ANTI HIPERTENSIReferensi : Katzung, 9th Ed.; Chap. 11 (pg. 160-183) Goodman and Gilman, 11th Ed.; Chap. 30 Renin and angiotensin; pp. 789-822 Chap. 33 Therapy for Hypertension; pp. 871-900 Online; www.AccessMedicine.com*ANTIHT/KV/2014*

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Objectives:*ANTIHT/KV/2014*Know mechanisms of blood pressure regulation and cardiovascular pathophysiology which chronically increase blood pressure (Review).Understand types and etiologies of major forms of clinical hypertension. General treatment strategy for hypertension.Know major classes of anti-hypertensive agents, their general sites and mechanisms of action. Identify specific, widely used, antihypertensive agents, sites of action, mechanisms of action, indications and contraindications. Understand strategies for hypertension management associated with other pathologies.

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Determinants of Arterial PressureMean Arterial Pressure=XArteriolarDiameterBloodVolumeStrokeVolumeHeartRateFilling PressureContractilityBlood VolumeVenous ToneCRITICAL POINT!Change any physical factors controlling CO and/or TPR and MAP can be altered. *ANTIHT/KV/2014*

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Mechanisms Controlling CO and TPRCRITICAL POINTS!1. These organ systems and mechanisms control physical factors of CO and TPR2. Therefore, they are the targets of antihypertensive therapy. *ANTIHT/KV/2014*

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2. Secondary hypertension- due to specific organ pathology1. renal artery stenosis2. pheochromocytoma3. aortic coarctation4. adrenal tumorSummary-Types and Etiology of Hypertension1. White coat hypertensionoffice or environmental 3. Essential Hypertension No known cause.CRITICAL POINT!Pharmacological Therapy used primarily for essential hypertension.*ANTIHT/KV/2014*

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SummaryGeneral Treatment Strategy of Hypertension5. Pharmacological treatment.4. If primary, initiate lifestyle changessmoking cessationweight lossdietstress reductionless alcoholetc.CRITICAL POINTS! Goal- normalize pressure- decrease CO and/or TPR Strategy- alter volume, cardiac and/or VSM function*ANTIHT/KV/2014*

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Classes of Antihypertensive Agents1. Diuretics2. Peripheral a-1 Adrenergic Antagonists4. b-Adrenergic Antagonists3. Central Sympatholytics (a-2 agonists)5. Anti-angiotensin II Drugs6. Ca++ Channel Blockers7. VasodilatorsPharmacological TreatmentCRITICAL POINTS!Each designed for specific control systemOften used in combination*ANTIHT/KV/2014*

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1. Diuretics1. Thiazideshydrochlorothiazide (HydroDIURIL, Esidrix);chlorthalidone (Hygroton)2. Loop diureticsfurosemide (Lasix); bumetadine (Burmex);ethacrynic acid (Edecrin)3. K+ Sparingamiloride (Midamor); spironolactone (Aldactone);triamterene (Dyrenium)4. Osmotic mannitol (Osmitrol); urea (Ureaphil)5. OtherCombination - HCTH + triamterene (Dyazide)acetazolamide (Diamox) *ANTIHT/KV/2014*

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Diuretics (cont)2. Mechanism of ActionUrinary Na+ excretionUrinary water excretionExtracellular Fluid and/or Plasma Volume3. Effect on Cardiovascular System Acute decrease in COChronic decrease in TPR, normal COMechanism(s) unknown1. Site of Action Renal Nephron*ANTIHT/KV/2014*

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Diuretics (cont)4. Adverse Reactionsdizziness, electrolyte imbalance/depletion,hypokalemia, hyperlipidemia,hyperglycemia (Thiazides)gout5. Contraindicationshypersensitivity, compromised kidney functioncardiac glycosides (K+ effects)hypovolemia,hyponatremia*ANTIHT/KV/2014*

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Diuretics (cont)6. Therapeutic Considerations Thiazides (most common diuretics for HTN) Generally start with lower potency diuretics Generally used to treat mild to moderate HTN Use with lower dietary Na+ intake, and K+ supplement or high K+ food K+ Sparing (combination with other agent)

Loop diuretics (severe HTN, or with CHF) Osmotic (HTN emergencies)

Maximum antihypertensive effect reachedbefore maximum diuresis- 2nd agent indicated*ANTIHT/KV/2014*

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Peripheral a-1 Adrenergic AntagonistsDrugs: prazosin (Minipres); terazosin (Hytrin)1. Site of Action- peripheral arterioles, smooth muscleCRITICAL POINT!Major mechanism/site of SymNS control of blood pressure.*ANTIHT/KV/2014*

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2. Mechanism of ActionCompetitive antagonist at a-1 receptors on vascular smooth muscle. 3. Effects on Cardiovascular SystemVasodilation, reduces peripheral resistancePeripheral a-1 Adrenergic Antagonists, cont.CRITICAL POINT! Blocking -receptors on vascular smooth muscle allows muscle relaxation, dilation of vessel, and reduced resistance.*ANTIHT/KV/2014*

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5. Contraindications Hypersensitivity

Peripheral a-1 Adrenergic Antagonists, cont.4. Adverse effectsnausea; drowsiness; postural hypotenstion;1st dose syncope6. Therapeutic Considerationsno reflex tachycardia; small 1st dose; does not impair exercise toleranceuseful with diabetes, asthma, and/or hypercholesterolemiause in mild to moderate hypertensionoften used with diuretic, antagonist

*ANTIHT/KV/2014*

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Central Sympatholytics (a-2 Agonists)Drugs: clonidine (Catapres), methyldopa (Aldomet)1. Site of ActionCNS medullary cardiovascular centersclonidine; direct a-2 agonistmethyldopa: false neurotrans. CNS a-2 adrenergic stimulation Peripheral sympathoinhibition Decreased norepinephrine release2. Mechanism of Action3. Effects on Cardiovascular SystemDecreased NE-->vasodilation--> Decreased TPR

CRITICAL POINT!Stimulation of a-2 receptors in the medulla decreases peripheral sympathetic activity, reduces tone, vasodilation and decreases TPR. *ANTIHT/KV/2014*

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5. Contraindications4. Adverse Effectsdry mouth; sedation; impotence;Central Sympatholytics (a-2 Agonists); cont.6. Therapeutic Considerationsgenerally not 1st line drugs;methyldopa drug of choice for pregnancyprolonged use--salt/water retention, add diureticRebound increase in blood pressure*ANTIHT/KV/2014*

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1. Sites of Actionb-1b-12. Mechanism of Actioncompetitive antagonist at b- adrenergic receptors*ANTIHT/KV/2014*

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b Adrenergic Antagonists, cont.3. Effects on Cardiovascular Systema. Cardiac-- HR, SV COb. Renal-- Renin Angiotensin II TPR 5. Contraindicationsasthma; diabetes; bradycardia; hypersensitivity*ANTIHT/KV/2014*

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b-Adrenergic Antagonists, cont.6. Therapeutic ConsiderationsSelectivity nadolol (Corgard) non selective, but 20 hr 1/2 life metoprol (Lopresor) b-1 selective, 3-4 hr 1/2 lifeRisky in pulmonary disease even selective b-1, Available as mixed a/b blocker available-labetalol (Trandate, Normodyne)Use post myocardial infarction- protectiveUse with diuretic- prevent reflex tachycardia*ANTIHT/KV/2014*

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Anti-Angiotensin II DrugsAngiotensin II FormationAngiotensin Converting Enzyme- Inhibitors enalopril (Vasotec); quinapril (Accupril); fosinopril (Monopril); moexipril (Univasc); lisinopril (Zestril, Prinivil); benazepril (Lotensin); captopril (Capoten)Ang IAng IIACE ACEAng IIReninAngiotensinogenAng IAT1AT2LungVSMBrainKidneyAdr Gland*ANTIHT/KV/2014*

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3. Effect on Cardiovascular SystemAnti-Angiotensin II Drugs, contVolume Aldosterone VasopressinCOAngiotensin IIVasoconstrictionTPRSymNSHR/SV Angiotensin II NorepinephrineCOSymNS*ANTIHT/KV/2014*

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Anti-Angiotensin II Drugs, cont4. Adverse Effectshyperkalemiaangiogenic edema (ACE inhib); cough (ACE inhib); rash; itching;

5. Contraindicationspregnancy; hypersensitivity; bilateral renal stenosis 6. Therapeutic Considerations:use with diabetes or renal insufficiency; adjunctive therapy in heart failure; often used with diuretic;Enalapril, iv for hypertensive emergency

*ANTIHT/KV/2014*

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Ca++ Channel BlockersDrugs: verapamil (Calan); nifedipine (Procardia); diltiazem (Cardizem); amlodipine (Norvasc)2. Mechanism of Action- Blocks Ca++ channeldecreases/prevents contraction3. Effect on Cardiovascular systemVascular relaxationDecreased TPR1. Site of Action- Vascular smooth muscleK+Ca++Na+*ANTIHT/KV/2014*

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Ca++ Channel Blockers, cont.5. ContraindicationsCongestive heart failure; pregnancy and lactation;Post-myocardial infarction6. Therapeutic Considerationsverapamil- mainly cardiac; interactions w/ cardiacglycosidesnifedipine- mainly arteriolesdiltiazem-both cardiac and arterioles at high doses, AV node block may occur; nifedipine may increase heart rate (reflex)4. Adverse Effectsnifedipine --Increase SymNS activity; headache; dizziness; peripheral edema*ANTIHT/KV/2014*

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VasodilatorsDrugs: hydralazine (Apresoline); minoxidil (Loniten); nitroprusside (Nipride); diazoxide (Hyperstat I.V.);fenoldopam (Corlopam) 1. Site of Action- vascular smooth muscle2. Mechanism of actionminoxidildiazoxidehydralazinefenoldopamnitroprussideCa++Ca++Na+K+DA*ANTIHT/KV/2014*

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Vasodilators, Cont3. Effect on cardiovascular systemvasodilation, decrease TPR4. Adverse Effects reflex tachycardia Increase SymNS activity (hydralazine, minoxidil,diazoxide)lupus (hydralazine)hypertrichosis (minoxidil)cyanide toxicity (nitroprusside)5. Contraindications*ANTIHT/KV/2014*

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SummarySites and Mechanisms of Action 3. -2 agonists4. b-blockersReceptor antag. 2. a-antag. 5. ang II antag.7. Vasodilators6. Ca++ antag.1. Diuretics4. b-blockersOther- 5. ACE inhibitors Lung, VSM, Kidney, CNSCRITICAL POINTS!*ANTIHT/KV/2014*

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Hypertension treatment with some common co-existing conditionsHeart FailureACE inhibitorsDiureticsMyocardial Infarctionb-blockersACE inhibitorsDiabetesACE InhibitorsAVOID- b-blockersIsolated systolic hypertension (Older persons)Diuretics preferredcalcium channel antagonist*ANTIHT/KV/2014*

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Renal InsufficiencyACE InhibitorsAnginab-blockerCalcium channel antagonistsAsthmaCa++ channel blockersAVOID- b-blockers Treatment Strategy with Some Common co-existing Conditions, cont *ANTIHT/KV/2014*

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Summary Important PointsHypertensive AgentsEach class of antihypertensive agent: 1. has as specific mechanism of action,2. acts at one or more major organ systems,3. on a major physiological regulator of blood pressure,4. reduces CO and/or TPR to lower blood pressure,5. has specific indications, contraindications, and therapeutic advantages and disadvantages associated with the mechanism of action. *ANTIHT/KV/2014*

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BaroreflexesCO X SVR= MAPMAP= set pointReflexes defend set pointArterial BaroreflexesPressure/NatriuresisChange in MAP opposed by reflex response to maintain set pressure.Hypertension- pressure resets to higher level-defended by reflex systems.

CRITICAL POINT!**Multiple therapies often needed to block reflex compensation.

*ANTIHT/KV/2014*

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*Abbreviations:ACE, angiotensin converting enzyme HDL, high density lipoproteinADH, antidiuretic hormone HT, hypertension Ang II, angiotensin IILDL, low density lipoproteinBP, blood pressure NE, norepinephrine CHF, congestive heart failureSV, stroke volume CO, cardiac outputSymNS, sympathetic nervous system CNS, central nervous systemTPR, total peripheral resistanceGFR, glomerular filtration rateVSM, vascular smooth muscle_____________________________________________________________________

*

*Review- 1. Cardiac and vascular function contribute to arterial pressure. 2. BP can be altered by changing either CO or TPR 3. Both CO and TPR are influenced by several physical factors 4. CO primarily function of heart, TPR a function of vasculature 5. Changes in BP opposed by reflexesa. Servo null control system- set point, sensor, processor, compensation 1. Arterial baroreflexes-short term (sec-min)2. Renal pressure/natriuresis response- long term b. Both major reflexes act as compensatory mechanism to maintain BP at a set levelc. Changes in pressure opposed by compensation in both CO/TPR

*Review-Major Mechanisms of BP control- a. Neural- control of autonomic nervous system (PSNS, SymNS) b. Vasoactive hormones 1. Controlled by CNS a. vasopressin; b. adrenal catecholamines; (SymNS activation) c. renal renin (SymNS activation) 2. Systemic control a. renal renin release (renal perfusion pressure; Na+ c. Local Factors 1. endothelial agents- derived from endothelial cells in arterioles 2. arteriolar gas concentration- circulating 0o, CO2, H+2. All interact to control blood pressure3. Targets of antihypertensive therapy

*1. White Coat hypertension Due to stress associated with office/hospital visit Need 3-6 independent measures of high blood pressure for diagnosis2. Secondary Hypertension- Common causes Increased blood pressure secondary to a known pathology 1. renal artery stenosis- systemic pressure increases to maintain renal perfusion pressure 2. pheochormocytoma- tumor in chromafin cells of adrenal gland hypersecretion of adrenal catecholamines 3. aortic coarctation- increased upper body pressure to maintain lower body perfusion 4. adrenal tumor- hypersecretion of aldosterone3. Essential (Primary) Hypertension Chronically increased blood pressure with no known cause Clinically- 95% of human hypertension

*1. General Strategies for treatment of Hypertension a. Hypertension easily detected, easily treated b. Secondary HT-treat primary pathology c. Essential HT- non-drug therapy1. Weight reduction2. salt restriction-dec.. BP in 50% moderate HT3. withdrawal of drugs (e.g. steroids, oral contraceptives 4. tobacco5. alcohol6. stress reduction2. Pharmacological Treatment Essential Hypertension a. Goal- reduce BP by decreasing CO and/or TPR b. Strategy- alter cardiac and/or VSM function 1. Reduce vascular volume 2. altering SymNS transmission 3. Altering cardiac and/or vascular smooth muscle function

*

Antihypertensive Agents- 7 classes1. Sites and mechanisms of action different a. All decrease CO and/or TPR2. Often used in combination a. to oppose compensatory reflex responses1. Baroreflex activation of compensatory systems b. to increase effectiveness of treatment1. Due to diminished effectiveness at high dose of single agent2. Due to onset of adverse side effects at high doses c. due to compelling conditions1. Coexistent conditions which make multiple agents more effective

*DIURETIC AGENTS1. Diuretics commonly used for hypertension a. vary in natriuretic efficacy, renal site of action, hypotensive efficacy2. Generally 1st pharmacological therapya. unless contraindicatedb. Diuretic as or more effective than 1. Ca++ channel blockers or ACE inhibitors (Dec., 2002, JAMA) 2. Alpha-adrenergic antagonists (Sept, 2003, Hypertension) 1st line treatment for hypertension

*1. Site of Action a. renal nephron b. diuretic agents work at different segments of nephron2. Mechanism of Action a. all diuretics decrease sodium reabsorption b. act on renal systems, transporters, hormones, ion channels c. Where Na+ goes, Water will surely follow3. Effect on cardiovascular system a. acute decrease in plasma volume b. chronically, decrease in TPR, CO returns to normal mechanism unknownc. often used to compensate for Na+ retaining reflex induced by other antihypertensive agents.

*4. Adverse Reactions a. most secondary to decreased volume or altered electrolyte status 1. many renal mechanisms of Na+ reabsorption tied to transport of other electrolytes i.e. K+ Ca++, Mg++. b. hyperlipidemia and increased low density lipoprotein- unknown mechanism c. hyperglycemia, K+ depletion inhibits insulin secretion5. Contraindications a. exaggerated response leading to adverse reactions- hypersensitivity b. compromised kidney function- insufficient delivery to site of action 1. agents act on lumen, decreased kidney function decreases access of agent to renal tubule, due to decreased GFR and/or renal blood flow c. cardiac glycoside sensitivity changes with K+ 1. Decreased Plasma K+ increases sensitivity to cardiac glycosides (Digitalis) d. exacerbates existing low volume or salt conditions

*6. Therapeutic Considerations a.. Thiazides- Modest diuretic (distal conv. tubule) a. usually first therapy, mild to moderate hypertension b. Dec. BP 10-15 mmHg, 10-12 wks for max effectc. co-administered with K+ sparing if hypokalemia presentd. most effective with low sodium diete. Generally effective on their own, often used in combinationf. most commonly prescribed antihypertensive in US b.. Loop diuretics- rapid, profound diuresis (loop of Henle) a. More severe hypertension, or HT with CHF c. K+ sparing diuretics (distal convoluted tubule, collecting duct) a. Patients with hypokalemia b. only modest increase in Na+ excretion c. used in combination when K+ conservation is indicated d. Osmotic diuretics- very effective diuretics (throughout tubular lumen) a. usually iv only b. hypertension emergencies e. Max antihypertensive efficiency- more volume loss does not lower pressure farther, second class indicated

*Peripheral -adrenergic Antagonists

1. Site of Action -- Peripheral Arterioles (resistance vessels) a. surrounded by smooth muscle b. heavily innervated by post-synaptic SymNS nerves c. neurotransmitter = norepinephrine d. neuromuscular junction is major site of SymNS control ofarteriolar diameter, which directly effects TPR*2. Mechanism of action Competitive Antagonist of norepinephrine (a-1 receptor subtype) a. post-synaptic membrane1. a-1 receptors are post-junctional a. respond to neurally released norepinephrine2. a-2 receptors are extrajunctional a. respond to circulating catecholamines b. binds to a-1 adrenergic receptors c. . post-junctional receptor d. prevents effects of neurally released norepinephrine predominant mechanism of SymNS control of VSM constriction3. Effects of a-1 receptor blockade a. arteriolar dilation- removal of tone- allow relaxation of VSM b. decreased TPR c. little or no direct effects on CO

*4. Adverse effects a. 1st dose precipitous fall in BP b. due in part to no or minimum reflex tachycardia (a2-adrenergic autoinhibition of norepinephrine release in the heart). 5. Contraindications a. No compelling contraindications b. Hypersensitivity6. Therapeutic Considerations a. no reflex tachycardia- does not impair exercise tolerance b. can use with diabetes, asthma, hypercholesterolemia 1. does not alter plasma glucose or mask hypoglycemic tachycardia 2. does not inhibit airway b-adrenergic receptors 3. alters plasma lipids favorably (decreased LDL, mechanism unknown) c. combinations- 1. Diuretic to counteract sodium retention 2. b antagonist- can lower dose, additive 7. Other sympatholytic agents- not -antagonists 1. Guanethidine (Ismelin)-replaces norepinephrine in nerve terminal 2. Reserpine (Sandril, Serpasil)- depletes norepinephrine in terminal

*1. Site of Action CNS a. medullary cardiovascular centers 1. clonidine- direct agonist 2. methyldopa- converted to methylnorepinephrine a. acts like norepinephrine2. Mechanism of action a. a-2 agonist activates CENTRAL a-2 receptors b. hypotensive action due to CNS action3. Effects on Cardiovascular System a. CNS inhibition SymNS outflow b. decreased vasoconstriction c. decreased TPR

*4. Adverse Effects- due to CNS actions a. dry mouth b. sedation c. impotence5. Contraindications a. no strong contraindications6. Therapeutic Considerations a. Often used in conjunctions with diuretic b. Sudden discontinuation can lead to rebound SymNS and increase BP c. Methlydopa common drug in pregnancy d. NOT 1st line drug e. low dose predominant central hypotension high dose, begin to stimulate systemic vasoconstrictor -2 receptors

*1. Site of Action- b receptors a. Heart b. Kidney2. Mechanism of action a. Competitive antagonists b-receptors

*3. Effects on Cardiovascular System a.. Heart; decreases contractility; decreases COantagonizes catecholamine tachycardia b. Kidney; decreases renin release, Ang II, TPR4. Adverse effects a. chronic fatigue- cardiac effect b. low exercise tolerance- cardiac effect c. bradycardia d. possible increased airways resistance- b-2 receptor block5. Contraindications a. asthma; pulmonary disease- decreased pulmonary function b-2 receptor block b. diabetes- can mask hypoglycemic tachycardia, alters carbohydrate metabolism, increases recovery time from hypoglycemia c. low heart rate*6. Therapeutic Considerations a. b- selectivity 1 or 2 b. asthma- b-1 selective c. often used with diuretic to prevent reflex tachycardia d. nadolol (Corgard)- non-selective, but 1/2 life= 20-24 hrs e. metoprol (Lopresor)-selective b-1, but shorter 1/2 life 3-4 hr. f. use post myocardial infarction, cardioprotective g. Mixed a/b blocker available (labetalol)(Trandate, Normodyne)decreases TPR (), prevents reflex tachycardia () *Angiotensin II formation A. Renin cleaves Ang I from angiotensinogen B. Angiotenin I is inactive decapeptide C. Angiotensin Converting Enzyme cleaves 2 amino acids- resulting in the biologically active Angiotensin II D. Cardiovascular/fluid volume effects mediated by AT1 receptor stimulation2. Anti-angiotensin II Drugs/ Classes and Mechanism of Action A. ACE inhibitors- mechanism of action 1. Reduce or eliminate activity of angiotensin II converting enzyme 2. Decrease formation of ang II B. Angiotensin II AT1 receptor blockers- mechanism of action 1. Competitive antagonist at AT1 receptor 2. Prevents binding of angiotensin II

*3. Effects on Cardiovascular System a. Renal1. Maintenance of normal GFR2. Reduces plasma vasopressin and aldosterone Decreased CO b. Cardiac1. Decreased Ang II and Norepinephrine effects Decreased SymNS influence; Decreased CO c. Vascular1. Decreased Ang II Decreased TPR- due to Ang II Decreased TPR- due to SymNS activation from CNS Decreased TPR- due to Ang II/ NE terminal interaction

*4. Adverse Effects a. hyperkaelemia b. altered gustatory sensation c. angioedema- sudden edema skin/ mucous membranes; etiology unknown d. cough- increase bradykinin / prostaglandins5. Contraindications a. pregnancy- injury or death to fetus b. bilateral renal stenosis- renal function depends on renin- angII system6. Therapeutic Considerations a. use with diabetes or renal insufficiency 1. Ang II contributes to decreased renal function b. use in heart failure 1. Ang II contributes to ventricular remodeling c. usually used with diuretic, additive with thiazide 1. Decreases sodium retention by reducing aldosterone d. used where diuretic or b-blocker contraindicated or ineffective

*1. Site of Action a. Ca++ channels on vascular and cardiac muscle2. Mechanism of Action a. inhibition of Ca++ influx into muscle tissue b. dilates coronary and vascular smooth muscle3. Effects on Cardiovascular System a. decreased TPR; predominant hypotensive effect *4. Adverse Effects a. most associated with excessive vasodilation1. mild to moderate edema2. flushing3. tachycardia- Nifedipine- due to reflex SymNS activation aggravates angina4. bradycardia- Diltiazem, verapamil, 5. Contraindications a. congestive heart failure for all- negative inotropic effect b. pregnancy and lactation- injury to fetus, neonate??? c. myocardial infarction- cardiac effects6. Therapeutic Considerations a. wide efficacy profile including African Americans and elderly b. differential effects on cardiac and arterioles c. long acting appear safe *1. Site of Action2. Mechanism of Action- Systemic vascular vasodilation a. hydralazine- alters intracellular calcium, increases nitric oxide in arterioles b. minoxidil- opens K+ channels on arteriolar membranes, stabilizes membrane c. nitroprusside- induces nitric oxide from endothelial cells (arterioles and veins) d. diazoxide- opens K+ channels, stabilizes membrane (arterioles) e. fenoldopam- activates dopamine(D1) receptors on VSM (arterioles) 1. Low doses dopamine stimulates primarily dopamine receptors-Vasodilation 2. Higher doses- stimulates B1 receptors- positive inotropic effectIncreases CO Also releases NE from vascular nerve terminals-- vasoconstriction

*3. Effects on Cardiovascular System a. vasodilation resulting in decreased TPR4. Adverse effects a. reflex tachycardia b. nausea, vomiting c. possible fluid retention d. hypertrichosis (excessive hair growth)- minoxidil e. cyanide poisoning (nitroprusside) f. lupus (hydralazine)5. Contraindications6. Therapeutic Considerations a. used for resistant hypertension or hypertensive emergencies b. nitroprusside- emergency, malignant hypertension, iv only c. hydralazine, may cause lupus but safe for pregnancy d. diazoxide, emergency hypertension, iv.*1. Sites of action a. each class acts by specific mechanism, some at multiple sites2. Antihypertensives work on all systems and all levels of regulation a. Neural (SymNS)1. Brain2. Vascular Smooth Muscle3. Kidney b. Hormonal1. Blocks circulating catecholamines2. Blocks Ang II system c. Local1. Alters mechanism of smooth muscle contraction2. releases vasodilatory factors3. All alter CO and/or TPR

*1. Heart Failure ACE inhibitors- decreases pressure, blocks direct effects of AngII on heartInhibits remodeling Decrease Pre- and Afterload Diuretics- decrease volume associates with heart failure2. Myocardial infarction -antagonist- cardioprotective; dec SymNS dominance ACE-inhibitor- prevents AngII stimilatory effects on SymNS inhibits remodelling3. Diabetes ACE-inhibitors- increase renal function in diabetic renal neuropathyimproves intrarenal hemodynamics, dec. glomerular pressure AVOID blockers- mask signs of hypoglyciemia (tachycardia)4. Isolated systolic hypertension (Elderly) Diuretic preferred- decrease preload dihydropyridine Ca++ antagonist- decrease afterload*5. Renal Insufficiency ACE-inhibitors- can improve renal function; 6. Angina -antagonist- negative inotropic and chronotropic effect, decrease oxygen demand Ca++ antagonist- decreases afterload, decreases ischemia (dialtion) and O2 demand7. Asthma Ca++ channel blocker- inhibits contraction of airway smooth muscle AVOID -antagonist- b-2 stimulation increases airway diameter8. Elderly Diuretic preferred- long acting dihydropyridine Ca++ antagonist-*