DRUG TREATMENT OF ANGINA

WHAT IS ANGINA PECTORIS?

Condition occurs when oxygen supply to the heart is insufficient to meet its demands Paroxysmal chest pain which often radiates

TYPES OF ANGINA?
Three types: 1. Typical (exertional, classic, stable) most common form (90%) due to vessel occlusion (atherosclerosis) Attacks usually occur during exercise (climbing stairs, etc.) when oxygen demand exceeds supply

TYPES OF ANGINA?
2. Variant [rest angina] due to vasospasm Attacks often occur during rest (e.g., at night)

TYPES OF ANGINA?
3. Unstable angina Increased frequency & severity of attacks Caused by atherosclerotic plaques, platelet aggregation at fractured plaques (clots) & vasospasm High risk for myocardial infarction

ANTI-ANGINAL DRUGS
1. Nitrates 2. Calcium channel blockers 3. -blockers

ORGANIC NITRATES (Nitroglycerin)

MOA OF Nitroglycerin: Nitrates are metabolised to release nitric oxide (NO) NO causes Venodilation - primary mechanism Venodilation results in decreased preload(decreased ventricular chamber size, end diastolic pressure, fiber tension) = decreased work Decreased preload results in decreased O2 demand

SIDE EFFECTS OF NITROGLYCERIN

orthostatic hypotension headache dizziness tachycardia (baroreceptor mediated)

USE OF ORGANIC NITRATES

Nitrates are the mainstay of therapy for the immediate relief of angina Low doses (usually sublingual tablets) for acute attacks & for prophylaxis Patches used for prolonged prophylaxis Tablets oral high dose; first-pass metabolism Duration of action 10-30 min Tolerance develops with long term use (commonly nightly nitrate free gaps of ~8 hrs are used)

BETA BLOCKERS (Propranolol)

MOA: Block beta receptors on the heart resulting in HR and force of contraction BP

Reduced oxygen consumption (demand) due to reduced heart rate (esp. during exercise), reduced force of contraction & reduced blood pressure during exercise.

USES OF PROPRANOLOL
1) Only for prophylaxis of exertional angina 2) Ineffective (or contraindicated) for variant angina ---- (may make attacks worse) 3) Often combined with other drug types

SIDE EFFECTS OF PROPANOLOL

fatigue insomnia erectile dysfunction Avoid use in patients with: Asthma / bronchospastic disorders bradycardia Depression

CALCIUM CHANNEL BLOCKERS (Amlodipine)

MOA of Amlodipine: Blocks calcium influx via L-type channels in cardiac and vascular smooth muscle; produce decreased force of contraction of the heart and vasodilation preload, afterload, oxygen consumption by the heart

Increase coronary blood flow (useful in vasospastic angina)

SIDE EFFECTS OF CA 2+ CHANNEL BLOCKERS Constipation Nausea Flushing dizziness

AVN & SAN depression (more common w/ verapamil)

USEFUL DRUG COMBINATIONS

Nitrate + blocker Different mechanism of action - additive efficacy blocker can prevent reflex tachycardia & positive inotropic effects caused by nitrates

USEFUL DRUG COMBINATIONS

Add a CCB w/ a blocker + Nitrate
Different mechanisms of action - additive efficacy CCB may cause improvement if there is a vasospastive component to the angina blocker can prevent reflex tachycardia caused by nitrate or CCB (& further lower HR & BP)

DRUG TREATMENT OF CONGESTIVE HEART FAILURE

WHAT IS CONGESTIVE HEART FAILURE (CCF)?

failure of the heart to provide sufficient cardiac output to meet the physiological needs of the body Congestive describes abnormal accumulation of venous blood and edema (lungs and legs). Leads to breathlessness and swelling of legs Chronic or acute

CCF
CCF: pumping action of ventricles is impaired resulting in back pressure of blood, with congestion of the lungs and liver

CAUSES OF CCF
Ischemic heart disease Hypertension Valvular heart disease Cardiomyopathies These conditions prevent the heart from providing sufficient output

TREATMENT OF CCF
Treatment objectives: 1. Reduce congestion ( edema) 2. Improve cardiac contraction and relaxation

DRUGS USED TO TREAT CCF

1. Cardiac glycosides 2. Angiotensin converting enzyme inhibitors (ACE inhibitors) 3. Angiotensin receptor blockers 4. -Blockers

CARDIAC GLYCOSIDES (Digoxin)

Extracted from the foxglove plant (Digitalis spp.) A similar drug is ouabain The main action of digoxin is on the heart

MOA OF DIGOXIN
IN CCF digoxin: force of contraction of the heart MOA: binds to Na+/K+ ATPase pump and inhibits it Increases intracellular Na+ concentrations resulting in increased intracellular Ca2+ concentrations Increased intracellular calcium concentration results in increased storage in the sarcoplasmic reticulum, which increases the FOC of the heart

MOA OF DIGOXIN
Digoxin also slows AV conduction allowing for improved ventricular filling in CCF. Also useful in Supraventricular tachycardia

DIGOXIN
Digoxin given op or iv Half life=36 hrs Interactions with amiodarone, verapamil Side effects: hypokalemia*, abdominal discomfort, nausea and vomiting

ACE INHIBITORS (Captopril, Enalapril, Lisinopril)

First line therapy for CCF MOA:
Inhibits ACE, hence inhibits the conversion of angiotensin I to angiotensin II Reduces cardiac afterload Prevents aldosterone mediated Na retention (reduces cardiac preload) Increase cardiac output

ACE INHIBITORS
T captopril 4hrs enalapril Adverse effectsElimination Hypotension, cough Renal and hepatic Renal and hepatic renal

30-35hrs same same

lisinopril >30hrs

ANGIOTENSIN RECEPTOR BLOCKERS (losartan)

MOA: block the effects of angiotensin II at the angiotensin receptor Role in the treatment of CCF not well ascertained

BETA BLOCKERS
These agents have paradoxical benefit in CCF increases cardiac output Their MOA in CCF is not well understood Suspected mechanism is up-regulation of Beta one receptor expression on the heart

BETA BLOCKERS
Selective beta- Metoprolol 1 antagonist Bisprolol Reduces death rate in CCF

Non-selective carvedilol beta antagonist

Reduces death rate in CCF

DRUGS AFFECTING THE BLOOD

DRUGS AFFECTING THE BLOOD

1. Anti-coagulant drugs 2. Thrombolytic drugs 3. Anti-platelet drugs 4. Vitamin K and plasma fractions

COAGULATION CASCADE

ANTI-COAGULANTS (heparin, warfarin)

1. Injectable anticoagulant: heparin (IV & SC). MOA: Inhibits thrombin by activating anti-thrombin III Low molecular weight heparin Unwanted effects include haemorrhage, osteoporosis, hypersensitivity rxns

ANTI-COAGULANTS (heparin, warfarin)

2. Oral anticoagulant: warfarin MOA: Inhibits the enzymic reduction of vitamin K to its active form Hydroquinone which is necessary for the formation of certain clotting factors. II, VII, IX, X Unwanted effects include haemorrhaging, teratogenicity, hepatotoxicity

CLINICAL USES OF ANTI-COAGULANTS

Prevention of: Deep vein thrombosis Thrombosis on prosthetic heart valves Clotting during haemodialysis or bypass surgery

THROMBOLYTIC DRUGS (streptokinase, anistreplase)

Clot-busting drugs: dissolve clots

Also referred to as fibrinolytics

MOA: increase fibrinolysis by increasing the formation of plasmin from plasminogen

THROMBOLYTIC DRUGS (streptokinase, anistreplase)

Streptokinase: protein extracted from streptococci which activates plasminogen (clots +circulation)

Anistreplase (APSAC): anisolyated plasminogen-streptokinase activator complex. - form of streptokinase with 4x longer T - prebound to a plasminogen molecule

ANISTREPLASE
ROA: iv Side effects: allergic rxns, hypotension given within 3hrs after ischemic stroke IV (acute attacks)-to dissolve clot

ANTI-PLATELETS (aspirin)
Aspirin MOA: Inhibits cyclo-oxygenase enzymes and hence the synthesis of thromboxanes Prevents platelet aggregation through inhibition of thromboxane A2*

Arachidonic Acid

--------

COX ASPIRIN

PGG2 & PGH2

endoperoxidases

Thromboxane A2

--------------

ASPIRIN PHARMACOKINETICS
Orally well absorbed: weak acid 50-80% PPB Low dose T=4hrs, high dose T=15hrs hydrolysed by esterases in plasma and liver (75%) to salicylate(active) and acetic acid

ASPIRIN/SIDE EFFECTS
Git effects Hypersensitivity Prolonged bleeding time nephrotoxicity Interactions with warfarin, uricosuric agents

CLINICAL USES OF ASPIRIN

Mycocardial infarction Following coronary bypass grafting Ischemic brain damage (stroke)

VITAMIN K
Fat soluble vitamin Essential for formation of clotting factors II, VII, IX and X Natural vitamin K given orally or iv Synthetic (menadiol sodium phosphate) mainly op Used in the treatment/prevention of bleeding and in vitamin K deficiencies