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Pharmacology II Test 2
Bealer - HTN Agents (notes)
55
Pharmacology
Professional
02/02/2013

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Cards

Term

Anti-HTN Agents

Antihypertensive Agents - 7 Classes

(10)

Definition
  • Sites and mechanisms of action different
    • All decrease CO and/or TPR 
  • Often used in combination
    • to oppose compensatory reflex responses
      • Baroreflex activation of compensatory systems
    • to increase effectiveness of treatment
      • Due to diminished effectiveness at high dose of single agent 
      • Due to onset of adverse side effects at high doses
  • due to compelling conditions
    • Coexistent conditions which make multiple agents more effective 
Term

Anti-HTN Agents

Diuretics: General

(8)

Definition
  • Diuretics commonly used for hypertension
    • vary in natriuretic efficacy, renal site of action, hypotensive efficacy
  • Generally 1st pharmacological therapy 
    •  unless contraindicated
    • Diuretic as or more effective than
      • Ca++ channel blockers or ACE inhibitors (Dec., 2002, JAMA)
      • Alpha-adrenergic antagonists (Sept, 2003, Hypertension) 
  • 1st line treatment for hypertension 
Term

Anti-HTN Agents

Diuretics: SOA, MOA

(7)

Definition
  • Site of Action
    • renal nephrondiuretic agents work at different segments of nephron
  • Mechanism of Action
    • all diuretics decrease sodium reabsorption
    • act on renal systems, transporters, hormones, ion channels 
    • Where Na+ goes, Water will surely follow 
Term

Anti-HTN Agents

Diuretics: Effect on CV System

(4)

Definition
  • acute decrease in plasma volume
  • chronically, decrease in TPR, CO returns to normal
    • mechanism unknown
  • often used to compensate for Na+ retaining reflex induced by other 
Term

Anti-HTN Agents

Diuretics: Adverse Rxns

(4)

Definition
  • most secondary to decreased volume or altered electrolyte status
    • many renal mechanisms of Na+ reabsorption tied to transport of other electrolytes i.e. K+ Ca++, Mg++.
  • hyperlipidemia and increased low density lipoprotein- unknown mechanism
  • hyperglycemia, K+ depletion inhibits insulin secretion 
Term

Anti-HTN Agents

Diuretics: Contraindications

(6)

Definition
  • exaggerated response leading to adverse reactions- hypersensitivity 
  • compromised kidney function- insufficient delivery to site of action
    • agents act on lumen, decreased kidney function decreases access of agent to renal tubule, due to decreased GFR and/or renal blood flow
  • cardiac glycoside sensitivity changes with K+
    • Decreased Plasma K+ increases sensitivity to cardiac glycosides (Digitalis)
  • exacerbates existing low volume or salt conditions 
Term

Anti-HTN Agents

Diuretics: Therapeutic Considerations

Thiazides

(7)

Definition
  • Thiazides- Modest diuretic (distal conv. tubule)
    • usually first therapy, mild to moderate hypertension
    • Dec. BP 10-15 mmHg, 10-12 wks for max effect
    • co-administered with K+ sparing if hypokalemia present
    • most effective with low sodium diet
    • Generally effective on their own, often used in combination 
    • most commonly prescribed antihypertensive in US 
Term

Anti-HTN Agents

Diuretics: Therapeutic Considerations

Loop Diuretics

(2)

Definition
  • Loop diuretics- rapid, profound diuresis (loop of Henle) 
    • More severe hypertension, or HT with CHF 
Term

Anti-HTN Agents

Diuretics: Therapeutic Considerations

K+ Sparing Diuretics

(4)

Definition
  •  K+ sparing diuretics (distal convoluted tubule, collecting duct) 
    • Patients with hypokalemia
    • only modest increase in Na+ excretion
    • used in combination when K+ conservation is indicated
Term

Anti-HTN Agents

Diuretics: Therapeutic Considerations

Osmotic Diuretics

(3)

Definition
  • Osmotic diuretics- very effective diuretics (throughout tubular lumen)
    • usually iv only
    • hypertension emergencies 
Term

Anti-HTN Agents

Diuretics: Therapeutic Considerations

Max Antihypertensive Efficiency

(1)

Definition
  • more volume loss does not lower pressure further, second class indicated 
Term

Anti-HTN Agents

Peripheral α-adrenergic Antagonists

SOA

(5)

Definition
  • Peripheral Arterioles (resistance vessels) 
    • surrounded by smooth muscle
    • heavily innervated by post-synaptic SymNS nerves
    • neurotransmitter = norepinephrine
    • neuromuscular junction is major site of SymNS control of arteriolar diameter, which directly effects TPR 
Term

Anti-HTN Agents

Peripheral α-adrenergic Antagonists

MOA

(10)

Definition
  • Competitive Antagonist of norepinephrine (α-1 receptor subtype)
    • post-synaptic membrane
      • α-1 receptors are post-junctional
        • respond to neurally released norepinephrine 
      • α-2 receptors are extrajunctional
        • respond to circulating catecholamines
    • binds to α-1 adrenergic receptors
    • post-junctional receptor
    • prevents effects of neurally released norepinephrine
      • predominant mechanism of SymNS control of VSM constriction 
Term

Anti-HTN Agents

Peripheral α-adrenergic Antagonists

Effects of α-1 Receptor Blockade

(3)

Definition
  • arteriolar dilation- removal of tone- allow relaxation of VSM 
  • decreased TPR
  • little or no direct effects on CO 
Term

Anti-HTN Agents

Peripheral α-adrenergic Antagonists

Adverse Effects/Contraindications

(6)

Definition
  • Adverse Effects
    • 1st dose precipitous fall in BP
    • due in part to no or minimum reflex tachycardia (α2-adrenergic autoinhibition of norepinephrine release in the heart).
  • Contraindications
    • No compelling contraindications
    • Hypersensitivity 
Term

Anti-HTN Agents

Peripheral α-adrenergic Antagonists

Therapeutic Considerations

(8)

Definition
  •  no reflex tachycardia- does not impair exercise tolerance 
  • can use with diabetes, asthma, hypercholesterolemia
    • does not alter plasma glucose or mask hypoglycemic tachycardia
    • does not inhibit airway β-adrenergic receptors
    • alters plasma lipids favorably (decreased LDL, mechanism unknown)
  • combinations-
    • Diuretic to counteract sodium retention
    • β antagonist- can lower dose, additive 
Term

Anti-HTN Agents

Other Peripheral Sympatholytic Agents

(3)

Definition
  • Not α-antagonists
  • Guanethidine (Ismelin)-
    • replaces norepinephrine in nerve terminal 
Term

Anti-HTN Agents

Central Sympatholytics (α-2 Agonists)

SOA, MOa

(8)

Definition
  • Site of Action CNS
    • medullary cardiovascular centers
      • clonidine- direct agonist
      • methyldopa- converted to methylnorepinephrine
        • acts like norepinephrine 
  • Mechanism of action
    • α-2 agonist activates CENTRAL α-2 receptors
    • hypotensive action due to CNS action 
Term

Anti-HTN Agents

Central Sympatholytics (α-2 Agonists)

Effects on CV System

(3)

Definition
  •  CNS inhibition SymNS outflow 
  • decreased vasoconstriction
  • decreased TPR 
Term

Anti-HTN Agents

Central Sympatholytics (α-2 Agonists)

Adverse Effects/Contraindications

(6)

Definition
  • Adverse Effects- due to CNS actions 
    • dry mouth
    • sedation
    • impotence
  • Contraindications
    • no strong contraindications 
Term

Anti-HTN Agents

Central Sympatholytics (α-2 Agonists)

Therapeutic Consideration

(6)

Definition
  • Often used in conjunctions with diuretic
  • Sudden discontinuation can lead to rebound SymNS and increase BP
  • Methlydopa common drug in pregnancy
  • NOT 1st line drug
  • low dose predominant central hypotension 
    • high dose, begin to stimulate systemic vasoconstrictor α-2 receptors 
Term

Anti-HTN Agents

β-Adrenergic Antagonists

SOA,MOA

(5)

Definition
  • Site of Action- β receptors 
    • Heart
    • Kidney
  • Mechanism of action
    • Competitive antagonists β-receptors 
Term

Anti-HTN Agents

β-Adrenergic Antagonists

Effects on CV System

(8)

Definition
  •  Heart; 
    • decreases contractility; 
    • decreases CO
    • antagonizes catecholamine tachycardia 
  • Kidney; 
    • decreases 
      • renin release, 
      • Ang II, 
      • TPR 
Term

Anti-HTN Agents

β-Adrenergic Antagonists

Adverse Effects

(4)

Definition
  • chronic fatigue- cardiac effect
  • low exercise tolerance- cardiac effect
  • bradycardia
  • possible increased airways resistance- β-2 receptor block 
Term

Anti-HTN Agents

β-Adrenergic Antagonists

Contraindications

(5)

Definition
  •  asthma; pulmonary disease- decreased pulmonary function β-2 receptor block
  • diabetes- can mask hypoglycemic tachycardia,
    • alters carbohydrate metabolism, 
    • increases recovery time from hypoglycemia 
  • low heart rate 
Term

Anti-HTN Agents

β-Adrenergic Antagonists

Therapeutic Considerations

(6)

Definition
  • β- selectivity 1 or 2
  • asthma- β-1 selective
  • often used with diuretic to prevent reflex tachycardia
  • nadolol (Corgard)- non-selective, but 1/2 life= 20-24 hrs
  • metoprolol (Lopresor)-selective β-1, but shorter 1/2 life 3-4 hr. 
  • use post myocardial infarction, cardioprotective 
Term

Anti-HTN Agents

Angiotensin II Formation

(5)

Definition
  • Renin cleaves Ang I from angiotensinogen
  • Angiotenin I is inactive decapeptide
  • Angiotensin Converting Enzyme cleaves 2 amino acids-
    • resulting in the biologically active Angiotensin II
  • Cardiovascular/fluid volume effects mediated by AT1 receptor stimulation 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Classes and MOA

(6)

Definition
  • ACE inhibitors- mechanism of action
    • Reduce or eliminate activity of angiotensin II converting enzyme
    • Decrease formation of ang II
  • Angiotensin II AT1 receptor blockers- mechanism of action
    • Competitive antagonist at AT1 receptor 
    • Prevents binding of angiotensin II 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Effects on CV System

Renal

(3)

Definition
  • Maintenance of normal GFR
  • Reduces plasma vasopressin and aldosterone
    • Decreased CO 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Effects on CV System

Cardiac

(3)

Definition
  • Decreased Ang II and Norepinephrine effects
  • Decreased SymNS influence; 
    • Decreased CO 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Effects on CV System

Vascular
(4) 

Definition
  • 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 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Adverse Effects

(4)

Definition
  •  hyperkaelemia
  • altered gustatory sensation
  • angioedema- sudden edema skin/ mucous membranes; etiology unknown 
  • cough- increase bradykinin / prostaglandins 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Contraindications

(4)

Definition
  •  pregnancy- 
    • injury or death to fetus
  • bilateral renal stenosis- 
    • renal function depends on renin- angII system 
Term

Anti-HTN Agents

Anti-Angiotensin II Drugs

Therapeutic Considerations

(7)

Definition
  •  use with diabetes or renal insufficiency
    • Ang II contributes to decreased renal function 
  • use in heart failure
    • Ang II contributes to ventricular remodeling 
  • usually used with diuretic, additive with thiazide
    • Decreases sodium retention by reducing aldosterone
  • used where diuretic or β-blocker contraindicated or ineffective 
Term

Anti-HTN Agents

Ca++ Channel Blockers

SOA,MOA

(5)

Definition
  • Site of Action
    • Ca++ channels on vascular and cardiac muscle
  • Mechanism of Action
    • inhibition of Ca++ influx into muscle tissue 
    • dilates coronary and vascular smooth muscle 
Term

Anti-HTN Agents

Ca++ Channel Blockers

Effects on CV System

(1)

Definition
 Decreased TPR; predominant hypotensive effect    
Term

Anti-HTN Agents

Ca++ Channel Blockers

Adverse Effects
(5)
Definition
  • most associated with excessive vasodilation
    • mild to moderate edema
    • flushing
    • tachycardia- Nifedipine- due to reflex SymNS activation 
      • aggravates angina
    • bradycardia- Diltiazem, verapamil, 
Term

Anti-HTN Agents

Ca++ Channel Blockers

Contraindications

(3)

Definition
  • congestive heart failure for all- negative inotropic effect
  • pregnancy and lactation- injury to fetus, neonate???
  • myocardial infarction- cardiac effects 
Term

Anti-HTN Agents

Ca++ Channel Blockers

Therapeutic Considerations

(3)

Definition
  • wide efficacy profile including African Americans and elderly 
  • differential effects on cardiac and arterioles
  • long acting appear safe 
Term

Anti-HTN Agents

Ca++ Channel Blockers

MOA

(11)

Definition
  • Mechanism of Action- Systemic vascular vasodilation
  • hydralazine- alters intracellular calcium, increases nitric oxide in arterioles 
  • minoxidil- opens K+ channels on arteriolar membranes, stabilizes membrane
  • nitroprusside- induces nitric oxide from endothelial cells (arterioles and veins)
  • diazoxide- opens K+ channels, stabilizes membrane (arterioles)
  • fenoldopam- activates dopamine(D1) receptors on VSM (arterioles)
    • Low doses dopamine stimulates primarily dopamine receptors-
      • Vasodilation
    • Higher doses- stimulates B1 receptors- positive inotropic effect
      • Increases CO
    • Also releases NE from vascular nerve terminals-- vasoconstriction 
Term

Anti-HTN Agents

Ca++ Channel Blockers

Effects On CV System

Definition
Vasodilation results in decresed TPR
Term

Anti-HTN Agents

Ca++ Channel Blockers

Adverse Effects

(6)

Definition
  • reflex tachycardia
  • nausea, vomiting
  • possible fluid retention
  • hypertrichosis (excessive hair growth)- minoxidil 
  • cyanide poisoning (nitroprusside)
  • lupus (hydralazine) 
Term

Anti-HTN Agents

Ca++ Channel Blockers

Therapeutic Considerations

(4)

Definition
  •  used for resistant hypertension or hypertensive emergencies 
  • nitroprusside- emergency, malignant hypertension, iv only 
  • hydralazine, may cause lupus but safe for pregnancy
  • diazoxide, emergency hypertension, iv. 
Term

Anti-HTN Agents

Summary: SOA

Definition
  • Each class acts by specific mechanisms, some at multiple sites
Term

Anti-HTN Agents

Summary: MOA

Antihypertensives work on all systems and on all levels of regulation

Neural (SymNS)

(3)

Definition
  • Brain 
  • VSM
  • Kidney
Term

Anti-HTN Agents

Summary: MOA

Antihypertensives work on all systems and on all levels of regulation

Hormonal

(2)

Definition
  • Blocks circulating catecholamines
  • Blocks Ang II system
Term

Anti-HTN Agents

Summary: MOA

Antihypertensives work on all systems and on all levels of regulation

Local

(2)

Definition
  • Alters mechanism of smooth muscle contraction 
  • releases vasodilatory factors 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Heart Failure

(4)

Definition
  • ACE inhibitors- decreases pressure, blocks direct effects of AngII on heart
    • Inhibits remodeling 
  • Decrease Pre- and Afterload
  • Diuretics- decrease volume associates with heart failure 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

MI

(3)

Definition
  • β-antagonist- cardioprotective; dec SymNS dominance 
  • ACE-inhibitor- prevents AngII stimilatory effects on SymNS
    • inhibits remodelling 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Diabetes

(3)

Definition
  • ACE-inhibitors- increase renal function in diabetic renal neuropathy 
    • improves intrarenal hemodynamics, dec. glomerular pressure
  • AVOID β blockers- mask signs of hypoglyciemia (tachycardia) 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Isolated Systolic HTN (Elderly)

(2)

Definition
  • Diuretic preferred- decrease preload dihydropyridine 
  • Ca++ antagonist- decrease afterload 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Renal Insufficiency

Definition
  • ACEIs can improve renal function
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Angina

(2)

Definition
  • β-antagonist- negative inotropic and chronotropic effect, decrease oxygen demand
  • Ca++ antagonist- decreases afterload, decreases ischemia (dilation) and O2 demand 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Asthma

(2)

Definition
  • Ca++ channel blocker- inhibits contraction of airway smooth muscle
  • AVOID β-antagonist- β-2 stimulation increases airway diameter 
Term

Anti-HTN Agents

HTN Treatment w/ Some Common Co-existing Conditions

Elderly

(2)

Definition
  • Diuretic preferred-
  • long acting dihydropyridine Ca++ antagonist- 
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