Drug Treatment of Angina

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

USEFUL DRUG COMBINATIONS
• Add a CCB w/ a β blocker + Nitrate
– Different mechanisms of action - additive efficacy – CCB may cause improvement if there is a vasospastive component to the angina β 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. β-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
T½ 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 T½ - 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 T½=4hrs, high dose T½=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

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