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
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
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
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
• 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
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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