Drugs for Heart failure & Angina Department of pharmacology Liming zhou 2010,3

Q. Importance of Heart Failure A common & fatal cardiovascular (CV) diseases. 20% die within 1 year of diagnosis & 50% within 5 years Increases with age- more men and more risk if high BP. Decline in death from other CV diseases since 1980 – but not heart failure ?

Q. What is heart failure ? INABILITY OF THE VENTRICLES TO PUMP ENOUGH BLOOD TO MEET METABOLIC DEMANDS Not a distinct disease – associated with several disorders No cure for Heart failure (HF): prevent, treat & remove underlying cause. Effective drug treatment removes symptoms & prolong life.

Q. What are the disorders associated with heart failure ? DISEASE DESCRIPTION Mitral stenosis mitral valve fault Myocardial infarction clot in coronary arteries Chronic hypertension high blood pressure Coronary artery disease atherosclerosis Diabetes lack of insulin

DEVELOPMENT OF ATHERO-SCLEROTIC PLAQUES

Q. What is the Physiological consequence of Heart Failure ? In HF myocardium weakened – heart cannot reject all blood it receives Weakening on left side: blood accumulates in left ventricle – walls thicken- blood backs-up to lung cough & shortness of breath Weakening of right side: blood backs-up to peripheral veins – odema of feet/ankles/liver Or failure on both sides

Q. What are the common Symptoms of heart failure ? Progressive chronic disorder Anxiety/Restlessness Persistent cough Rapid breathing Fast Heart Rate Edema of lower limbs Skin cyanotic & clammy

General Anatomy of the human Circulatory System Arteries carry blood away from heart Veins return Blood to heart Valves Ensure Blood flows in one direction Heart Atrium: receives blood returning Ventricle:pumps blood out Right side of heart receives blood from tissues & sends to lungs for oxygenation Left side of heart receives newly oxygenated blood from lungs & pumps to tissues. IN HEART FAILURE ATTEMPT TO MAINTAIN HOMEOSTASIS

Non-Pharmacological Therapy In early stages stop smoking & limit alcohol limit sodium intake – food rich in k + & Mg 2+ exercise plan understand how to reduce stress reduce weight to optimal limit caffeine

Q. What drug classes are used for HF ? 1. Cardiac Glycosides 2. Angiotensin Converting Enzyme Inhibitors 3. Vasodilators & Diuretics 4. Phosphodiesterase Inhibitors 5. Beta- Adrenergic Blockers

Cardiac Glycosides: Digoxin Known for 2000 years – from Digitalis Still widely described for lung congestion/peripheral edema

Mode of action: Inhibits Na/K ATPase & effects resting membrane potential, Na+ accumulates & Ca2+ stays in cytosol - more forceful contractions   Cardiac Output  urine ↓ blood vol. Adverse: Heart- Dysrhythmias Digestive system – nausea, vomiting Nervous system – blurred vision TOXIC & MANY DRUG-DRUG INTERACTIONS

DIGITALIS GLYCOSIDES Increase the force of the heart’s contractions. Derived from digitalis which is a substance that occurs naturally in foxglove plants and certain toads. Digoxin most frequently used.

DIGITALIS GLYCOSIDES Pharmacokinetics: Absorption varies according to form; distributed widely throughout the body; bound extensively to skeletal muscles; small amount is metabolized by the liver; excreted by the kidneys unchanged.

DIGITALIS GLYCOSIDES Pharmacodynamics: Used to treat heart failure by increasing intracellular calcium at the cell membrane making the heart contractions stronger. Also used to treat supraventricular arrhythmias because it acts on the CNS to slow the heart rate.

DIGITALIS GLYCOSIDES Pharmacotherapeutics: Also used to treat paroxysmal atrial tachycardia. Because of a long half-life, a loading dose must be given in this situation.

DIGITALIS GLYCOSIDES Drug interactions: Many drugs can interact with digoxin. Amphotericin B, potassium-wasting diuretics, and steroids taken with digoxin may cause hypokalemia and increase the risk of dig toxicity.

DIGITALIS GLYCOSIDES Adverse reactions: Because of a narrow therapeutic index, monitoring blood levels are required to prevent dig toxicity.

PDE INHIBITORS Used for short-term management of heart failure or long-term management for patients awaiting a transplant. Include the drugs inamrinone lactate(Inocor) and milrinone (Primacor).

PDE INHIBITORS Pharmacokinetics: Both drugs are administered IV; distributed rapidly; metabolized by the liver; excreted by the kidneys.

PDE INHIBITORS Pharmacodynamics: Improve cardiac output by strengthening contractions by moving calcium into the cardiac cell.

PDE INHIBITORS Pharmacotherapeutics: Used for the management of heart failure when patients haven’t responded adequately to treatment with dig, diuretics, or vasodilators.

PDE INHIBITORS Drug interactions: Because they reduce serum potassium levels, when taken with potassium-wasting diuretics may cause hypokalemia.

PDE INHIBITORS Adverse reactions: Uncommon but the risk increases with prolonged use.

Angiotensin Converting Enzyme inhibitors; Lisinopril Commonly used for slow progressive Heart failure (Hf) Replaced digoxin as first line drugs in chronic Hf

Mechanism: Inhibit ACE = reduced water/sodium retention decreased peripheral vascular resistance Dilate veins returning blood = ↓ peripheral odema  Decrease heart workload & allow it to function more efficiently Adverse: cough (  bradykinin) electrolyte imbalance, taste disturbances

The renin –angiotensin –aldosterone pathway

Vasodilators: Isosorbide dinitrate (organic nitrate) Minor role in HF therapy Mechanism: Release NO &  cGMP (direct venodilation) = ↓ cardiac workload &  cardiac output Also dilates coronary arteries =  oxygen to myocardium Adverse: headache, hypotension, tachycardia SERIOUS HYPOTENSION CONTRAINDICATION WITH VIAGRA

Phosphodiesterase Inhibitor Milrinone Inhibitor to ‘heart’ specific phosphodiesterase III given intravenously in Advanced HF Actions:  force of contraction & cardiac output.  vasodilation by  cAMP = increasing amount of calcium for myocardial contraction

Adverse: Serious (chest pain. Bronchospasm, tremor)  for patients not responding to ACE inhibitors + Ventricular Dysrhythmia in 10% patients (ECG monitored during drug infusion)

Cardiac Glycosides Phosphodiesterase Inhibitors L-type calcium channels

Beta-Adrenergic Blocker Carvedilol Only a few registered for HF. Not first-line. Mechanism: blocks  1 &  2 (&  1 ) adrenergic receptors = reduction in heart-rate & bp. = ↓ bp reduces workload on heart. Adverse: Dose monitored – worsen heart failure by reducing contractility !

Q. What is Angina pectoris ? Symptoms: sharp /moving chest/left arm pain on physical excretion or emotional stress -produces many symptoms of heart attack More frequently in women – over 70. Cause: atherosclerosis - myocardial ischemia Types: Stable- predictable in frequency/duration Unstable: severe & at rest Variant: Prognosis: rarely fatal

Q. How do you treat Angina ? Life Style changes (obvious) & Surgical Procedures (bypass graft or angioplasty) Drug treatment 3 classes of drugs 1.Organic nitrates 2. Beta-adrenergic blockers 3. Calcium channel blockers

Q. What are the pharmacological goals of angina treatment ? Reduce the frequency of angina episodes & terminate acute anginal pain - reduce myocardial demand for oxygen - increase oxygen to myocardium

1.Slow heart-rate 2.Reduce blood to heart by dilating veins (reduce preload) 3.Cause heart to contract with less force 4. Lower blood pressure – less resistance in heart to pushing blood from chambers (reduce after-load)

Organic Nitrates Properties known since 1857: mainstay treatment for stable angina. Mode of action: a) relax arterial & venous smooth muscle by release of NO & stimulation by cGMP. b) increase blood flow to coronary artery

Types: a) short-acting. Nitroglycerin sub-lingually for acute attack. B) long-acting. Isosorbide dinitrate orally/dermal patch for decreasing frequency & severity of episodes Adverse: Tolerance with long-acting drugs

Case Study: Nitroglycerin Many Routes: Sub-lingually reaches plasma levels in 4 mins.- rapid relief of pain by dilating vessels. If chest pain does not respond - myocardial infarction ? Adverse: Headache (vessel dilation) Reflex tachycardia (not common)

Calcium Channel Blockers Mode of action Acts on L-type calcium channels. Reduces myocardial oxygen demand by lowering bp & slowing heart-rate - inhibit calcium uptake & relax blood vessels Vasodilation will increase oxygen supply. Adverse Related to vasodilation: headache, dizziness, edema (ankles& feet)

Beta-Adrenergic Blockers Why for Angina ? reduce workload on heart – angina prophylaxis How ? Slow heart rate & reduce contractility

What types ? Cardioselective beta 1 blockers & mixed beta 1 – beta 2 blockers.