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UCSD BIMM 118 - Lecture 8

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Cardiovascular PharmacologySlide 2Slide 3Slide 4Slide 5Slide 6Slide 7Antihypertensive DrugsSlide 9Antihypertensive Drugs:VasodilatorsAntihypertensive Drugs: VasodilatorsSlide 12Antihypertensive Drugs: RAAS-targeting drugsSlide 14Slide 15Slide 16Angina pectorisAngina pectoris - NitratesSlide 19Cardiac ArrhythmiaSlide 21Slide 22Slide 23Slide 24Congestive Heart FailureSlide 26Slide 27Slide 28Slide 29Slide 30Slide 31BIMM118Cardiovascular Pharmacology•Hypertension•Angina pectoris•Cardiac Arrhythmias•Heart FailureQuickTime™ and aTIFF (Uncompressed) decompressorare needed to see this picture.BIMM118Cardiovascular 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 and viscosity of bloodBIMM118Cardiovascular PharmacologyCardiac 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.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 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.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: – 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 diureticsBIMM118Antihypertensive Drugs:VasodilatorsCalcium 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•Nicardipine •Nimodipine•Nisoldipine•AmlodipineBIMM118Antihypertensive Drugs: VasodilatorsPotassium 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®)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) => blood pressure “titration”–Used only to treat hypertensive emergenciesBIMM118Antihypertensive Drugs: RAAS-targeting drugsRenin-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 -adrenoceptors), 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).BIMM118Antihypertensive Drugs: RAAS-targeting drugsRenin-angiotensin systemAngiotensin II•Constricts vessels thereby increasing vascular resistance and arterial pressure•Stimulates the


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UCSD BIMM 118 - Lecture 8

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