BIMM118Cardiovascular Pharmacology• Hypertension• Angina pectoris• Cardiac Arrhythmias• Heart FailureBIMM118Cardiovascular 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 pressureResistance to flow depends on vessel diameter, length andviscosity of bloodBIMM118Cardiovascular PharmacologyCardiac blood flow• The mammalian heart is a double pump in which the right sideoperates as a low-pressure system delivering de-oxygenated bloodto the lungs, while the left side is a high pressure system deliveringoxygenated blood to the rest of the body.• The walls of the right ventricle are much thinner than those of theleft, because the work load is lower for the right side of the heart.• The ventricular muscle is relatively stiff, and it would take some timeto fill with venous blood during diastole. The thin, flexible atria serveto buffer the incoming venous supply, and their initial contraction atthe begining of each cardiac cycle fills the ventricles efficiently in ashort space of time.BIMM118Cardiovascular PharmacologyBIMM118Cardiovascular PharmacologyRegulation of cardiac output~ 5L /minute; dependent on:• Heart rate• Stroke volume• Preload• AfterloadStarling’s LawVentricular contraction is proportional to muscle fiber stretchAortic output pressure rises as the venous filling pressure is increasedIncreased venous return – increase cardiac output – up to a point!BIMM118Cardiovascular PharmacologyCardiac electrical activity• Cardiac muscle does not require any nervous stimulation to contract.• Each beat is initiated by the spontaneous depolarisation of pacemakercells in the sino-atrial (SA) node. These cells trigger the neighbouring atrialcells by direct electrical contacts and a wave of depolarisation spreads outover the atria, eventually exciting the atrio-ventricular (AV) node.• Contraction of the atria precedes that of the ventricles, forcing extra bloodinto the ventricles and eliciting the Starling response.• The electrical signal from the AV node is carried to the ventricles by aspecialised bundle of conducting tissue (the bundle of His)• The conducting tissues are derived from modifiedcardiac muscle cells, the Purkinje fibers.The conducting bundles divide repeatedly throughthe myocardium to coordinate electrical andcontractile activity across the heart.• Although each cardiac muscle cell is in electricalcontact with most of its neighbours, the messagenormally arrives first via the Purkinje system.BIMM118Cardiovascular PharmacologyVenous return• Systemic filling pressure• Auxiliary muscle pump• Resistance to flow between peripheral vessels and right atrium• Right atrial pressure - elevationRegulation 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)BIMM118Antihypertensive DrugsPotential drug targets:• CNS, ANS: decrease sympathetic tone• Heart: decrease cardiac output• Veins: dilate => decrease preload• Arterioles: dilate => decrease afterload• Kidneys: increase diuresis; inhibit RAA systemHypertension:• Usually symptom-free• Consequences: Heart failure, kidney damage,stroke, blindness …BIMM118Antihypertensive DrugsFour major drug categories• Sympathetic nervous system suppressors:– α1 and β1 antagonists– α2 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 diureticsBIMM118Antihypertensive Drugs:VasodilatorsCalcium channel blockers (= Calcium antagonists):– Inhibit calcium entry into cells of the arteries=> decreased afterloadDihydropyridines:– Target specifically L-type channels on vascular smooth muscle cells– No cardiac effects (“Vasoselective Ca++ antagonists”)– Can cause peripheral edema• Nifedipine– Prototype• Nicardipine• Nimodipine• Nisoldipine• AmlodipineBIMM118Antihypertensive Drugs: VasodilatorsPotassium channel agonists:• Minoxidil– Increases outward K+ current => membrane hyperpolarization, whichinhibits Ca++ channel activity– Used only for severe, treatment-resistant hypertension– Major side effect: Hirsutism => used topically to treat baldness (Rogaine®)BIMM118Antihypertensive 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) => bloodpressure “titration”– Used only to treat hypertensive emergenciesBIMM118Antihypertensive Drugs: RAAS-targeting drugsRenin-angiotensin system• Important role in regulating blood volume, arterialpressure, and cardiac and vascular function.• Most important site for renin release is the kidney:sympathetic stimulation (acting via β1-adrenoceptors), renal artery hypotension (e.g.stenosis), and decreased sodium delivery to thedistal tubules stimulate the release of renin by thekidney.• Renin acts upon a circulating substrate,angiotensinogen (produced mainly by the liver)which undergoes proteolytic cleavage to form thedecapeptide angiotensin I (AT I).• Vascular endothelium, particularly in the lungs,contains angiotensin converting enzyme (ACE),which cleaves off two amino acids to form theoctapeptide, angiotensin II (AT II).BIMM118Antihypertensive Drugs: RAAS-targeting drugsRenin-angiotensin systemAngiotensin II• Constricts vessels thereby increasing vascularresistance and arterial pressure• Stimulates the adrenal cortex to releasealdosterone, which acts upon the kidneys toincrease sodium and fluid retention• Stimulates the release of vasopressin (antidiuretichormone, ADH) from the pituitary which acts uponthe kidneys to increase fluid retention• Facilitates norepinephrine release and inhibits re-uptake from nerve endings, thereby enhancingsympathetic adrenergic function• Stimulates cardiac and vascular hypertrophyBIMM118Antihypertensive Drugs: RAAS-targeting drugsACE -
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