Cardiovascular Pharmacology

Hypertension Angina pectoris Cardiac Arrhythmias Heart Failure

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Cardiovascular Pharmacology

Cardiovascular (=Circulatory) system heart and blood vessels Arteries transport blood to tissues Capillaries sites of exchange, fluid O2, CO2, nutrients etc. Venules collect blood from capillaries Veins transport blood back to heart Blood moves within vessels higher pressure to lower pressure Resistance to flow depends on vessel diameter, length and viscosity of blood

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Cardiovascular Pharmacology
Cardiac blood flow
The mammalian heart is a double pump in which the right side operates as a low-pressure system delivering de-oxygenated blood to the lungs, while the left side is a high pressure system delivering oxygenated blood to the rest of the body. The walls of the right ventricle are much thinner than those of the left, because the work load is lower for the right side of the heart. The ventricular muscle is relatively stiff, and it would take some time to fill with venous blood during diastole. The thin, flexible atria serve to buffer the incoming venous supply, and their initial contraction at the begining of each cardiac cycle fills the ventricles efficiently in a short space of time.

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Cardiovascular Pharmacology

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Cardiovascular Pharmacology
Regulation of cardiac output
~ 5L /minute; dependent on: Heart rate Stroke volume Preload Afterload

Starlings Law
Ventricular contraction is proportional to muscle fiber stretch
Aortic output pressure rises as the venous filling pressure is increased Increased venous return increase cardiac output up to a point!

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Cardiovascular Pharmacology
Cardiac electrical activity
Cardiac muscle does not require any nervous stimulation to contract. Each beat is initiated by the spontaneous depolarisation of pacemaker cells in the sino-atrial (SA) node. These cells trigger the neighbouring atrial cells by direct electrical contacts and a wave of depolarisation spreads out over the atria, eventually exciting the atrio-ventricular (AV) node. Contraction of the atria precedes that of the ventricles, forcing extra blood into the ventricles and eliciting the Starling response. The electrical signal from the AV node is carried to the ventricles by a specialised bundle of conducting tissue (the bundle of His) The conducting tissues are derived from modified cardiac muscle cells, the Purkinje fibers. The conducting bundles divide repeatedly through the myocardium to coordinate electrical and contractile activity across the heart. Although each cardiac muscle cell is in electrical contact with most of its neighbours, the message normally arrives first via the Purkinje system.

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Cardiovascular Pharmacology
Venous return
Systemic filling pressure Auxiliary muscle pump Resistance to flow between peripheral vessels and right atrium Right atrial pressure - elevation

Regulation of Arterial Pressure

Arterial pressure = cardiac output + peripheral resistance Arterial pressure affected by:
the autonomic nervous system (fast) the renin-angiotensin system (hours or days) the kidneys (days or weeks)

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Antihypertensive Drugs
Hypertension: Usually symptom-free Consequences: Heart failure, kidney damage, stroke, blindness

Potential drug targets: CNS, ANS: decrease sympathetic tone Heart: decrease cardiac output Veins: dilate => decrease preload Arterioles: dilate => decrease afterload Kidneys: increase diuresis; inhibit RAA system

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Antihypertensive Drugs
Four major drug categories
Sympathetic nervous system suppressors:
1 and 1 antagonists 2 agonists

Direct vasodilators:
Calcium channel antagonists Potassium channel agonists

Renin-angiotensin system targeting drugs:

ACE inhibitors Angiotensin II receptor antagonists

Diuretics:
Thiazides Loop diuretics K+ - sparing diuretics

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Antihypertensive Drugs:Vasodilators
Calcium channel blockers (= Calcium antagonists):
Inhibit calcium entry into cells of the arteries => decreased afterload

Dihydropyridines:
Target specifically L-type channels on vascular smooth muscle cells No cardiac effects (Vasoselective Ca++ antagonists) Can cause peripheral edema

Nifedipine
Prototype

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Nicardipine Nimodipine Nisoldipine Amlodipine

Antihypertensive Drugs: Vasodilators

Potassium channel agonists:
Minoxidil
Increases outward K+ current => membrane hyperpolarization, which inhibits Ca++ channel activity Used only for severe, treatment-resistant hypertension Major side effect: Hirsutism => used topically to treat baldness (Rogaine)

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Antihypertensive Drugs: Vasodilators

Nitroprusside
Very unstable (only iv) Metabolized by blood vessels into NO => activates cGMP production => vasodilation Rapid action (30 sec !), short duration (effect ends after 3 min) => blood pressure titration Used only to treat hypertensive emergencies

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Antihypertensive Drugs: RAAS-targeting drugs

Renin-angiotensin system
Important role in regulating blood volume, arterial pressure, and cardiac and vascular function. Most important site for renin release is the kidney: sympathetic stimulation (acting via 1adrenoceptors), renal artery hypotension (e.g. stenosis), and decreased sodium delivery to the distal tubules stimulate the release of renin by the kidney. Renin acts upon a circulating substrate, angiotensinogen (produced mainly by the liver) which undergoes proteolytic cleavage to form the decapeptide angiotensin I (AT I). Vascular endothelium, particularly in the lungs, contains angiotensin converting enzyme (ACE), which cleaves off two amino acids to form the octapeptide, angiotensin II (AT II).

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Antihypertensive Drugs: RAAS-targeting drugs

Renin-angiotensin system
Angiotensin II
Constricts vessels thereby increasing vascular resistance and arterial pressure Stimulates the adrenal cortex to release aldosterone, which acts upon the kidneys to increase sodium and fluid retention Stimulates the release of vasopressin (antidiuretic hormone, ADH) from the pituitary which acts upon the kidneys to increase fluid retention Facilitates norepinephrine release and inhibits reuptake from nerve endings, thereby enhancing sympathetic adrenergic function Stimulates cardiac and vascular hypertrophy

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Antihypertensive Drugs: RAAS-targeting drugs

ACE - Inhibitors
Captopril
First ACE inhibitor Given po Frequent side effect: cough (reduced inactivation of kinins)

Enalapril

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Benazepril Ramipril Lisinopril Etc

Antihypertensive Drugs: RAAS-targeting drugs

AT II Receptor Antagonists
Do not interfer with kinin processing => no cough

Losartan Candesartan Eprosartan Valsartan Irbesartan Etc

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Angina pectoris
Medical term for chest pain or discomfort due to coronary heart disease.Typical angina pectoris (=tight heart is uncomfortable pressure, fullness, squeezing or pain in the center of the chest Angina is a symptom of myocardial ischemia, which occurs when the myocardium does not receive sufficient oxygen. People with stable angina have episodes of chest discomfort that are usually predictable, such as on exertion or under stress (Treatment: Nitrates, -blockers). In people with unstable angina, the chest pain is unexpected and usually occurs while at rest.The discomfort may be more severe and prolonged than typical angina (Treatment: Nitrates). Variant angina is also called Prinzmetal's angina. Unlike typical angina, it nearly always occurs when a person is at rest, and does not follow physical exertion or emotional stress. Variant angina is due to coronary artery spasm (Treatment: Ca++ channel blockers).

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Angina pectoris - Nitrates

Nitroglycerin
Organic nitrate Acts on vascular smooth muscle to promote vasodilation Primarily works on veins, only modest dilation of arterioles Decreases oxygen demand by decreasing venous return => use in stable angina
It was originally believed that nitrates and nitrites dilated coronary blood vessels, thereby increasing blood flow to the heart. It is now believed that atherosclerosis limits coronary dilation and that the benefits of nitrates and nitrites are due to dilation of arterioles and veins in the periphery. The resultant reduction in preload, and to a lesser extent in afterload, decreases the workload of the heart and lowers myocardial oxygen demand.

Oral, sublingual, IV, buccal and transdermal administration Adverse effects headache, tachycardia, hypotension Never to be combined with other drugs causing vasodilation (Viagra) or hypotension

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Angina pectoris - Nitrates

Isosorbide-dinitrate (ISDN)
More stable than nitroglycerol Longer lasting effect Tolerance can occur give lowest dose possible

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Nitroprusside

Cardiac Arrhythmia
Arrhythmias:
Abnormal rhythms of the heart that cause the heart to pump less effectively
Arrhythmia occurs:
when the hearts natural pacemaker develops an abnormal rate or rhythm when the normal conduction path is interrupted when another part of the heart takes over as pacemaker

Types of arrhythmia:
Tachycardia: unusually fast heartbeat Bradycardia: unusually slow heartbeat Atrial fibrillation: the atria quiver rather than contract normally because of rapid and irregular electrical signals in the heart. Beside the abnormal heart beat, there is also a risk that blood will pool in the atria, possibly causing the formation of blood clots. Ventricular fibrillation: life threatening condition in which the heart ceases to beat regularly and instead quivers or fibrillates very rapidly sometimes at 350 beats per minute or more (causes 350,000 death/year in the US - sudden cardiac arrest)

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Cardiac Arrhythmia

Arrhythmias:
Drug Classes:
Class I: Sodium channel blockers Class II: -blockers Class III: Potassium channel blockers Class IV: Calcium channel blockers Other arrhythmic drugs

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Cardiac Arrhythmia
Arrhythmias:
Class I - Sodium channel blockers:
Block Na+ entry during depolarization phase

For atrial and ventricular arrhythmias (all-purpose) Procainamide Quinidine

For acute treatment of ventricular arrhythmias Lidocaine

For chronic treatment of ventricular arrhythmias

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Flecainide Propofenone

Cardiac Arrhythmia
Arrhythmias:
Class II - -blockers: For tachycardia Propranolol

Class III - Potassium channel blockers:

Prolong repolarization phase by blocking outward potassium flux

For treatment of intractable ventricular arrhythmias Bretylium Amiodarone

Class IV - Calcium channel blockers:

Prolong repolarization phase by blocking inward calcium current

Predominantly for treatment of atrial arrhythmias

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Verapamil

Cardiac Arrhythmia
Arrhythmias:
Other antiarrhythmics: Adenosine For paroxysmal supraventricular tachycardia iv only, extremely short half-life used to terminate arrhythmias (blocks reentrant pathway) (Paroxysmal = an arrhythmia that suddenly begins and ends)

Digoxin For atrial fibrillation

Epinephrine, Isoproterenol For bradycardia

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Congestive Heart Failure

Congestive heart failure:
characterised by inadequate contractility, so that the ventricles have difficulty in expelling sufficient blood => rise in venous blood pressures Raised venous pressures impair fluid drainage from the tissues and produce a variety of serious clinical effects:
Right sided heart failure causes lower limb oedema. Blood pooling in the lower extremities is associated with intravascular clotting and thromboembolism Left sided heart failure produces pulmonary oedema and respiratory distress

Causes: Blocked coronary arteries; viral infections; hypertension; MI; leaky heart valves
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Congestive Heart Failure

Classification of severity
I no limitation of physical activity II slight limitation III marked limitation IV symptoms occur at rest

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Congestive Heart Failure

Treatment options:
Diuretics
Loop diuretics Thiazides Spironolactone

ACE inhibitors & AT II antagonists Vasodilators

Nitrates

Cardiac Glycosides

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Congestive Heart Failure Cardiac Glycosides:

Chief active ingredient in several plant families and animals:

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Congestive Heart Failure

Cardiac Glycosides:
Two main categories:
Cardenolides (Digitalis, Convallaria, Oleandra) Bufadienolides (Helleborus, Poison Arrow Frog)

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Congestive Heart Failure

Cardiac Glycosides:
Cardiac glycosides slow the heart rate and increase the force of contraction Extracts of D. purpurea have been used clinically for over 200 years to treat heart failure and edema (dropsy) The cardiac glycosides inhibit the Na+/K+-ATPase pump, which causes an increase in intracellular Na+ => slowing of the Na+/Ca++-exchanger => increase in intracellular Ca++. Low therapeutic index => Associated with an appreciable risk of toxicity Digoxin is the most widely used preparation of digitalis (half-life = 1-2 days), although digitoxin (half-life = 7 days) is used in situations where long half-life may be an advantage. Digitalis is the drug of choice for heart failure associated with atrial fibrillation

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Congestive Heart Failure

Cardiac Glycosides:
Improve cardiac performance (=positive inotrope) Increases cardiac output Decreased sympathetic tone Increase urine output Decreased renin release Does not prolong life (only symptom relief)

Toxicity:
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Overdose; drug interaction; accidental ingestion of plants (children!) Potassium competes with cardiac glycoside for binding to Na+/K+-ATPase pump => potassium is an antidot for cardiac glycoside poisoning Injection of anti-cardiac glycoside antibodies