ANTI - HYPERTENSIVE

Anatomy of Heart

Circulation of Heart

Electrial Conduction System Of Heart

HYPERTENSION Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. Normal blood pressure is 120/80 mm of Hg. High blood pressure is anything above 140/90 mm of Hg. Hypertension is classified into : Primary hypertension (Essential hypertension) -90-95% cases –high blood pressure with no medical cause. Secondary hypertension -5%cases –caused by conditions that affect kidneys,arteries,heart or endocrine systems.

Antihypertensive Drugs All antihypertensive drugs act on the familiar formula… BP = SVR x CO (HR v SV) They act by Reducing SVR .. or by... Reducing cardiac output …by… Reducing heart rate …or by… Reducing stroke volume

Classes of Antihypertensive Agents Diuretics ACE Inhibitors Angiotensin-II Receptor Blockers Renin Inhibitors Calcium Channel Blockers Beta Adrenergic Blockers Alpha Adrenergic Blockers Centrally acting Sympatholytics Vasodialators Potassium Channel Openers Endothelin Antagonist

Diuretics A reduction in blood volume reduces blood returning to the heart and so preload is reduced A reduction in preload reduces stroke volume CO = HR x SV Stroke volume and cardiac output decrease BP = CO x SVR Blood pressure decreases

1. Diuretics Chlorthalidone (Hygroton) Ethacrynic acid (Edecrin) 1. Thiazides Hydrochlorothiazide (HydroDIURIL, Esidrix); Chlorthalidone (Hygroton) 2. Loop diuretics Furosemide (Lasix); Bumetadine (Burmex); Ethacrynic acid (Edecrin) 3. K+ Sparing Amiloride (Midamor); Spironolactone (Aldactone); Triamterene (Dyrenium) 4. Osmotic Mannitol (Osmitrol); Urea (Ureaphil) DIURETIC AGENTS 1. Diuretics commonly used for hypertension a. vary in natriuretic efficacy, renal site of action, hypotensive efficacy 2. Generally 1st pharmacological therapy a. unless contraindicated b. 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 5. Other Combination - HCTH + Triamterene (Dyazide) Acetazolamide (Diamox)

Potassium sparing diuretics Loop diuretics Thiazide diuretics Potassium sparing diuretics Diuretics reduce the rate at which water is reabsorbed. This results in more water being lost from the body and ultimately a fall in blood volume

Site of Action Renal Nephron Urinary Na+ excretion 2. Mechanism of Action Urinary Na+ excretion Urinary water excretion Extracellular Fluid and/or Plasma Volume 3. Effect on Cardiovascular System 1. Site of Action a. renal nephron b. diuretic agents work at different segments of nephron 2. 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 follow 3. Effect on cardiovascular system a. acute decrease in plasma volume b. chronically, decrease in TPR, CO returns to normal mechanism unknown c. often used to compensate for Na+ retaining reflex induced by other antihypertensive agents. Acute decrease in CO Chronic decrease in TPR, normal CO Mechanism(s) unknown

Electrolyte imbalance/Depletion, Hypokalemia, Hyperlipidemia, 4. Adverse Reactions Dizziness, Electrolyte imbalance/Depletion, Hypokalemia, Hyperlipidemia, Hyperglycemia (Thiazides) Gout ( Hyperuricaemia) 5. Contraindications Hypersensitivity, Compromised kidney function Cardiac glycosides (K+ effects) Hypovolemia, Hyponatremia 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 secretion 5. 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

Angiotensin Converting Enzyme (ACE) inhibitors Examples – captopril, ramipril, perindopril etc. Used to treat hypertension and also heart failure ACE inhibitors interfere with the renin, angiotensin, aldosterone system that regulates long term BP. This system responds to a drop in blood pressure and works in conjunction with the baroreceptor reflex.

Renin, angiotensin, aldosterone system BP Renin Angiotensinogen Angiotensin I Angiotensin Converting Enzyme Angiotensin II

Renin, angiotensin, aldosterone system Angiotensin II ADH- vasopressin Aldosterone Vasoconstriction Thirst Blood Pressure Sodium retention

2. ACE Inhibitors & Angiotensin-II Receptor Blockers

  Angiotensin Converting Enzyme Inhibitors 2. Ang II Receptor Antagonists Losartan (Cozaar); Candesartan (Atacand); Valsartan (Diovan) Angiotensin Converting Enzyme Inhibitors Enalapril (Vasotec); Quinapril (Accupril); Fosinopril (Monopril); Moexipril (Univasc); Lisinopril (Zestril) Benazepril (Lotensin); Captopril (Capoten) 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 stimulation 2. 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 Angiotensinogen Ang I ACE Lung VSM Brain Kidney Adr Gland Ang I  AT1 Ang II ACE AT2  Ang II Renin

        Volume Aldosterone Vasopressin HR/SV Angiotensin II 3. Effect on Cardiovascular System Volume Aldosterone Vasopressin   HR/SV Angiotensin II Norepinephrine  Angiotensin II 3. Effects on Cardiovascular System a. Renal 1. Maintenance of normal GFR 2. Reduces plasma vasopressin and aldosterone Decreased CO b. Cardiac 1. Decreased Ang II and Norepinephrine effects Decreased SymNS influence; Decreased CO c. Vascular 1. 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 Vasoconstriction  SymNS   SymNS CO  TPR  CO

5. Contraindications 4. Adverse Effects Angiogenic edema (ACE inhib); Hyperkalemia Angiogenic edema (ACE inhib); Cough (ACE inhib); Rash; Itching; 5. Contraindications Pregnancy; Hypersensitivity; Bilateral renal stenosis

3. Calcium Channel Blocker

Effect on Cardiovascular system Vascular relaxation Decreased TPR Adverse Effects Nifedipine – Increase SymNS activity; Headache; Dizziness; Ankle edema(joint btn leeg &feet

Drugs: Mechanism of Action 4. β Adrenergic Blocker Propranolol (Inderal); Metoprolol (Lopressor) Atenolol (Tenormin); Nadolol (Corgard); Pindolol (Visken) Mechanism of Action Competitive antagonist at β- adrenergic receptors

3. Effects on Cardiovascular System a. Cardiac--  HR,  SV  CO b. Renal--  Renin   Angiotensin II   TPR 4. Adverse Effects Impotence; Bradycardia; Fatigue; Exercise intolerance; 5. Contraindications Asthma; Diabetes; Bradycardia; Hypersensitivity

5. A) Peripheral α-1 Adrenergic Blocker Drugs: Prazosin(Minipres); Terazosin (Hytrin) Site of Action- Peripheral arterioles, smooth muscle 2. Mechanism of Action Competitive antagonist at α-1 receptors on vascular smooth muscle.

3. Effects on Cardiovascular System Vasodilation, Reduces peripheral resistance 4. Adverse effects Nausea; Drowsiness; Postural hypotenstion;(first dose phenmenone)

B) Central Sympatholytics (α-2 Agonists) Drugs: Clonidine ( Direct α-2 Agonist ) Methyldopa ( False Neurotransmitter ) Site of Action CNS medullary Cardiovascular centers Mechanism of Action CNS α-2 Adrenergic Stimulation Peripheral Sympatho inhibition Decreased norepinephrine release

Effects on Cardiovascular System Decreased NE Vasodilation Decreased TPR Adverse Effects Dry mouth; Sedation; Impotence;

6 ) Vasodialators Drugs: Hydralazine (Apresoline); Minoxidil (Loniten); Nitroprusside (Nipride); Diazoxide (Hyperstat I.V.); Fenoldopam (Corlopam) Site of Action- Vascular smooth muscle

   NO DA Mechanism of action Nitroprusside Fenoldopam (Dopamine D1 Agonist) DA    K+ Minoxidil Diazoxide Na+ Ca++ Ca++ Hydralazine (directly acting arteriolar vasodilator)

Effect on cardiovascular system Decrease TPR Vasodilation, Decrease TPR Adverse Effects Reflex tachycardia Increase SymNS activity (hydralazine, minoxidil,diazoxide) Lupus (hydralazine) Cyanide toxicity (nitroprusside) Hypertrichosis (minoxidil)

7) Endothelin Antagonist Bosentan, a non-selective ET-1 receptor antagonist (blocks for ETA and ETB receptors) is currently used in the treatment of pulmonary hypertension

Sites and Mechanisms of Action Summary Sites and Mechanisms of Action 3. -2 agonists Receptor antag. 2. α-antag. 5. A-II Antag. 7. Vasodilators 6. Ca2+ Antag. 4. β-blockers 1. Diuretics 4. b-blockers Other- 5. ACE inhibitors Lung, VSM, Kidney, CNS 1. Sites of action a. each class acts by specific mechanism, some at multiple sites 2. Antihypertensives work on all systems and all levels of regulation a. Neural (SymNS) 1. Brain 2. Vascular Smooth Muscle 3. Kidney b. Hormonal 1. Blocks circulating catecholamines 2. Blocks Ang II system c. Local 1. Alters mechanism of smooth muscle contraction 2. releases vasodilatory factors 3. All alter CO and/or TPR CRITICAL POINTS! 1. Can alter CO/TPR at number of sites and/or mechanisms. 2. Antihypertensives mechanistically specific, and alter blood pressure through physiologically diverse effects on CO/TPR. 3. All organ systems and/or effector mechanisms are p’col targets.

Antiarrhythmic Drugs

Normal heartbeat and atrial arrhythmia Normal rhythm Atrial arrhythmia AV septum

ECG (EKG) showing wave segments Contraction of ventricles ECG (EKG) showing wave segments Repolarization of ventricles Contraction of atria

PHASES OF ACTION POTENTIAL >Plateau Stage >Cell less permeable to Na+ >Ca++ influx through slow Ca++ channels >K+ begins to leave cell Phase 1 >Limited depolarization >Inactivation of fast Na+ channels→ Na+ ion conc equalizes >↑ K+ efflux & Cl- influx Phase 3 >Rapid repolarization >Na+ gates closed >K+ efflux >Inactivation of slow Ca++ channels Phase 0 >Rapid depolarization >Opening fast Na+ channels→ Na+ rushes in →depolarization Phase 4 >Resting Membrane Potential >High K+ efflux >Ca++ influx

ARRHYTHMIAS result from: ARRHYTHMIA Absence of rhythm DYSRRHYTHMIA Abnormal rhythm ARRHYTHMIAS result from: Disturbance in Impulse Formation 2. Disturbance in Impulse Conduction Block results from severely depressed conduction Re-entry or circus movement / daughter impulse

ARRHYTHMIAS: Supraventricular: Ventricular: - Atrial Tachycardia - Paroxysmal Tachycardia Multifocal Atrial Tachycardia - Atrial Fibrillation - Atrial Flutter Ventricular: Wolff-Parkinson-White (preexcitation syndrome) Ventricular Tachycardia Ventricular Fibrillation Premature Ventricular Contraction

CLASS I: Sodium Channel Blocking Drugs IA - lengthen AP duration - Intermediate interaction with Na+ channels - Quinidine, Procainamide, Disopyramide IB - shorten AP duration - rapid interaction with Na+ channels - Lidocaine, Mexiletene, Tocainide, Phenytoin IC - no effect or minimal  AP duration - slow interaction with Na+ channels - Flecainide, Propafenone, Moricizine

CLASS II: BETA-BLOCKING AGENTS Increase AV nodal conduction Increase PR interval Prolong AV refractoriness Reduce adrenergic activity Propranolol, Esmolol, Metoprolol, Sotalol

CLASS III: POTASSIUM CHANNEL BLOCKERS Prolong effective refractory period by prolonging Action Potential Drugs : Amiodarone Ibutilide Bretylium Dofetilide Sotalol BIDAS

CLASS IV: CALCIUM CHANNEL BLOCKERS Blocks cardiac calcium currents → slow conduction → increase refractory period *esp. in Ca++ dependent tissues (i.e. AV node) Verapamil, Diltiazem, Bepridil

Miscellaneous: ADENOSINE → Inhibits AV conduction & Increases AV refractory period MAGNESIUM → Na+/K+ ATPase, Na+, K+, Ca++ channels POTASSIUM → Normalize K+ gradients

Implantation of Pacemaker