antihypertensive drugs. learning objectives: 1.list the anti-hypertensive agents, their general...

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  • Antihypertensive drugs

  • Learning Objectives:List the anti-hypertensive agents, their general target 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. by the end of this session, you can

  • Ideal BP
  • Determinants of Arterial PressureMean Arterial Pressure=ArteriolarDiameterBloodVolumeStrokeVolumeHeartRateFilling PressureContractilityBlood VolumeVenous ToneCRITICAL POINT!Change any physical factors controlling CO and/or TPR and MAP can be altered.

  • 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.

  • 2. Secondary hypertension- due to specific organ pathology1. renal artery stenosis2. pheochromocytoma3. aortic coarctation4. adrenal tumorTypes and Etiology of Hypertension1. Essential Hypertension No known cause.CRITICAL POINT!Pharmacological Therapy used primarily for essential hypertension.

  • General 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 blood volume, cardiac and/or VSM function

  • Classes of Antihypertensive Agents1. Diuretics2. Peripheral a-1 Adrenergic Antagonists4. b-Adrenergic Antagonists3. Central Sympatholytics (a-2 agonists)5. Anti-angiotensin II Drugs(RAASI)6. Ca++ Channel Blockers7. VasodilatorsPharmacological TreatmentCRITICAL POINTS!Each designed for specific control systemOften used in combination

  • Major groups of drugsMAIN CLASSES ( First line agents)A ACEIs & ARBsB - - blockersC Ca channel blockersD DiureticsOthers Vasodilators Central sympathetic outflow inhibitors

  • 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)

  • 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 CO1. Site of Action Renal Nephron?

  • Vasodilatory effects of Diuretics

    Na Na Ca Ca

    Na Prostaglandin( PGE2), Kinin

    Na sensitivity to vasoconstrictor,

    Noradrenalin (NA)

  • AgAgACEAldosteroneAngiotensinogenReninRAAShydrolyzationNa Na retentionK excretionJaxtaglomerular cell

  • Diuretics (cont)4. Adverse Reactionsdizziness, electrolyte imbalance/depletion,hypokalemia, hyperlipidemia,hyperglycemia (Thiazides)gouturic acid 5. Contraindicationshypersensitivity, compromised kidney functioncardiac glycosideshypovolemia,hyponatremia

  • 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)

  • 2. Mechanism of ActionCompetitive antagonist at a-1 receptors on vascular smooth muscle. Peripheral a-1 Adrenergic AntagonistsCRITICAL POINT! Blocking -receptors on vascular smooth muscle allows muscle relaxation, dilation of vessel, and reduced resistance.Drugs: prazosin (Minipres); terazosin (Hytrin)1. Site of Action- peripheral arterioles, smooth muscle3. Effects on Cardiovascular SystemVasodilation, reduces peripheral resistance

  • 5. Contraindications Hypersensitivity

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

  • Central Sympatholytics (a-2 Agonists)Drugs: clonidine (Catapres), methyldopa (Aldomet)1. Site of ActionCNS medullary cardiovascular centersclonidine: direct a-2 agonist imidazoline-1 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.

  • 4. Adverse Effectsdry mouth; sedation; impotence;Central Sympatholytics (a-2 Agonists); cont.5. Therapeutic Considerationsgenerally not 1st line drugs;prolonged use--salt/water retention, add diureticRebound increase in blood pressure

  • 1. Sites of Actionb-1b-12. Mechanism of Actioncompetitive antagonist at b- adrenergic receptorsb-1SNSHeartKidney

  • The mechanism for reduction of BP of -R blockers-R blockersBlockade of 1-R on heart CardiacoutrputPeripheralresistance Renin AngiotensinII Aldosterone sodium, water retention blood volume Decrease in BPBlockade of -R in peripheraland central nervous systemInhibit NA release and vasomotor center PGI2 synthesis

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

  • 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- protective

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

  • RAAS and its inhibitors

  • Anti-Angiotensin II Drugs, cont3. Adverse Effectshyperkalemiaangiogenic edema (ACE inhib); cough (ACE inhib); rash; itching; Mnemonic for CAPTOPRIL side effects: Cough, Angioedema, Proteinuria, Taste change, hypOtension, Pregnancy problems, Rash, Increased renin, Lower pressure (lack of vasoconstriction)4. Contraindicationspregnancy; hypersensitivity; bilateral renal stenosis 5. Therapeutic Considerations:use with diabetes or renal insufficiency; adjunctive therapy in heart failure; often used with diuretic;Enalapril, iv for hypertensive emergency

  • Ca++ Channel BlockersDrugs: Phenylalkylamines; Dihydropyridines; Benzothiazepines Verapamil ; Nifedipine; Diltiazem ; Very Nice Drug2. Mechanism of Action- Blocks Ca++ channeldecreases/prevents contraction3. Effect on Cardiovascular systemVascular relaxationDecreased TPR1. Site of Action- Vascular smooth muscleK+Ca++Na+

  • Ca++ Channel Blockers, cont.5. ContraindicationsCongestive heart failure; pregnancy and lactation;Post-myocardial infarction6. Therapeutic Considerationsnifedipine t1/2 3-4h amlodipine t1/2 35-50h nitrendipine t1/2 8-12h

    t.i.d ===q8h4. Adverse Effectsnifedipine --Increase SymNS activity; headache; dizziness; peripheral edema?* long-acting or slow-release formulations should be used for high blood pressure

  • 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

  • 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)

  • Sites and Mechanisms of Action 3. -2 agonists4. b-blockersReceptor antag. 2. a-antag. 5. ang II antag. 7. Vasodilators 6. Ca++ antag.1. Diuretics4. b-blockersOther- 5. ACE inhibitorsVSM, Kidney, CNSCRITICAL POINTS!

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

  • Renal InsufficiencyACE InhibitorsAnginab-blockerCalcium channel antagonistsAsthmaCa++ channel blockersAVOID- b-blockers Treatment Strategy with Some Common co-existing Conditions, cont

  • principles of medication - Long-time/lifelong medication - the least effective

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