Hemodynamic-pharmacological approach to reduce blood pressure Equations BP CO SVR Increased vasoconstriction with decreased arterial compliance due to... Progression of Hypertension Preferred method to reduce BP

Equations BP = CO \ SVR (systemic vascular resistance) CO = SV \ HR SVR = PVR (peripheral) + RVR (renal) Increased vasoconstriction with decreased arterial compliance due to... Abnormalities in capacitance, oscillatory and resistance arteries Structural abnormalities in VSM cells Imbalance between vasodilators and vasoconstrictors Progression of HTN Early HTN: Increased CO & relative (inappropriate) increase in SVR Established HTN: Decreased CO & increased SVR Late HTN: Decreased CO (-25%) & markedly elevated SVR (25-30%) Preferred method to reduce BP Method Reduce SVR Preserve CO Improve arterial compliance Maintain organ perfusion Avoid compensatory neurohumoral reflexes (tachycardia, salt and water overload, reflex vasoconstriction: NE, Ang II & ADH release) Maintain full 24-hour BP control Maintain BP control under all circumstances: rest, exercise, mental function

Therapeutic objectives in HTN Essential HTN stage 1-2 Goal during a 4-8 week period In most of the cases...

Essential HTN stage 1-2 Ultimate goal: CV reduce morbidity and mortality Lower BP Use BP as a surrogate end-point to guide therapy Goal during a 4-8 week period Bring BP within physiological range... \<140/90 \<130/80 mmHg for pts w/ diabetes or chronic renal disease ...by the least intrusive means possible No side effects or an acceptable placebo-like side effect profile) In most of the cases... This is a life-long treatment of an asymptomatic disease

Thiazides drugs Bendroflumethiazide Benzthiazide Chlorothiazide Hydrochlorothiazide Hydroflumethiazide Methyclothiazide Polythiazide Thiazide-like drugs Chlorthalidone Indapamide Metolazone

Diuretics: Thiazide & thiazide-like Mech Initial drop in BP is due to... Chronic action of TZD diuretics is due to... Low doses of TZDs Most common side effect Adverse effects Esp useful in... Low dose TZDs are combined with... Should be avoided in...

Mech Inhibition of the sodium/chloride symport in DT Reduce sodium and chloride re-absorption Initial drop in BP is due to... Increased sodium excretion and water loss Reduced extracellular fluid and plasma volume Chronic action of TZD diuretics is due to... Reduction of peripheral vascular resistance TZDs have some direct vasodilating properties and decreases vasocontrictor response of vascular smooth muscle cells to other vasoconstricting agents Low doses of TZDs 12.5-25 mg of hydrochlorothiazide [HCTZ] or its equivalent Relatively well tolerated Rarely cause severe rash, tombocitopenia and leucopenia Most common side effect Hypokalemia Adverse effects Reduction in serum potassium varies with the dose and is between 0.3-1 mmol Increase plasma lipid elevation Induce glucose intolerance and hyperuricemia Metabolic side effects don't compromise their expected beneficial effects on CVmorbidity and mortality Due to anti-HTn effects, TZDs are esp useful in... Elderly African Americans Pts w/ mild or incipient heart failure In pts w/ poorly controlled salt intake When cost is crucial Low dose TZDs are combined with... Other first line antihypertensive drugs Should be avoided in... Pts with NIDDM, hyperlipidemia or gout

Diuretics: Sodium channel inhibitors (K-sparing) Drugs Effects

Drugs Amiloride Triamterene Effects Produce little reduction in BP themselves May be useful in combination with other diuretics to prevent hypokalemia

``` Diuretics: Aldo antagonists (K-sparing) ``` Spironolactone Effects Unlike amiloride and triamterene, spironolactone... Aldo antagonism Clinical effects Eplerenone Treats... Effects Compared to spironolactone

Spironolactone Effects Mild anti-HTN due to inhibiting aldo's effect on arteriole smooth muscle Alters the EC-IC Na gradient across the membrane Inhibits the effects of aldo on the DT Unlike amiloride and triamterene, spironolactone... Exhibits its diuretic effect only in the presence of alo These effects are enhanced in pts w/ hyperaldosteronism Aldo antagonism Enhances sodium, chloride, and water excretion Reduces the excretion of potassium, ammonium, and phosphate Clinical effects Improves survival and reduces hospitalizations in pts w/ severe heart failure (NYHA Class IV) when added to conventional therapy (ACE-I & loop diuretic, w/ or w/o digoxin) Eplerenone Treats... HTN Post-MI pts w/ heart failure Effects More selective aldo receptor antagonist Lower incidence of side effects (gynecomastia) due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors Compared to spironolactone More expensive

Beta blockers All treat...except Other indications Sotalol Esmolol BB mechs

All treat HTN except Esmolol Sotalol Other indications Angina pectoris MI Ventricular arrhythmia Migraine prophylaxis Heart failure Perioperative HTN Sotalol Delays ventricular repolarization Maintains sinus rhythm in pts w/ chronic atrial fibrilation Esmolol Short half-life Treats hypertensive (perioperative) urgency & atrial arrhythmias after cardiac surgery BB mechs Block the action of catecholamines at β adrenergic receptors throughout the circulatory system and other organs Slow the HR and reduce force of contraction Inhibit renin release via inhibition of β1 receptors at JG cells

Beta blocker classification Cardoiselective BBs BBs w/ intrinsic sympathomimetic activity (ISA) Lipophilic BBs BBs in general

Cardoiselective BBs High affinity for cardiac β1 Less affinity for bronchial and vascular β2 receptors Reduces β2 receptor-mediated side effects Increasing doses --\> cardiac selectivity disappears Lipid-soluble agents cross the BBB more readily & are associated w/ more central side effects BBs w/ intrinsic sympathomimetic activity (ISA) Stimulate β receptors when background SNS activity is low Block β receptors when background SNS activity is high Less likely to cause bradycardia, bronchospasm, reduced cardiac, peripheral vasoconstriction & increased lipids Less frequently used to treat HTN Lipophilic BBs Ex. labetalol & carvedilol Have both α1- and β1-blocking properties Decrease HR & peripheral vascular resistance Possess the side effects common for both classes of drug BBs in general Less effective in the elderly and in black pts To reduce side effects, use a BB w/ high cardioselectivity, low lipid solubility, & long half-life that allows once daily dosing

Beta blocker adverse effects General Conduction HR Lungs Extremities Lipid-soluble agents CNS Exercise Glucose

General Slow the rate of conduction at the AV node Contraindicated in pts w/ 2nd & 3rd degree heart block Sinus bradycardia (common) Treatment should be stopped if pt is symptomatic or HR \ vasoconstriction --\> adverse effects in patients with peripheral circulatory insufficiency Reasonably tolerated in patient with mild peripheral vascular disease Lipid-soluble agents CNS: insomnia, nightmares, & fatigue Reduced exercise capacity --\> tiredness and fatigue Worsen glucose intolerance & hyperlipidemia Diabetic pts: mask signs of hypoglycemia Diabetic HTN pts w/ previous MI should not be denied BB because of concerns about metabolic side effects

Alpha-1 adrenergic receptor blockers Drugs Effects Doxazosin, terazosin, (& prazosin) Alfuzosin & tamsulosin Treatment of HTN Adverse effects

Drugs (-osin) Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin Effects Block NE at post-synatpic α 1 receptors in arteries & veins --\> vasodilation --\> decrease peripheral resistance w/o a compensatory rise in CO Doxazosin, terazosin, (& prazosin) Used orally to treat HTN More selective for α 1b - and α 1d-receptors Involved in vascular smooth muscle contraction Alfuzosin & tamsulosin Used to symptomatically treat BPH Less anti-HTN effects More selective as antagonists at the α1a subtype Primary subtype in the prostate Treatment of HTN No longer first-line Drugs of choice to treat HTN in pts w/ BPH Adverse effects First dose HoTN Dizziness Lethargy Fatigue Palpitation Syncope Peripheral edema Incontinence

Angiotensin converting enzyme Inhibitors (ACE-Is) Drugs Captopril Benazepril, enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril Lisonopril Others Mech RAAS Vasodilators Adrenergic tone Renal hemodynamics Treatment of HTN Other indications Adverse effects

Drugs (-pril) Captopril Short acting, sulfhydryl-group containing agent Benazepril, enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril Pro-drugs that have to be converted to active metabolites Lisonopril Active non-metabolized ACE-I Others Perindopril, Trandolapril Mech Inhibit conversion of AI to AII --\> block RAAS AII: powerful vasoconstrictor & stimulator of release of Na-retaining aldo --\> decreased peripheral vascular resistance --\> reduction in aldo plasma levels Reduce the breakdown of bradykinin (vasodilator) Enhance their action --\> cough (most common side effect) Reduce central adrenergic tone Influence renal hemodynamics (i.e., reduce intraglomerular HTN) --\> beneficial effects in proteinuric renal disease Treatment of HTN Less effective in pts w/ lower renin levels African Americans & elderly Ineffectiveness can be overcome by... Higher doses of ACEI Adding a diuretic Other indications Heart failure LV dysfunction Diabetic nephropathy Acute MI Adverse effects Cough (most frequent 3-10%) HoTN (particularly in volume depleted patients) Hyperkalemia Angioedema Renal Insufficiency Fetal injury (2nd & 3rd trimesters)

Angiotensin II receptor antagonists (ARBs) Drugs Mech ARBs vs. ACE-Is

Drugs (-sartan) Losartan, Valsartan, Irbesartan, Candesartan, Eprosartan, Tasosartan, Telmisartan Mech Block AII type-1 receptors --\> Inhibit RAAS Don't inhibit breakdown of bradykinin --\> don't cause cough Lack the additional physiological benefits that rises in bradykinin levels may bring ARBs vs. ACE-Is Similar physiological effects Produce similar falls in BP Same indications & adverse effects profile (except cough)

Renin inhibitors Drug General Renin Use Effects Adverse events Doses \> 300 mg

Drug Aliskiren General Non-peptide, orally active Renin Catalyzes the 1st & rate-limiting step of RAAS Conversion of angiotensinogen to inactive decapeptide anigotensin I Use Treat HTN either alone or in combination with other anti-HTN First new anti-HTN agent in \> 15 years Effects Modest anti-HTN effects Adverse events Headache Dizziness Some GI events Doses \> 300 mg Don't improve BP response Associated w/ increased GI adverse events

Calcium channel blockers (CCBs) Mech Dihydropyridines Non-dihydropiridines Adverse effects Vasodilatation --\> Some effects can be offset by... Verapamil and Diltiazem --\> Verapamil, diltiazem & short-acting dihydropyridines should be avoided in pts w/...

Mech Block L-class voltage gated Ca channels --\> block transmembrane entry of Ca into arteriolar smooth muscle cells & cardiac myocytes --\> inhibit the excitation-contraction process Dihydropyridines Potent vasodilators of peripheral and coronary arteries Non-dihydropiridines Verapamil and Diltiazem Moderate vasodilators w/ significant cardiac effects Adverse effects Vasodilatation (esp short-acting dihydropyridines) --\> Ankle edema (most common) Headache Flushing Palpitation Some effects can be offset by combining a CCB + BB Verapamil and Diltiazem --\> Constipation More seriously: heart block, esp in pts w/ underlying conduction problems Verapamil, diltiazem & short-acting dihydropyridines should be avoided in pts w/... Heart failure

Pharmacologic effects of CCBs: Dihydropyridines, Verapamil & Diltiazem for each Peripheral Vasodilation Heart Rate Cardiac Contractility SA/AV nodal conduction Coronary Blood Flow

Peripheral Vasodilation Dihydropyridines ↑↑ Verapamil ↑ Diltiazem ↑ Heart Rate Dihydropyridines ↑ Verapamil ↓↓ Diltiazem ↓ Cardiac Contractility Dihydropyridines 0 / ↓ Verapamil ↓↓ Diltiazem ↓ SA/AV nodal conduction Dihydropyridines 0 Verapamil ↓ Diltiazem ↓ Coronary Blood Flow Dihydropyridines ↑↑ Verapamil ↑ Diltiazem ↑

25 Pharmacology of Antihypertensive Drugs Flashcards by Heather Acuff

Hemodynamic-pharmacological approach to reduce blood pressure

Equations
- BP
- CO
- SVR
Increased vasoconstriction with decreased arterial compliance due to…
Progression of Hypertension
Preferred method to reduce BP

Equations
- BP = CO * SVR (systemic vascular resistance)
- CO = SV * HR
- SVR = PVR (peripheral) + RVR (renal)
Increased vasoconstriction with decreased arterial compliance due to…
- Abnormalities in capacitance, oscillatory and resistance arteries
- Structural abnormalities in VSM cells
- Imbalance between vasodilators and vasoconstrictors
Progression of HTN
- Early HTN: Increased CO & relative (inappropriate) increase in SVR
- Established HTN: Decreased CO & increased SVR
- Late HTN: Decreased CO (-25%) & markedly elevated SVR (25-30%)
Preferred method to reduce BP
- Method
  - Reduce SVR
  - Preserve CO
  - Improve arterial compliance
  - Maintain organ perfusion
- Avoid compensatory neurohumoral reflexes (tachycardia, salt and water overload, reflex vasoconstriction: NE, Ang II & ADH release)
- Maintain full 24-hour BP control
- Maintain BP control under all circumstances: rest, exercise, mental function

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Therapeutic objectives in HTN

Essential HTN stage 1-2
Goal during a 4-8 week period
In most of the cases…

Essential HTN stage 1-2
- Ultimate goal: CV reduce morbidity and mortality
- Lower BP
  - Use BP as a surrogate end-point to guide therapy
Goal during a 4-8 week period
- Bring BP within physiological range…
  - <140/90
  - <130/80 mmHg for pts w/ diabetes or chronic renal disease
- …by the least intrusive means possible
  - No side effects or an acceptable placebo-like side effect profile)
In most of the cases…
- This is a life-long treatment of an asymptomatic disease

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Diuretics

Thiazides drugs
- Bendroflumethiazide
- Benzthiazide
- Chlorothiazide
- Hydrochlorothiazide
- Hydroflumethiazide
- Methyclothiazide
- Polythiazide
Thiazide-like drugs
- Chlorthalidone
- Indapamide
- Metolazone

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Diuretics:
Thiazide & thiazide-like

Mech
Initial drop in BP is due to…
Chronic action of TZD diuretics is due to…
Low doses of TZDs
Most common side effect
Adverse effects
Esp useful in…
Low dose TZDs are combined with…
Should be avoided in…

Mech
- Inhibition of the sodium/chloride symport in DT
- Reduce sodium and chloride re-absorption
Initial drop in BP is due to…
- Increased sodium excretion and water loss
- Reduced extracellular fluid and plasma volume
Chronic action of TZD diuretics is due to…
- Reduction of peripheral vascular resistance
- TZDs have some direct vasodilating properties and decreases vasocontrictor response of vascular smooth muscle cells to other vasoconstricting agents
Low doses of TZDs
- 12.5-25 mg of hydrochlorothiazide [HCTZ] or its equivalent
- Relatively well tolerated
- Rarely cause severe rash, tombocitopenia and leucopenia
Most common side effect
- Hypokalemia
Adverse effects
- Reduction in serum potassium varies with the dose and is between 0.3-1 mmol
- Increase plasma lipid elevation
- Induce glucose intolerance and hyperuricemia
- Metabolic side effects don’t compromise their expected beneficial effects on CVmorbidity and mortality
Due to anti-HTn effects, TZDs are esp useful in…
- Elderly
- African Americans
- Pts w/ mild or incipient heart failure
- In pts w/ poorly controlled salt intake
- When cost is crucial
Low dose TZDs are combined with…
- Other first line antihypertensive drugs
Should be avoided in…
- Pts with NIDDM, hyperlipidemia or gout

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Diuretics:
Sodium channel inhibitors (K-sparing)

Drugs
Effects

Drugs
- Amiloride
- Triamterene
Effects
- Produce little reduction in BP themselves
- May be useful in combination with other diuretics to prevent hypokalemia

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Diuretics:
Aldo antagonists (K-sparing)

Spironolactone
- Effects
- Unlike amiloride and triamterene, spironolactone…
- Aldo antagonism
- Clinical effects
Eplerenone
- Treats…
- Effects
- Compared to spironolactone

Spironolactone
- Effects
  - Mild anti-HTN due to inhibiting aldo’s effect on arteriole smooth muscle
  - Alters the EC-IC Na gradient across the membrane
  - Inhibits the effects of aldo on the DT
- Unlike amiloride and triamterene, spironolactone…
  - Exhibits its diuretic effect only in the presence of alo
  - These effects are enhanced in pts w/ hyperaldosteronism
- Aldo antagonism
  - Enhances sodium, chloride, and water excretion
  - Reduces the excretion of potassium, ammonium, and phosphate
- Clinical effects
  - Improves survival and reduces hospitalizations in pts w/ severe heart failure (NYHA Class IV) when added to conventional therapy (ACE-I & loop diuretic, w/ or w/o digoxin)
Eplerenone
- Treats…
  - HTN
  - Post-MI pts w/ heart failure
- Effects
  - More selective aldo receptor antagonist
  - Lower incidence of side effects (gynecomastia) due to its reduced affinity for glucocorticoid, androgen, and progesterone receptors
- Compared to spironolactone
  - More expensive

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Beta blockers

All treat…except
Other indications
Sotalol
Esmolol
BB mechs

All treat HTN except
- Esmolol
- Sotalol
Other indications
- Angina pectoris
- MI
- Ventricular arrhythmia
- Migraine prophylaxis
- Heart failure
- Perioperative HTN
Sotalol
- Delays ventricular repolarization
- Maintains sinus rhythm in pts w/ chronic atrial fibrilation
Esmolol
- Short half-life
- Treats hypertensive (perioperative) urgency & atrial arrhythmias after cardiac surgery
BB mechs
- Block the action of catecholamines at β adrenergic receptors throughout the circulatory system and other organs
- Slow the HR and reduce force of contraction
- Inhibit renin release via inhibition of β1 receptors at JG cells

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Beta blocker classification

Cardoiselective BBs
BBs w/ intrinsic sympathomimetic activity (ISA)
Lipophilic BBs
BBs in general

Cardoiselective BBs
- High affinity for cardiac β1
- Less affinity for bronchial and vascular β2 receptors
  - Reduces β2 receptor-mediated side effects
- Increasing doses –> cardiac selectivity disappears
- Lipid-soluble agents cross the BBB more readily & are associated w/ more central side effects
BBs w/ intrinsic sympathomimetic activity (ISA)
- Stimulate β receptors when background SNS activity is low
- Block β receptors when background SNS activity is high
- Less likely to cause bradycardia, bronchospasm, reduced cardiac, peripheral vasoconstriction & increased lipids
- Less frequently used to treat HTN
Lipophilic BBs
- Ex. labetalol & carvedilol
- Have both α1- and β1-blocking properties
- Decrease HR & peripheral vascular resistance
- Possess the side effects common for both classes of drug
BBs in general
- Less effective in the elderly and in black pts
- To reduce side effects, use a BB w/ high cardioselectivity, low lipid solubility, & long half-life that allows once daily dosing

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Beta blocker adverse effects

General
- Conduction
- HR
- Lungs
- Extremities
Lipid-soluble agents
- CNS
- Exercise
- Glucose

General
- Slow the rate of conduction at the AV node
  - Contraindicated in pts w/ 2nd & 3rd degree heart block
- Sinus bradycardia (common)
  - Treatment should be stopped if pt is symptomatic or HR < 40 bpm
- Bronchospasm
  - Due to blockade of pulmonary ß2 receptors
  - Less common with cardioselective agents
  - All BBs are contraindicated in asthma
- Cold extremities, Raynaud’s phenomenon, & intermittent claudication
  - Blockade of ß receptors in the peripheral circulation –> vasoconstriction –> adverse effects in patients with peripheral circulatory insufficiency
  - Reasonably tolerated in patient with mild peripheral vascular disease
Lipid-soluble agents
- CNS: insomnia, nightmares, & fatigue
- Reduced exercise capacity –> tiredness and fatigue
- Worsen glucose intolerance & hyperlipidemia
  - Diabetic pts: mask signs of hypoglycemia
  - Diabetic HTN pts w/ previous MI should not be denied BB because of concerns about metabolic side effects

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Alpha-1 adrenergic receptor blockers

Drugs
Effects
Doxazosin, terazosin, (& prazosin)
Alfuzosin & tamsulosin
Treatment of HTN
Adverse effects

Drugs (-osin)
- Prazosin, Terazosin, Doxazosin, Alfuzosin, Tamsulosin
Effects
- Block NE at post-synatpic α 1 receptors in arteries & veins
- –> vasodilation
- –> decrease peripheral resistance w/o a compensatory rise in CO
Doxazosin, terazosin, (& prazosin)
- Used orally to treat HTN
- More selective for α 1b - and α 1d-receptors
  - Involved in vascular smooth muscle contraction
Alfuzosin & tamsulosin
- Used to symptomatically treat BPH
- Less anti-HTN effects
- More selective as antagonists at the α1a subtype
  - Primary subtype in the prostate
Treatment of HTN
- No longer first-line
- Drugs of choice to treat HTN in pts w/ BPH
Adverse effects
- First dose HoTN
- Dizziness
- Lethargy
- Fatigue
- Palpitation
- Syncope
- Peripheral edema
- Incontinence

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Angiotensin converting enzyme Inhibitors (ACE-Is)

Drugs
- Captopril
- Benazepril, enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril
- Lisonopril
- Others
Mech
- RAAS
- Vasodilators
- Adrenergic tone
- Renal hemodynamics
Treatment of HTN
Other indications
Adverse effects

Drugs (-pril)
- Captopril
  - Short acting, sulfhydryl-group containing agent
- Benazepril, enalapril, fosinopril, moexipril, quinapril, ramipril, spirapril
  - Pro-drugs that have to be converted to active metabolites
- Lisonopril
  - Active non-metabolized ACE-I
- Others
  - Perindopril, Trandolapril
Mech
- Inhibit conversion of AI to AII –> block RAAS
  - AII: powerful vasoconstrictor & stimulator of release of Na-retaining aldo
  - –> decreased peripheral vascular resistance
  - –> reduction in aldo plasma levels
- Reduce the breakdown of bradykinin (vasodilator)
  - Enhance their action
  - –> cough (most common side effect)
- Reduce central adrenergic tone
- Influence renal hemodynamics (i.e., reduce intraglomerular HTN)
  - –> beneficial effects in proteinuric renal disease
Treatment of HTN
- Less effective in pts w/ lower renin levels
  - African Americans & elderly
- Ineffectiveness can be overcome by…
  - Higher doses of ACEI
  - Adding a diuretic
Other indications
- Heart failure
- LV dysfunction
- Diabetic nephropathy
- Acute MI
Adverse effects
- Cough (most frequent 3-10%)
- HoTN (particularly in volume depleted patients)
- Hyperkalemia
- Angioedema
- Renal Insufficiency
- Fetal injury (2nd & 3rd trimesters)

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Angiotensin II receptor antagonists (ARBs)

Drugs
Mech
ARBs vs. ACE-Is

Drugs (-sartan)
- Losartan, Valsartan, Irbesartan, Candesartan, Eprosartan, Tasosartan, Telmisartan
Mech
- Block AII type-1 receptors –> Inhibit RAAS
- Don’t inhibit breakdown of bradykinin –> don’t cause cough
  - Lack the additional physiological benefits that rises in bradykinin
    levels may bring
ARBs vs. ACE-Is
- Similar physiological effects
- Produce similar falls in BP
- Same indications & adverse effects profile (except cough)

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Renin inhibitors

Drug
General
Renin
Use
Effects
Adverse events
Doses > 300 mg

Drug
- Aliskiren
General
- Non-peptide, orally active
Renin
- Catalyzes the 1st & rate-limiting step of RAAS
- Conversion of angiotensinogen to inactive decapeptide anigotensin I
Use
- Treat HTN either alone or in combination with other anti-HTN
- First new anti-HTN agent in > 15 years
Effects
- Modest anti-HTN effects
Adverse events
- Headache
- Dizziness
- Some GI events
Doses > 300 mg
- Don’t improve BP response
- Associated w/ increased GI adverse events

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Calcium channel blockers (CCBs)

Mech
Dihydropyridines
Non-dihydropiridines
Adverse effects
- Vasodilatation –>
- Some effects can be offset by…
- Verapamil and Diltiazem –>
Verapamil, diltiazem & short-acting dihydropyridines should be avoided in pts w/…

Mech
- Block L-class voltage gated Ca channels
- –> block transmembrane entry of Ca into arteriolar smooth muscle cells & cardiac myocytes
- –> inhibit the excitation-contraction process
Dihydropyridines
- Potent vasodilators of peripheral and coronary arteries
Non-dihydropiridines
- Verapamil and Diltiazem
- Moderate vasodilators w/ significant cardiac effects
Adverse effects
- Vasodilatation (esp short-acting dihydropyridines) –>
  - Ankle edema (most common)
  - Headache
  - Flushing
  - Palpitation
- Some effects can be offset by combining a CCB + BB
- Verapamil and Diltiazem –>
  - Constipation
  - More seriously: heart block, esp in pts w/ underlying conduction problems
Verapamil, diltiazem & short-acting dihydropyridines should be avoided in pts w/…
- Heart failure

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Pharmacologic effects of CCBs:
Dihydropyridines, Verapamil & Diltiazem for each

Peripheral Vasodilation
Heart Rate
Cardiac Contractility
SA/AV nodal conduction
Coronary Blood Flow

Peripheral Vasodilation
- Dihydropyridines ↑↑
- Verapamil ↑
- Diltiazem ↑
Heart Rate
- Dihydropyridines ↑
- Verapamil ↓↓
- Diltiazem ↓
Cardiac Contractility
- Dihydropyridines 0 / ↓
- Verapamil ↓↓
- Diltiazem ↓
SA/AV nodal conduction
- Dihydropyridines 0
- Verapamil ↓
- Diltiazem ↓
Coronary Blood Flow
- Dihydropyridines ↑↑
- Verapamil ↑
- Diltiazem ↑

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Central alpha-2 agonists

Drugs
Mech
Methyl-dopa
Clonidine
Moxonidine

Study These Flashcards

Drugs
- Methyl-dopa
- Clonidine
Mech
- Stimulate central α 2 adrenergic receptors in rostral ventrolateral medulla which control sympathetic outflow
- –> decrease in central sympathetic tone
- –> decrease CO & peripheral vascular resistance
Adverse effects
- Sedation
- Dry mouth
- Fluid retention
Methyl-dopa
- Requires conversion to alpha-methyl NE
- Safe in pregnancy
  - Only indication for its use as a first line agent in HTN
Clonidine
- Does not require conversion to alpha-methyl NE
- Rapid onset of action (30-60 min)
  - Used in HTN urgency
- Short acting agent
  - Transdermal patch system was developed to provide 7-day constant dose of drug
- Abrupt withdrawal –> “rebound hypertension”
Moxonidine
- New centrally acting drug
- Acts on central imidazoline receptors
- Less side effects

Peripheral vasodilators

Drugs
Mech
Use
High doses of hydralazine in slow acetilators may induce…
Minoxidil
- Effects
  - Due to…
- Use
- Adverse effects
- Topical minoxidil
Parenteral vasodilators

Study These Flashcards

Drugs
- Hydralazine
- Minoxidil
Mech
- Oral vasodilators –> relax vascular smooth muscle –> decrease peripheral vascular resistance & BP
- –> compensatory responses mediated by baroreceptors, SNS, & RAAS
  - Reflex tachycardia
  - Fluid & Na retention
Use
- Long-term outpatient therapy of HTN
- 2nd line to treat HTN
- Must be combined w/ 1st line anti-HTNs to offset adverse effects
High doses of hydralazine in slow acetilators may induce…
- “Lupus-like” syndrome (arthralgia, myalgia, skin rashes, & fever)
Minoxidil
- –> reflex SNS stimulation & Na/fluid retention
  - Due to opening of K channels in smooth muscle membranes by its active metabolite minoxidil sulfate
- Must be used in combination with a BB & loop diuretic
- Adverse effects: headache, sweating, and hirsutism
- Topical minoxidil (Rogaine): stimulates hair growth to correct baldness
Parenteral vasodilators
- Nitroprusside, nitroglycerin, fenoldopam, diazoxide
- Used to treat HTN crisis

Adrenergic neural terminal inhibitors

Drugs
Mech
Use

Study These Flashcards

Drugs
- Guanethidine
- Guanadrel
- Reserpine
Mech
- Prevent normal physiologic release of NE from post-ganglionic SNS neurons –> lower BP
Use
- Rarely used to treat HTN due to unacceptable adverse effects (“pharmacologic sympathectomy”)

Ganglionic blockers

Drugs
Mech
Use
Adverse effects
- SNS
- PNS

Study These Flashcards

Drugs
- Mecamylamine
Mech
- Competitively block nicotinic cholinergic receptors on postganglionic neurons in both SNS & PNS ganglia
Use
- No longer used due to unacceptable adverse effects related to their primary action
Adverse effects
- Due to SNS inhibition
  - Excessive HoTN
  - Sexual dysfunction
- Due to PNS inhibition
  - Constipation
  - Urinary retention
  - Precipitatoin of glaucoma
  - Blurred vision
  - Dry mouth

Renal protective effects of antihypertensive drugs

HTN, proteinuria, & increased RAAS activity
The majority of pts w/ CKD
Treating HTN in pts w/ CKD requires > 2 drugs
- Main drugs
- Dif therapeutic modalities
- Additional beneficial effects

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HTN, proteinuria, & increased RAAS activity
- Play critical roles in the development/progression of renal damage
- Independent risk factors for both CKD & CV disease
- Influence each other in a vicious circle –> glomerulosclerosis & tubulointerstitial fibrosis
The majority of pts w/ CKD
- Have HTN
- BP should be controlled to < 130/80mmHg
Treating HTN in pts w/ CKD requires > 2 drugs
- RAAS inhibitor: ACE-I, ARB, or renin inhibitor
- Dif therapeutic modalities
  - Fixed dose of RAAS inhibitor + other anti-HTN agent
  - Dual blockade (ACEIs+ARB)
  - Supra-max doses of individual RAAS inhibitor
- Additional beneficial effects
  - Adding renin inhibitor or aldo antagonist to avoid “angiotensin escape” or “aldo escape”

Antihypertensive drugs for treatment of hypertensive emergency/urgency

HTN crisis
HTN emergencies
HTN urgencies
Absolute BP level (i.e., >250/150 mm Hg) or the rate of rise of BP
Therapeutic principles in HTN crisis
- General
- Treatment
- HTN emergency
- HTN urgency

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HTN crisis
- Severe HTN (DBP > 120 mmHg) which –> high morbidity & mortality if untreated
HTN emergencies
- Severe HTN + acute or ongoing end-organ damage
- Diagnosis based on clinical state > BP level
HTN urgencies
- Severe HTN - target-organ involvement
Absolute BP level (i.e., >250/150 mm Hg) or the rate of rise of BP
- –> HTN emergency due to risk of developing…
  - HTN encephalopathy
  - Intracerebral hemorrhage
  - Acute CHF
- Ex. children w/ acute GN or women w/ severe preeclampsia - eclampsia
Therapeutic principles in HTN crisis
- General
  - Be cautious but aggressive
  - Distinguish situations where rapid BP reduction is not necessary or may be even hazardous
- Treatment may be necessary based on a presumptive diagnosis (i.e., before results of laboratory tests are done)
  - Select an agent that allows for “precise” control of the BP (“titration”of BP)
- HTN emergency
  - Reduce BP (i.e., by 30% or to 105 mm Hg DBP) within minutes - hour
  - Prevent further rapid deterioration of the target organs’ function
- HTN urgency
  - Reduce BP within 1-24 hours

Antihypertensive drugs for treatment of hypertensive emergency/urgency

CNS emergencies
Cardiac emergencies
Renal emergencies

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CNS emergencies
- Hypertensive encephalopathy
- Intracerebral or subarachnoidal hemorrhage
- Thrombotic brain infarction w/ severe HTN
Cardiac emergencies
- Acute heart failure
- Acute coronary insufficiency
- Aortic dissection
- Post vascular surgery HTN
Renal emergencies
- Severe HTN w/ rapidly progressive renal failure
- Rapidly rising BP w/ rapidly progressive GN

Antihypertensive drugs for treatment of hypertensive emergency/urgency:
Sodium nitroprusside

General
Onset & duration
Effects
- General
- In pts w/ HTN
- In pts w/ heart failure
Peripheral vasodilatory effects
Metabolism
Contraindications
Toxicities
Safety
Adverse effects
Not drug of choice to treat HTN emergency in pts w/…

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General
- Extremely potent vasodilator
Onset & duration
- Rapid onset
- Short duration of action (t½ = 1-2 minutes)
Effects
- General
  - Decreases pre-load (venodilatation) and after-load (arteriolar dilatation)
- In pts w/ HTN
  - Decreases CO
  - Increases HR
- In pts w/ heart failure
  - Increases cardiac index, CO, & stroke volume
  - Decreases HR
Peripheral vasodilatory effects
- Due to a direct action on arterial and venous smooth muscle cells
- Other smooth muscle tissue & myocardial contractility aren’t affected
Metabolism
- Rapidly metabolized into cyanide radicals in the liver
- Converted to thiocyanate (a metabolite excreted almost entirely in the urine)
Contraindications
- Pts w/ severe liver or renal disease
Toxicities
- Cyanide toxicity (rare unless large doses + renal insufficiency)
- Thiocyanate toxicity in pts with renal insufficiency
  - Onset is slower than cyanide toxicity
Safety
- When administered w/ a computerized continuous infusion device utilizing continuous intra-arterial blood pressure monitoring
- Safest agent to use to treat HTN emergency
Adverse effects
- Related to the abrupt reduction in BP
- Nausea, vomiting, tachycardia, hypoxemia & “coronary steal” phenomenon
Not drug of choice to treat HTN emergency in pts w/…
- Acute coronary insufficiency
- Aortic dissection
- Severe preeclampsia and eclampsia
- Increased intracranial pressure

Antihypertensive drugs for treatment of hypertensive emergency/urgency:
Nitroglycerin

General
Mech
Pharmacological profile
Drug of choice in HTN pts w/…
Should not be used in pts w/…
Should be used with caution in…

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General
- Organic nitrate available in various dosage forms
Mech
- Converted in the vascular smooth muscles cells to NO
- NO (free radical) activates guanylate cyclase –> increase cGMP
- –> relaxation of vascular smooth muscle
Pharmacological profile
- Same as Na nitroprusside
- Exceptions
  - Greater effect on veins (venous pooling)
  - Beneficial redistribution of coronary blood flow
Drug of choice in HTN pts w/…
- Post coronary bypass HTN
- Acute coronary insufficiency
- Acute CHF when BP is only slightly increased.
Should not be used in pts w/…
- Increased intracranial pressure
- Glaucoma
- Severe anemia
- Constrictive pericarditis
Should be used with caution in…
- Elderly
- Volume depleted pts
- Pts w/ hepatic disease (increased risk of methemoglobinemia).

Antihypertensive drugs for treatment of hypertensive emergency/urgency: Nicardipine, Esmelol, & Fenoldapam * Nicardipine * Type * Treats... * Pharmacological profile * Selectivity * Esmelol * Type * Administration * Treats... * Pharmacological profile * Fenoldapam * Type * Treats... * Effects * Onset & duration * Adverse effects

* Nicardipine * Dihydropyridine CCB * Used intravenously to treat... * Postoperative HTN * HTN w/ increased intracranial pressure * Similar pharmacological profile with other CCBs * More selective for cerebral & coronary blood vessels * Esmelol * β1-selective BB * Administered via continuous IV infusion * Short duration --\> used to treat... * Acute HTN * Certain supraventricular arrhythmias * Otherwise similar pharmacological profile to other BBs * Fenoldapam * Selective agonist at postsynaptic dopamine DA1 receptors * Used intravenously to treat acute severe HTN * Effects * Dilates renal & mesenteric vascular beds * Decrease BP & total peripheral resistance * Increase renal plasma flow * Onset \> 5 min, duration ~30 minutes * Adverse effects: dose-related * Flushing, headache, nausea, vomiting, tachycardia, & HoTN

Antihypertensive drugs for treatment of hypertensive emergency/urgency: Drugs given by intermittent intravenous infusion * Labetalol * Enalaprilat * Diazoxide

* Labetalol * Combined α +β adrenergic receptor blocker * Enalaprilat * ACE-I * Active metabolite of pro-drug enalapril * Diazoxide * Prevents vascular smooth muscle contraction by opening K channels & stabilizing the membrane potential at the resting level * Induces rapid fall in systemic vascular resistance & BP associated w/ substantial tachycardia and an increase in CO * Causes renal salt & water retention * Can be avoided if the drug is used for short periods only * Inhibits insulin secretion --\> induces hyperglycemia * Used for treatment hyperinsulinoma -related hypoglycemia

Antihypertensive drugs for special populations * Heart Failure * Post-MI * High coronary disease risk * Diabetes * Chronic kidney disease * Recurrent stroke prevention

* Heart Failure * Diuretic * BB * ACE-I * ARB * Aldo antagonist * Post-MI * BB * ACE-I * Aldo antagonist * High coronary disease risk * Diuretic * BB * ACE-I * CCB * Diabetes * Diuretic * BB * ACE-I * ARB * Chronic kidney disease * ACE-I * ARB * CCB * Recurrent stroke prevention * Diuretic * ACE-I

Antihypertensive drugs for special populations: Hypertension in elderly * Pharmacological treatment * Recommended therapeutic goals * Drugs that lower BP * Treatment of HTN in very elderly (\>80yo)

* Pharmacological treatment * Lower initial doses * 1/2 dose than in younger pts * Reduction in BP should be gradual * Greater caution in pts w/ co-existing diseases or orthostatic HoTN * Recommended therapeutic goals * 85-90 mmHg in pts w/ diastolic HTN * SBP \< 150 * SBP reduction of –20 mmHg if initial is 160-180mmHg * Drugs that lower BP * Thiazide diuretics & BBs (also reduce mortality) * ACE-Is & long-acting Ca antagonists * Treatment of HTN in very elderly (\>80yo) * Anti-HTN treatment reduces stroke & overall mortality

Antihypertensive drugs for special populations: Hypertension in diabetic patients * HTN * Relationship b/n HTN & renal disorder * Kidneys in diabetic pts * Proteinuria * Treatment * Timing * BP vs. glycemic control * Initial therapy * Goal BP to prevent CVD * Drug of choice for diabetic HTN pts * If fail --\>

* HTN * Common prob in diabetic pts * In IDDM, the incidence of HTN is 5% at 10 years, 30% at 20 years, and 70% at 40 years * Relationship b/n HTN & renal disorder * BP rises 3 years after microalbuminuria * HTN in 15-25% of microalbuminuric pts * HTN in 75-85% of pts w/ overt nephropathy * In NIDDM (type II diabetes), 40% HTN before microalbuminuria occurs * Kidneys in diabetic pts * More sensitive to any increase in BP * Proteinuria * Marker of renal damage * Risk factor for progression of renal & CV disease * Treatment * Early to prevent CV disease & minimize progression of renal & retinal disease * Tight BP control _\>_ benefits of strict glycemic control * Initial therapy: non-pharmacological methods * Weight reduction, exercise, Na restriction, & avoidance of smoking & excessive alcohol ingestion. * Goal BP to prevent CVD in diabetic pts: 140/90 mm Hg. * Drug of choice for diabetic HTN pts: ACE-Is * If fail --\> low-dose long-acting (thiazide or thiazide-like) diuretic * ACE-I + diuretic normalizes BP in \>80% of pts w/ diabetes & HTN

Antihypertensive drugs for special populations: Hypertension in patients with ischemic heart disease (IHD) * IHD * 1st line treatment in HTN pt w/ stable angina pectoris * Treatment for HTN pts w/ unstable angina or MI * Treatment for pts w/ post-MI

* IHD * Most common form of target-organ damage associated w/ HTN * 1st line treatment in HTN pt w/ stable angina pectoris * BBs + long-acting CCBs * Treatment for HTN pts w/ unstable angina or MI * BBs or ACE-Is * Treatment for pts w/ post-MI * ACE-Is, BBs, & aldo antagonists reduce progression of LV dysfunction & mortality

Antihypertensive drugs for special populations: Hypertension in patients with heart failure (HF) * Treatment for HTN pts w/ asymptomatic ventricular dysfunction * Treatment for HTN pts w/ symptomatic ventricular dysfunction (NYHA III and IV) * Treatment for volume depleted HTN HF pt

* Treatment for HTN pts w/ asymptomatic ventricular dysfunction * ACE-Is + BBs * Treatment for HTN pts w/ symptomatic ventricular dysfunction (NYHA III and IV) * ACE-Is + BBs * + diuretics + AII receptor antagonists + aldo antagonists * Treatment for volume depleted HTN HF pt * ACE-Is may induce HoTN & acute renal failure * BBs may induce initial/transient worsening of HF

Antihypertensive drugs for special populations: Hypertension in patients with asthma * Beta-blockers * Cardioselective beta-blockers * ACE-Is * Diuretics * Treatment in pts w/ COPD and chronic hypercapnia

* Beta-blockers * Aren't safe in pts w/ asthma * Increase bronchial obstruction & airways reactivity * Inhibit the bronchodilatatory effects of beta agonist * Cardioselective beta-blockers * Also aren't safe in pts w/ asthma * Even topical to treat glaucoma --\> asthmatic exacerbations * ACE-Is * Not contraindicated & may be used * Rarely worsen airflow obstruction * Produce persistent dry cough * Aren't first line for HTN pts w/ asthma or COPD * Diuretics * Can be effectively used * Increased risk of **hypokalemia** * Inhaled beta-2 agonists drive potassium into cell * Orally administered corticosteroids increase urinary K excretion * Only low dose thiazides are used * Treatment in pts w/ COPD and chronic hypercapnia * Diuretics-induced metabolic alkalosis may suppress the ventilatory drive & exacerbate the hypoxia

Antihypertensive drugs for special populations: Hypertension in pregnancy * 4 major clinical presentations of elevated BP in pregnancy * Treatment in asymptomatic preeclamptic women * Acute reduction of BP is achieved by... * Treatment for chronic HTN

* 4 major clinical presentations of elevated BP in pregnancy * Preeclampsia (PE)-eclampsia * PE superimposed on preexisting HTN * Chronic HTN * Gestational HTN * Treatment in asymptomatic preeclamptic women * Initiated if diastolic pressure is 105 - 110 mmHg or systolic pressure is 160 mmHg * Acute reduction of BP is achieved by... * Short i.v. infusion of labetalol or hydralazine, followed by intermittent boluses if necessary * Calcium channel blockers nicardipiene & extend release nifedipine may be used * Immediate release nifedipine should be avoided * Treatment for chronic HTN * Methyldopa or labetalol alone * Resistant HTN: methyldopa or labetalol + CCBs

Non-Compliance and Pharmacotherapy of Hypertension

* Possible causes - contributing factors for noncompliance * Misunderstandings about the medication regimen * Complexity of the medication regimen * Adverse side effects * Concerns about taking medications * Patient–physician relationship * Cost/insurance coverage * Strategies to improve compliance * Simplifying the medication regimen * Appropriate drug selection based on patient’s characteristics * Improved patient–physician communication * Appropriate education * Behavioral strategies (self-monitoring of BP, BP diary) * Social support (family, physicians, nurses) * Continual monitoring of patient compliance by the physician

25 Pharmacology of Antihypertensive Drugs Flashcards

(34 cards)