed.

Side effects:

-Bleeding, intracranial hemorrhage, gastric ulcers

(b) Prasugrel

Mechanism of action: Active metabolite irreversibly binds to and antagonises platelet P2Y12 receptor for the life of the platelet. Prevents ADP from binding and activatoin of glycoprotein IIb/IIIa complex


  • t1/2-7 hours
  • 98% plasma protein bound
  • Inactive Prodrug (thus must be converted by CYP3A4, CYP2B6 and to a lesser extent CYP2C9 and CYP2C19. Needs hydrolysis by intestinal carboxyl-esterases and hepatic conversion to become active.

(c) Ticlopidine

Mechanism of action: Blocks platelet-fibrinogen binding by inhibiting ADP

-Has active metabolites which are 10x more potent than the parent drug


98% plasma protein bound

(d) Ticagrelor

Mechanism of action: Ticagrelor and major metabolites reversibly bind to platelet P2Y12 ADP receptor. Antagonises ADP and prevents platelet activation


-Ticagrelor and active metabolite are 99% plasma protein bound

-Ticagrelor is a substrate and inhibitor of CYP3A4

7. Glycoprotein IIb/IIIa complex inhibitors

(A) Abciximab (humanised monoclonal antibody)


-Initial phase t1/2 of less than ten minutes and a second phase half life of about 30 mins (related to rapid binding to the platelet IIb/IIIa receptors)

-Platelets recover in 2 days.

Adverse effects: Allergic reaction against monoclonal antibodies, increasing risk of thrombocytopenia.

(B) Eptifibatide (cyclic heptapeptide blocking agent)


-Protein binding 25%

-No major metabolites detected in blood, but deamination takes place in the urine

-In patients with coronary artery disease, the mean clearance of eptifibatide is 55-80 ml/kg/hour

-t1/2 is 2.5 hours

Adverse effects: Bleeding/ thrombocytopenia, care in renal and hepatic dysfunction

(C) Torofiban (non-peptide antagonist)

-Bind/block glycoprotein IIb/IIIa receptor and so prevent fibrinogen binding to

platelet. This leads to decreased platelet agggregation.


-Urinary and biliary excretion

-Half life-1.5 hours

Adverse effects: Bleeding/ Thrombocytopenia

Pharmacological treatment of Angina-Part I


-Cardiac myocytes extract  60% of oxygen out of the coronary artery whereas skeletal muscle only extracts 20%.

1. 1 Organic Nitrates (Decrease Oxygen Demand)

(a) Introduction:

-Nitrate esters (-C-O-NO2)and nitrite esters (-C-O-NO)

-Glyceral trinitrate/Nitroglycerin (Not a nitro compound but a organic nitrate compound)

-Organic nitrates of low molecular mass (e.g. nitroglycerin) are volatile (dosage form considerations), oily liquids

-High molecular mass  (e.g. erythrityl tetranitrate, isosorbide dinitrate, isosorbide mononitrate) are solids (dosage form considerations)

Organic nitrates + Nitrites => Collectively known as Nitrovasodilators (Non active)

***They must be reduced by aldehyde dehydrogenase (in vivo) to produce free radical Nitric Oxide (NO) which is the active component of the drug

(b) Mechanism of action:

NO must be formed

-Nitrites, organic nitrates, nitroso compounds, nitrogen oxide containing substances (including nitroprusside) can lead to NO formation

Organic nitrates

-NO activates GC, activates PKG, Modulates activities of Phosphodiesterase (PDE), reduces breakdown of cGMP and cAMP in endothelial cells and smooth muscles.

In smooth muscles, NO mediated increase in intracellular cGMP would activate PKG which leads to

*reduced phosphorylation of myosin light chain (MLK) and reduced calcium ion concentration in the cytosolol

*Vasodilation (Vasorelaxation)

1.2 Effects of Nitric Oxide

1) Cardiovascular effects: Hemodynamic Effects (Blood flow/Circulation effects)

At low concentrations of Nitroglycerin,

-Veins are preferentially dilated compared to arterioles

-The venodilation decreases left and right ventricular chamber size and end-diastolic pressures.

-However, there is little change in systemic vascular resistance (because arterioles are not significantly dilated). Systemic arterial pressure may decrease slightly, no change or slight increase in heart rate (baroreceptor reflex).

*Venous return to the heart affected, preload is decreased.

*****Therapeutic Point: Dose of nitroglycerin don’t alter systemic arterial pressure often produce arteriolar dilation in the face and neck, resulting in flush or dilation in the meningeal arterial vessels, resulting in headache.

At high concentrations of Nitroglycerin,

-Furthur venous pooling occurs

Aterioles are dilated (resulting in decreased arteriolar resistance)

-This decreases systolic and diastolic blood pressure (Decreases preload and afterload–>Reduces cardiac workload) and cardiac output (CO)

*Adverse effects:

1. Pallor (reduced amount of oxyhemoglobin in the skin)

2. Weakness, dizziness and activation of compensatory baroreceptor-mediated sympathetic reflexes

-Reflex tachycardia and peripheral arteriolar vasconstriction tend to restore systemic vascular resistance.

-Coronary blood may increase transiently due to vasodilation of coronary arteries but may decrease due to baroreceptor reflex which occurs if BP and CO drop too much.

2) Cardiovascular effects: Effects on Total and Regional (flow of blood through/around an organ) Blood Flow

(a) ***Ischemia is a powerful stimulus to coronary vasodilation

***Regional blood flow is adjusted by auto-regulatory mechanisms

Autoregulation: To increase blood flow to starved tissues and NO assist to restore blood flow

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

Cardiac catheterization and coronary angiography i

(b) Significant coronary stenoses disproportionately reduce blood flow to the subendocardial regions of the heart

-These regions are subjected to compression of vessels during systole (less blood flow to subendocardial regions)

***For (a) and (b), Organic nitrates tend to restore blood flow in these regions. This is due to the ability of organic nitrates to cause dilation and prevent vasoconstriction of large epicardial vessels without impairing autoregulation in the small arterial vessels (unlike sildenafil, sodium nitroprusside and dipyridamole).

This results in an increase in blood flow which would be distributed preferentially to ischemic regions due to vasodilation induced by autoregulation.

*This is known as vascular steal (the diversion of blood to ischemic regions)

Vascular steal

-Nitric Oxide dilates collateral blood vessels (extra blood vessels that connect portions of the same artery)–>Blood flow to the ischemic area increased.

3) Cardiovascular effects: Effects on Myocardial Oxygen Requirements

-Organic nitrates reduce myocardial oxygen demand (increase systemic circulation means more blood flow to visceral, afterload and preload decreases)

-These nitrate drugs increase venous capacitance (circulation) which results in decreased venous return to the heart. This decreases ventricular end-diastolic volume and pressure (less preload, distention of myocytes). This reduces oxygen demand/ consumption.

Decreasing pheripheral arteriolar resistance (at high concentrations of nitrates) reduces afterload and thus cardiac work and oxygen consumption. Reduces oxygen demand.

Thus, Organic nitrates decreases both preload and afterload as a result of dilation of venous capacitance and arteriolar resistance vessels.

4) Cardiovascular effects: Relief the symptoms of Angina Pectoris

-Nitrates reduce angina pain due to

  • Fall in systemic arterial pressure (Major factor)
  • decrease in cardiac work (secondary factor)
  • Also, dilation of epicardial coronary arteries (outermost layer)

***However, high doses of organic nitrates may reduce blood pressure to such an extent that coronary flow is compromised.

 Reflex tachycardia and adrenergic enhancement of contractility also occur

-These effects may override the beneficial action of the drugs on myocardial oxygen demand

1.3 Pharmacokinetics of Organic nitrates: Absorption, Fate and Excretion

Absorption: **Peak concentrations of nitroglycerin are found in the plasma within 4 mins of sublingual administration of tablet

Fate: Drug only has half life t1/2 of 1-3 minutes.

Metabolism: No 1st pass metabolism, rapid entry

Note: Onset of action of nitroglycerin more rapid if delivered as sublingual spray

-Angina pain may be prevented when drug is used prophylatically immediately prior to exercise, sex or stress

***Very important Therapeutic Point:

If patients do not get pain relief from 3 nitrate tablets over 15 mins, myocardial infarction (Heart attack) may have occurred and medical attention should be sought immediately.

(i.e. 1st spray/tablet–>Wait 5 mins–>If pain still persists, take another tablet/spray and call the ambulance)

Dosage forms available: Sprays/Tablets/Patches

-Transdermal nitroglycerin disks use nitroglycerin impregnated polymer that permits gradual absorption and continuous plasma nitrate concentration over 24 hours.

-The onest of action is slow, with peak effects at 1-2 hours

Tolerance: Avoid continuous use. Therapy should be interrupted for at least 8 hours a day. (Advise patients to use during day time where physical activities are highest)


1.4 Types of organic nitrates:

  • Isosorbide Dinitrate (ISORDIL)-Sublingual route (Unstable half life)

Administration route: Sublingual,  maximal plasma concentrations of the drug by 6 mins.

Pharmacokinetics: Half life of ~45 mins

Metabolism: Major route is by enzymatic denitration (aldehyde dehydrogenase) followed by glucorinide conjugation.

*Initial metabolites: Isorbide-2 mononitrate and isosorbide-5 mononitrate have a longer half life (3-6 hours) and contribute to therapeutic effects.


*Therapeutic point: Sublingual organic nitrates (e.g. glyceral trinitrate) should be taken at the time of angina attack or anticipation of exercise or stress.

However, continuous exposure to high doses of organic nitrates leads to attenuation/tolerance.


  • Isosorbide 5-mononitrate (IMDUR)-Tablet (Relatively more stable)

+ Does not undergo significant first pass metabolism and has excellent bioavailability after oral administration

+IMDUR has a significantly longer half life than isosorbide dinitrate, thus formulated as a plain tablet or sustained release preparation


+Both of these dosage forms have significantly longer durations of action than the corresponding dosage of isosorbide dinitrate. 


-Tolerance has also been observed with isosorbide 5 mononitrate (IMDUR). A daily p.o dosing schedule maintains efficacy.



Tolerance… Why does it occur?

-As mentioned previously, continuous high doses of glyceryl trinitrate (sublingual use) will  lead to attenuation/tolerance.

1. Tolerance may result from reduced capacity of the vascular smooth muscle to convert nitroglycerin to NO (true vascular tolerance) [i.e. vascular smooth muscle cannot convert nitroglycerin to NO well]

-Inactivation of aldehyde dehydrogenase enzyme required to generate nitric oxide from organic nitrates implicated in nitroglycerin biotransformation.

-A reactive intermediate formed (superoxide) during generation of nitric oxide from organic nitrates may itself damage and inactivate the enzymes of the activation pathway.

2. Also, activation of mechanisms extraneous to the vessel wall (pseudotolerance) may occur as well [i.e. net reduction in vasodilator response due to neurohumoral response-mediated vasoconstriction]


***Therapeutic point: A good way to avoid tolerance is to interrupt therapy for at least 8 hours -12 hours (preferentially 10 hours) daily to restore efficacy.


-Usually patients with exertional (stable) angina are advised to omit dosing at night. Oral or Buccal dosages can be adjusted accordingly. Also, patches of nitroglycerin can be removed.


Note: Patients whose angina pattern occurs in association with orthopnoea (shortness of breath when lying flat) or paroxysmal nocturnal dyspnea (sudden attack of breathlessness which occurs at night), may benefit from continuing nitrates at night and omitting them during a quiet period of the day.


-Tolerance has also been observed with isosorbide 5 mononitrate (IMDUR). A daily p.o dosing schedule maintains efficacy.



1.5 Adverse effects/Side effects/Toxicity


1. Headache is common

-(vasodilation of meningeal vessels) Decreases over few days if treatment is continued and responds to decreasing doses. [Esp. low doses]


2. Dizziness, weakness and postural hypotension may develop

-(Due to vasodilation in peripheral vessels). Blood accumulates in periphery. Reaction is worsened by alcohol.


3. Syncope (loss of consciousness-fainting)

-Remedies include positioning head low and facilitating venous return.


4. Rashes

-All organic nitrates can occasionally produce rash (excessive vasodilation?)


5. Monday Morning disease

-Development of tolerance over work week. Over the weekend, the tolerance is lost and on monday, headache occurs due to drastic vasodilation.


6. Reflex tachycardia

-Occurs with high doses of nitric oxide.

-Baro-receptor mediated reflex


7. Erectile dysfunction

-Erectile dysfunction is a frequently encountered problem whose risk factors are similar to those with coronary artery disease (CAD)

-People with erectile dysfunction tend to also have diabetes which inhibits circulation, leads to circulation problems.


1.6 Drug interactions associated with nitrates


-As mentioned above, erectile dysfunction is a common problem.

-If nitrates were taken with erectile dysfunction medications (i.e. phosphodiesterase 5 inhibitors-Sildenafil, tadalafil and vardenafil), dramatic reduction in blood pressure occurs.




-cAMP and cGMP both causes smooth muscle dilation–>Relaxation

-PDE 5 breaksdown cAMP and cGMP (thus reducing muscle dilation–>Contraction)

-Since PDE 5 inhibitors prevents breakdown of cAMP and cGMP, it will prevent smooth muscle from contracting.

-In the presence of Nitrates, dramatic increase in cGMP will dramatically reduce blood pressure.

-Thus, all 3 PDE5 inhibitors are contraindicated in patients taking nitrodilators.






Questions associated with organic nitrates:


1. Difference between glyceryl trinitrate and isosorbide dinitrate (ISODRIL)

2. Does the 8 hour of non-continuous use daily mean that 2 x 4 hour intervals is equivalent?

3.  Why does organic nitrates cause rash? Due to excessive vasodilation?

4. Interactions with beta blockers? Calcium channel blockers?


Angina Pectoris -mismatch between oxygen demand and oxygen supply

Angina Pectoris

-‘strangling feeling in the chest’

Chest pain resulting from low blood supply to cardiac muscle

Main cause of Angina: Coronary Artery Disease (CAD)

-Imbalance between heart’s oxygen demand and supply.  Either an increase in myocardial  oxygen demand or decrease in myocardial oxygen supply.

Factors that would increase myocardial oxygen demand or decrease myocardial oxygen supply: 

Age, Smoking, Diabetes Mellitus (DM), Dyslipidemia (abnormal amount of lipids in blood-usually hyperlipidemia), Family history of cardiovascular disease, Hypertension, Kidney Disease (esp. microalbuminuria  or GFR<60ml/min), Obesity, Physical inactivity and prolonged psychosocial stress.

-Symptoms: Chest Discomfort (a pressure,heaviness or tightness, choking sensation). Separately, discomfort may also be experienced in the back, neck, jaw or shoulders (referred pain)  and shortness of breath (dypsnea).

*Pain may/may not be accompanied with breathlessness, sweating and nausea.

-Myocardial ischemia occurs when heart muscles receive inadequate supply of blood and oxygen to function normally either because of increased oxygen demand or decreased supply to myocardia (tissue hypoxia occurs)

-This inadequate perfusion of blood could be due to blocked or narrowed arteries (artherosclerosis).

1) Inadequate oxygen delivery

Inadequate oxygen transfer from lungs to blood.

-Inadequate delivery of oxygenated blood to cells (ischemia) due to low cardiac output (CO) which is determined by :



by the back pressure against the aortic valve (diastolic blood pressure-preload)

which the heart must push against the valve to deliver the blood


Increased Heart Rate (HR)=Increased Workload=Increased CO=Increased oxygen demand

Increased stroke volume (SV)=Increased Workload=Increased oxygen demand

Increased Stroke volume (SV)=Increased stretch of heart muscle which increases contractility or how hard the muscle contracts=Increased Workload=Increased oxygen demand

Increased diastolic BP=Increased workload to open aortic valve=Increased oxygen demand

The treatment of angina should then:

(a) Increase supplemental oxygen to the heart, deliver oxygen enriched blood via an adequate perfusion pressure (Increases oxygen supply)

(b) Dilate coronary arteries to increase flow of oxygen-enriched blood around any blockage to reach hypoxic cardiac muscle. (Increases oxygen supply)

(c) Decrease the workload of the heart to reduce oxygen demand

-Decrease preload by dilating the large veins, which decreases blood return to the atria and ventricles. This decreases stroke volume, which decreases cardiac output and thus decreases cardiac workload.

-Decrease afterload by dilating the large arteries, which decreases the diastolic BP, decreasing the amount of pressure the heart has to generate to open the aortic valve, which decreases cardiac workload.

-Decrease heart rate and contractility which will decrease Cardiac output, which will decrease cardiac workload.

Conditions that increases Oxygen supply

3.During increased heart rate

Conditions that decrease Oxygen supply 

1.Coronary arteries diseases
—Accumulation of plaques
—Platelets aggregation
—Stenosis or spasm or constriction or narrowing
2.Reduction in blood flow to heart
—Due to constriction of blood vessels
3.Reduction in o2carrying capacity of blood
—Decrease Hb levels (in anemic conditions)
—Normal blood flow  and supply but decrease in o2 carrying capacity

Types of Angina:

1) Stable Angina (Effort angina)- Chest pain due to ischemia of the heart muscle (generally due to obstruction/spasm of the coronary arteries-Decreases oxygen supply)

Therapeutic treatment outcome: Improves balance of myocardial oxygen supply and demand (Decrease workload of heart)

(a) By increasing supply by dilating the coronary vasculature

(b) Decreasing demand by reducing cardiac work (Reducing CO)

*Most Drugs target (b) by decreasing heart rate, decreasing myocardial contractility (increase ESV, decreases SV), decreasing ventricular wall stress (decreasing preload, EDV by reducing the stretch of myocytes)

2) Prinzmetal Angina (Invariant)-Cornary artery spasm /Non-Exertional Angina

Due to: Spasms in the arteries that supply blood to the heart. Temporary constriction in one or more of the coronary arteries leads to lack of oxygen supply and nutrients (i.e. Reduced blood flow–>Reduced blood supply)

-Coronary vasoconstriction results in reduced blood flow and ischemic pain.

-Occurs in people aged 50 or younger

Severe and lasts more than 15 mins (DOES NOT GO AWAY!)

-Discomfort or pain usually in the early hours of the morning. Occurs more often during rest or extreme motion rather than physical activity.

Root cause: Unknown but females with a family history of coronary heart disease or aggressive behaviour (Type A) personality would increase risk. Drugs such as antibiotics, medicines and chemotherapy medications could precipitate CAS.

Recreational Drugs such as cocaine, Amphetamine, alcohol can also cause CAS.

Therapeutic treatment outcome: Prevent coronary vasospasm

Note: Calcium channel blockers, but not nitrates influence mortality and the incidence of Myocardial infarction favourably in variant angina.

Why? Ans: Calcium channel blockers (e.g. Verapamil or Diltiazemmay reverse coronary spasm refractory (Symptoms reoccur despite therapy) to intracoronary nitroglycerin.

In addition to relaxation of vascular smooth muscle, Calcium channel blockers also produce negative inotropic effects (decreases force) and chronotropic effects in the heart (decreases heart rate).

NO, on the other hand, has effects on vascular smooth muscle. The use of high doses of organic nitrates may reduce blood pressure  to an extent that coronary flow is compromised, thus reflex tachycardia occurs (overrides benefical effect on oxygen demand–>aggrevate ischemia) 

3) Unstable Angina-Acute coronary syndrome

-Pathophysiology: Due to the reduction of coronary blood flow due to the transient platelet aggregation on apparently normal endothelium, coronary artery spasms or coronary thrombosis.

-Process usually starts with artherosclerosis (building up of plaque which undergoes thrombosis and results in ischemia, resulting in cell necrosis)

-Occurs at rest (minimal exertion) and last for more than 10 mins

-Severe and/or occurs with a crescendo pattern (i.e. intensifies over time)

Indication of an impending heart attack

Therapeutic treatment outcome: Increase myocardial blood flow

(a) Use of anti-platelet agents and heparin to remove blood clot in coronary arteries

(b) Coronary by pass surgery to restore blood flow via mechanial means

(c) Use of coronary stents (balloons) to artificially dilate the coronary arteries so as to restore blood flow

Coronary Artery Bypass Graft

***Definition of key terms:

  • Stroke Volume: The volume of blood pumped from one ventricle of the heart with each beat.


  • End-Diastolic Volume (EDV): Refers to the volume of blood in the right/left ventricle at the end load or filling in (Diastole). For an average man EDV approx 120 ml

Main factors affecting EDV are due to venous compliance. Increasing venous compliance means that the veins can be stretched more which implies more blood can be held in the periphery. Thus, venous return DECREASES and reduces EDV.

  • End-Systolic Volume (ESV): Refers to the volume of blood in a ventricle at the end of contraction or systole (beginning of diastole). For an average man ESV approx 50 ml, represented by the end of a T wave.

Main factors affecting ESV are afterload and contractility of the heart (Increase in contractility of the heart means lower End-Systolic Volume). 

  • Afterload: (aorta) The resistance to ejection during systole (the force opposing ventricular ejection). The ventricle must overcome aortic pressure in order to eject blood.

Increased afterload = increased workload and decreased cardiac output and slower contraction (More resistance)

Main factors affecting afterload: Aortic pressure and systemic vascular resistance

–>When afterload increases, there is an increase in end-systolic volume and a decrease in stroke volume.

  • Preload: End volumetric pressure that stretches the left or right ventricle of the heart to its greatest dimensions under physiological demands (i.e. the initial stretching of cardiomyocytes prior to contraction)

–>The pressure at the end of diastole (filling of ventricles)…aka left ventricular end diastolic pressure. Partial reflection of volume present in ventricles. 

Factors affecting preload: Influenced by venous return. Increased preload (to a point) = Increased cardiac output (More blood pumped out)

  • Ejection volume: Represents the volumetric fraction of EDV pumped out of the ventricle (heart) with each heart beat


  • Cardiac Workload: The amount of work the heart has to do to pump blood throughout the body.

-Main factors: Amount of blood pumped from left ventricle to the rest of the body + Arterial resistance + Strength and frequency of muscle contractions