PHAR301 - Myocardial Ischemia

What is myocardial ischemia?

A disease where there is an imbalance between the supply and demand of oxygen in the heart muscle.

Arteriovenous oxygen difference is near maximum in coronary circulation. Therefore, redistribution of regional myocardial flow is of major importance.

What is the main symptom of myocardial ischemia?

Angina pectoris: chest pain.

The pain is caused by transient episodes of myocardial ischemia, where metabolites accumulate in the heart muscle.

What are the manifestations of angina pectoris?

Stable angina,

Unstable angina,

Silent/effort ischemia,

Variant angina,

Myocardial infarction.

What is stable angina?

Atherosclerotic block of a coronary artery.

What is unstable angina?

Rupture of an atherosclerotic plaque.

What is silent/effort ischemia?

Ischemia induced by exercise.

What is variant angina?

Focal/diffuse coronary vasospasm.

what is atherosclerosis?

Deposition of fatty substances (mainly cholesterol) or fatty acids in arteries.

What are the associated risk factors of atherosclerosis?

Hypertension,

Hyperlipidemia,

Obesity,

Carbon monoxide in smoke,

Sedentary lifestyle

True or false: coronary artery spasms are a cause of myocardial ischemia (narrowing of blood vessels).

True

True or false: coronary artery spasms may be of unknown cause, and may occur in patients with or without atheroscleorsis.

True

What are some risks factors associated with coronary artery spasms?

Smoking,

Stress

How does atherosclerosis develop?

Accumulation of lipids in the blood vessels cause blood vessel damage.

Results in plaque formation due to inflammation (accumulates foam cells, macrophages, LDLs).

Results in narrowing of blood vessel lumen and reduced oxygen supply.

What are the two types of plaque in atherosclerosis?

Endothelium-smooth muscle interface: elevation in the repaired endothelium.

Ruptured lesion in the endothelium: ulcer that protrudes into the lumen.

What is a non-drug treatment of myocardial ischemia?

Change in lifestyle: lean diet, cardiovascular exercise.

What are the three drugs for symptomatic treatment of myocardial ischemia?

Nitrates,

Ca2+ channel blockers,

Beta-blockers

What are the four routes of prophylactic treatment for myocardial ischemia?

Lipid lowering drugs,

Anticoagulants,

Fibrinolytic,

Anti-platelet.

What are the four classes of lipid-lowering drugs?

Statins, resins, niacin, fibrates

What are two anticoagulant drugs?

Warfarin, heparin

What are two fibrinolytic drugs?

Streptokinase,

Tissue plasminogen activator.

What are two anti-platelet drugs?

Aspirin, ibuprofen,

Ticlopidine, clopidogrel

What is the principle of prophylactic therapy of myocardial ischemia?

Slowing the development of ischemia by affecting coagulation, fibrinolysis, platelet aggregation, and lowering lipids.

What is the principle of treatment of symptomatic myocardial ischemia?

Improving coronary flow via vasodilators and cardiac depressants.

Name a nitrate.

Nitroglycerin

What are the indications for nitroglycerin?

Effort angina,

Variant angina,

Acute coronary syndrome.

What is the mechanism of action of ntirates?

Reduction of venous return, cardiac size, and diastolic myocardial consumption.

They activate guanylyl cyclase to cause vasodilation, increasing blood flow.

What are some side effects of nitroglycerin?

Orthostatic hypotension,

Tachycardia,

Headache

Name three Ca2+ channel blockers.

Verapamil, Nifedipine, Diltiazem

What are the indications of Ca2+ channel blockers?

Prophylactic:

Effort angina,

Variant angina

What is the mechanism of action of Ca2+ channel blockers?

They trigger peripheral vasodilation and reduce cardiac work by reducing arterial constriction.

What are some side effects of Ca2+ channel blockers?

Orthostatic hypotension,

AV blockade,

Edema

What is are some indications of beta-blockers for myocardial ischemia?

Effort angina,

Acute coronary syndrome

What is the mechanism of action of beta-blockers in the treatment of myocardial ischemia?

Reduction of blood pressure, which reduces cardiac work.

What are some side effects of beta-blockers?

Orthostatic hypotension,

Tachycardia,

headache

What are the effects of the heart rate, arterial pressure, end-diastolic pressure, contractility, and ejection time with the use of nitrates alone?

Reflex increase in HR,

Decrease in arterial pressure,

Decrease in end-diastolic pressure,

Reflex increase in contractility,

Reflex decrease in ejection time.

What are the effects of the heart rate, arterial pressure, end-diastolic pressure, contractility, and ejection time with the use of beta-blockers or Ca2+ channel blockers alone?

Decrease in HR,

Decrease in arterial pressure,

Increase in end-diastolic pressure,

Decrease in contractility,

Increase in ejection time

What are the effects of the heart rate, arterial pressure, end-diastolic pressure, contractility, and ejection time with the combined use of nitrates and beta-blockers or Ca2+ channel blockers?

Decrease in HR,

Decrease in arterial pressure,

Decrease in end-diastolic pressure,

Decrease in contractility,

No effect on ejection time.

What are some clinical options for the treatment of atherosclerosis?

Dietary changes to reduce cholesterol and lipids,

Cessation of smoking,

Control of blood pressure,

Control of diabetes,

Regular, moderate exercise,

Drugs to reduce plasma cholesterol.

What is the goal of lipid lowering drugs in the treatment of myocardial ischemia?

Prevention of myocardial infarction and other atherosclerotic disorders such as stroke and peripheral vascular disease, prevent reinfarction, and increase survival.

In general, how do lipid lowering drugs have a prophylactic effect against myocardial ischemia?

They reduce the formation of plaque and subsequent narrowing of the lumen in cardiac arteries.

What are the two sources of choleserol?

Dietary,

De novo synthesis by the liver (HMG-CoA reductase).

What is the role of VLDL in the transport of lipids?

VLDL transports cholesterol and triglycerides to be deposited in adipose tissue and muscle after lipolysis lipase.

What is the role of LDL in the transport of lipids?

It transports cholesterol to the arteries, where it may collect in artery walls. Too much cholesterol in the arteries may lead to a buildup of plaque, increasing the risk of blood clots in the arteries.

Blood clots break up and can block an artery in the heart or brain, causing a heart attack or stroke.

What is the role of HDL in the transport of lipids?

It transports cholesterol to the liver to be expelled from the body.

HDL helps ride the body of excess cholesterol so it's less likely to end up in the arteries.

What are the four strategies of lipid lowering drugs?

Inhibition of cholesterol synthesis (inhibition of HMG-CoA reductase),

Prevention of cholesterol reabsorption (resins),

Reduction of VLDL secretion (niacin),

Increased synthesis of lipoprotein lipase (fibrates).

Which drugs inhibit the synthesis of cholesterol? Give an example.

Statins, e.g. Lovastatin

What is the mechanism of action of statins?

inhibition of HMG-CoA reductase; blocks de novo synthesis of cholesterol.

What are some side effects of statins?

May damage skeletal muscle or liver.

Interference with myelination of infants.

What drug prevent cholesterol reabsorption? Give an example.

Resins, e.g. cholestyramine

What is the mechanism of action of resins?

They are non-absorbable macromolecules that bind cholesterol, thus preventing reabsorption from the gut.

What are some side effects of resins?

They have an unpleasant gritty taste,

GI tract discomfort,

interference of vitamin or drug absorption

What drug reduces the secretion of VLDL?

Niacin (nicotinic acid, vitamin B3).

What is the mechanism of action of niacin?

Its action is not well understood; though, there is a decrease in the secretion of VLDL particles from the liver.

What are some side effects of niacin?

Occasional flush with itching (reduced with aspirin),

Rarely causes glucose intolerance

Which drug causes an increase synthesis of lipoprotein lipase? Give an example.

Fibrates, e.g. gemfibrozil

What is the mechanism of action of fibrates?

Activation of peroxisome proliferation-activated receptor-alpha which increases lipoprotein lipase synthesis.

What are some side effects of fibrates?

Nausea,

Skin rash,

Occasional increased risk of gallstones

What are the three approaches for drugs which affect plaque formation?

Inhibition of blood coagulation (blood thinners),

Inhibition of platelet function,

Stimulation of lysis of pre-formed thrombus.

Which two drugs inhibit blood coagulation?

Warfarin, heparin

What is the mechanism of action of Warfarin?

Blocking of reactivation of vitamin K epoxide.

Blocking of coagulation factors II, VII, IX, and X

What is the mechanism of action of heparin?

Binding of coagulation factor Xa and antithrombin III.

What is the difference between high molecular weight and low molecular weight heparin?

HMW heparin binds coagulation factors Xa and antithrombin III; its effects must be monitored.

LMW heparin only inhibits factor Xa; it has a predictable response and dose not need to be monitored.

What is the indication of anticoagulants?

Prevention and treatment of venous clotting, especially in deep vein thrombosis.

What are some side effects of anticoagulants?

Teratogenic, bleeding

What is the general action of a fibrinolytic drug?

It activates endogenous plasminogen to plasmin.

Plasmin is an enzyme that breaks down fibrin, dissolving blood clots.

What is the mechanism of action of streptokinase?

It converts plasminogen to plasmin.

What is the mechanism of action of tissue plasminogen activators?

Activation of plasminogen bound to fibrin.

What is a difference between streptokinase and tissue plasminogen activators?

Streptokinase is cost-effective,

tPA is expensive

What is the indication for fibrinolytic drugs?

Pulmonary embolism and myocardial infarction

What are some side effects of fibrinolytic drugs?

Allergic response (streptokinase),

Bleeding

What is the process of platelet aggregation?

Lesion in the wall releases collagen,

Collagen activates platelets,

Release of thromboxane A2,

Secretion of adenosine diphosphate (ADP),

Thromboxane A2 is a potent aggregating agent and vasoconstrictor,

Thromboxane A2 and ADP stimulate the appearance of fibrinogen binding sites on the platelet membrane.

What are two classes of anti-platelet drugs? Give two examples for each class.

Cyclooxygenase inhibitors: Aspirin, ibuprofen.

Adenosine receptor blockers: ticlopidine, clopidogrel.

What is the mechanism of action of COX inhibitors?

They inhibit COX I, which prevents the synthesis of thromboxane A2, and prevents platelet aggregation.

What is the indication for COX inhibitors?

Transient ischemic attacks and myocardial infarction.

What is a side effect of aspirin?

GI ulcers.

What is the mechanism of action of adenosine receptor blockers?

They inhibit the platelets' response to secreted ADP and adenosine receptors.

They are also an alternative to aspirin (when allergic).

What is the indication for adenosine receptor blockers?

Transient ischemic attacks and myocardial infarction.

What are some side effects of adenosine receptor blockers?

Bleeding,

Skin rashes.