1 - Cardiovascular Agents - Jinn

What is angina pectoris?

A condition where the coronary arteries don't supply enough blood and oxygen to the heart

Causing myocardial ischemia → low O₂ to heart tissue

Typical angina?

Caused by atherosclerotic narrowing of coronary arteries → low blood/O₂ to heart

Triggered by exercise, food, or emotional stress

Unstable angina?

Plaque rupture + platelet/thrombus formation

Inhibit platelet aggregation and thrombus formation

Variant / acute angina?

Caused by sudden coronary artery spasm → not necessarily atherosclerosis

Can occur at rest

What are the 3 main classes of antianginal drugs?

Organic nitrates

Calcium channel blockers

β-adrenergic blockers

What is the main goal of antianginal therapy?

Alleviate and prevent anginal attacks by improving blood/O₂ supply to the heart → primarily through coronary artery dilation

What are organic nitrates?

Esters of simple organic alcohols or polyols with nitric acid

Alcohol + HNO3 or HNO2

Ex: nitrate, amyl nitrate

5 members of the organic nitrates class that is still in use today?

Nitroglycerin

Amyl nitrite

Isosorbide Dinitrate

Pentaerythritol tetranitrate

Erythrityl Tetranitrate

What problems do organic nitrates have when being formulated?

Volatile → easily evaporate

Hydrolyze the ester bond with moisture → break down when exposed to water

Pure/concentrated form → requires extra caution

What types of angina can nitrates treat?

Both typical and variant

Typical → angina caused by atherosclerotic coronary narrowing

Variant → angina caused by coronary artery vasospasm

How do nitrates decrease preload?

Nitrates dilate veins → blood stays in veins → decreased blood returning to heart → decreased preload

How do nitrates decrease afterload?

Nitrates dilate arteries → decreases peripheral resistance, making it easier for blood to flow in arteries → decreased afterload

What are preload and afterload?

Preload → How much blood returns to the heart → more blood = more stretch/work.

Afterload → How much resistance the heart pumps against → more resistance = more work.

How do nitrates improve the oxygen balance of the heart?

They increase oxygen going to the heart and decrease how much oxygen the heart needs → less ischemia and chest pain

MOA of nitrates?

Nitrates → release NO / nitrous oxide → activate guanylate cyclase → increasing cGMP → decreasing Ca²⁺ → reduces Ca2+ catalyzed vascular contraction → blood vessels relax / vasodilation

Pharmaceutical preparations / dosage forms of nitrates?

Inhalation

Injection

Tablets

Capsule

Transdermal disks

Ointments

What kind of nitrates do you use for acute anginal attack?

A rapid acting preparation!

Examples of fast acting nitrates for acute anginal attacks?

Sublingual glyceryl trinitrate → onset within 2 min

Amyl nitrite by inhalation → fastest acting preparation, onset of 10-15 seconds but lasts 1 minute

Isosorbide dinitrate

What kind of nitrates are used for long acting prevention of anginal attacks?

Long acting preparations!

Examples of slow acting nitrates for prevention of anginal attacks?

Isosorbide dinitrate

Pentaerythritol tetranitrate

Erythrityl tetranitrate

What nitrite preparation can be used for both acute anginal attacks and prevention of anginal attacks?

Isosorbide dinitrate

Adverse effects of nitrites?

Headache and postural hypotension

Dizziness

Nausea and vomiting

Rapid pulse

Restlessness

What a concern with long-term use with nitrates?

Tolerance

Intermittent use of long-acting and sustained release preparations may limit the tolerance development

Drug interactions with nitrates?

Other BP-lowering drugs, alcohol, TCAs → increased risk for hypotension/orthostatic hypotension

What drugs can mess with the antianginal efficacy of nitrates?

Sympathomimetic amines → ephedrine / norepinephrine

Congestive heart failure (CHF)?

Inability to pump blood effectively at a rate that meets the needs of the tissues

Is the direct result of reduced contractility of cardiac muscles → especially reduced contractility of the ventricles

What types of medications are used to treat heart failure?

Drugs that increase the force of heart contraction

Cardiac glycosides → Digoxin, Digitoxin

Other positive inotropes → Amrinone, Milrinone, Dobutamine

Cardiac glycosides?

Naturally occuring positive inotropic drugs that increase the force of the heart’s contraction

Used to treat heart failure

Examples of cardiac glycoside drugs?

Digoxin

Digitoxin

What are cardiac glycosides composed of?

The sugar and the aglycone moiety

What is the aglycone of the cardiac glycoside?

A steroid nucleus

A-B Cis → both point up

B-C Trans → one down, one up

C-D Cis → both point up

Where are sugars attached in cardiac glycosides?

Attached to the C-3 position of the aglycone via → a β-1-4-glycosidic linkage

Most commonly found sugars → D-glucose, D-digitoxose, L-rhamnose, and D-cymarose

What cardiac glycosides come from plants?

Digitalis lanata → leaf

Digitalis purpurea → leaf

Strophanthus Kombe → seed

MOA of cardiac glycosides?

Inhibit the Na⁺/K⁺-ATPase pump → which normally exchanges Na⁺ and K⁺ across the cell membrane → increase Ca+ so heart contract harder

What are the structural requirements for intrinsic activity of cardiac glycosides?

The C-D cis ring junction → is critical

α,β-unsaturated lactone ring, A-B cis ring junction, and 14-β-OH are → not essential and can be modified without major loss of activity

What drugs can decrease cardiac glycoside absorption?

Laxatives, antacids, antidiarrheals, and cholestyramine

How can protein-binding drugs increase cardiac glycoside toxicity?

They can displace digoxin/digitoxin from plasma proteins → increasing free drug → and increasing toxicity

What are the common signs of mild-to-moderate cardiac glycoside toxicity?

Anorexia

Nausea/vomiting

Muscle weakness

Bradycardia

Ventricular premature contractions

What are the signs of severe cardiac glycoside toxicity?

Blurred vision

Disorientation

Diarrhea

Ventricular tachycardia → may progress to ventricular fibrillation

What happens during cardiac glycoside toxicity?

Na⁺/K⁺-ATPase blocked → increases Na⁺ inside → which then increases Ca²⁺ inside via the Na/Ca exchanger → toxicity

Why does hypokalemia make cardiac glycoside toxicity worse?

Low K⁺ → further inhibits the Na⁺/K⁺ pump → increases Na⁺ and Ca²⁺ inside further → increasing toxicity

How is cardiac glycoside toxicity treated?

Stop the drug and give K⁺ salt

Increasing K⁺ → stimulates Na⁺/K⁺ pump → decreasing Na⁺ inside → and decreasing Ca²⁺ inside → therefore decreasing toxicity

What is amrinone used for?

Short-term IV treatment of severe heart failure that has not responded to other treatments

MOA of Amrinone?

Inhibits phosphodiesterase in the myocardium → increases cAMP → increases heart muscle contraction

Adverse effects of amrinone?

GI disturbances

Thrombocytopenia

Impairment of liver function

How is milrinone related to amrinone?

Is an analog of amrinone and is about 10× more potent

Same MOA

Adverse effects of Milrinone?

Better tolerated than amrinone

No apparent thrombocytopenia or GI disturbances

What are B-adrenergic receptor agonists?

Drugs that stimulate β₁ receptors in the heart → increase cAMP → increase the force of heart contraction

Ex → Dobutamine, IV only

What is the major limitation of B-adrenergic receptor agonists?

Myocardial B-receptor desensitization → receptors get used to it over time

Cardiac Arrhythmias?

Is an abnormal heartbeat caused by abnormal electrical impulses in the myocardium

Manifests as an abnormal rate, site, or conduction through the myocardium

What causes arrhythmias?

Pacemaker cells don't work properly or when there is a block in electrical transmission through the AV node

What underlying diseases can cause arrhythmias?

Atherosclerosis

Hyperthyroidism

Lung disease

What are the main classes of antiarrhythmic agents?

Class I: Sodium (Na⁺) channel blockers → IA, IB, IC

Class II → β-adrenergic receptor blockers

Class III → Potassium (K⁺) channel blockers

Class IV → Calcium (Ca²⁺) channel blockers

What is a general effect of many antiarrhythmic agents?

They are negative inotropic agents

They decrease the force of heart contraction

What are Class I antiarrhythmic drugs?

Drugs that block Na⁺ channels

Slows electrical conduction in the heart

How are Class I antiarrhythmics divided?

They are divided into IA, IB, and IC based on → their effects on Na⁺ channels and cardiac action potentials

Quinidine?

Prototype Class IA antiarrhythmic

Is an alkaloid found in Cinchona bark

Adverse effects of Quinidine?

GI disturbances → nausea/vomiting, diarrhea, headache, dizziness

Anti-cholinergic effects

What is the relationship between quinidine and quinine?

Quinidine is a diastereomer of quinine

Same molecule formula/connectivity, different 3D orientation, but NOT mirror images of each other

Procainamide?

Class IA

Actions are similar to quinidine → may be effective in patients who are unresponsive to procaine

Is a non-hydrolyzable analog of procaine

Orally active

Adverse effects of Procainamide?

Drug-induced lupus syndrome

Anti-cholinergic effects

Disopyramide?

Class IA

Orally used for treatment of certain ventricular/atrial arrhythmias

Adverse effects of Disopyramide?

Anti-cholinergic effects

Lidocaine?

Class IB

Used for emergency treatment of ventricular arrhythmias

Only injection → IV

Adverse effects of Lidocaine?

CNS and cardiac effects

Dizziness, and paresthesia

Severe toxicity can lead to seizures

Tocainide?

Class IB

Similar to lidocaine → used to treat and prevent ventricular arrhythmias

Orally active

Adverse effects of Tocainide?

GI disturbance

CNS effects

Mexiletine?

Class IB

Oral activity

Similar adverse effects to those with tocainide/lidocaine

What is Phenytoin used for?

Treatment of arrhythmias from digitalis toxicity → digoxin, digitoxin

Oral / IV

Why can phenytoin toxicity occur with highly protein-bound drugs?

It is highly plasma protein bound so drugs that displace/liberate phenytoin → increase free phenytoin → leading to toxicity

Flecainide?

Class IC

Orally active

Adverse effects of Flecainide?

Can aggravate existing arrhythmias or cause new arrhythmias → can be life-threatening

Other effects include blurred vision, headache, nausea, and abdominal pain

Encainide?

Class IC

Similar to flecainide → but has less negative inotropic effect

How do Class II antiarrhythmics work?

They block β₁-adrenergic receptors → blocking the effects of catecholamines → decreasing sympathetic activity → decreasing cAMP → decreasing Ca²⁺ influx → decreasing AV node conduction.

Propranolol?

Class II

Prototype

How do Class III antiarrhythmic drugs work?

Block K⁺ channels → slow repolarization → prolong the action potential and refractory period → help prevent abnormal heart rhythms

Bretylium Tosylate?

Class III

Injection → only used in hospital setting

Adverse effects of Bretylium Tosylate?

Hypotension, including → orthostatic hypotension

Amiodarone?

Class III

Has serious side effects, only should be used for → significant ventricular arrhythmias

Common side effects of amiodarone?

Fatigue, tremor, nausea, and constipation

Serious adverse effects of amiodarone?

Lung toxicity, liver problems, arrhythmias, vision problems, and thyroid problems

It can also harm the baby during pregnancy/breastfeeding

How do Class IV antiarrhythmics work?

Block Ca²⁺ channels → slow conduction through the AV node → help control abnormal heart rhythms

Verapamil?

Class IV

Prototype drug

Adverse effects of verapamil?

Few AE with oral verapmil

IV → may lead to hypotension, bradycardia, or asystole in individuals with atrioventricular block