25 Pharmacology of Antihypertensive Drugs

Question 1

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

Answer 1

• 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

Question 2

Therapeutic objectives in HTN

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

Answer 2

• 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

Question 3

Diuretics

Answer 3

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

Question 4

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…

Answer 4

• 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

Question 5

Diuretics:
Sodium channel inhibitors (K-sparing)

• Drugs
• Effects

Answer 5

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

Question 6

Diuretics:
Aldo antagonists (K-sparing)

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

Answer 6

• 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

Question 7

Beta blockers

• All treat…except
• Other indications
• Sotalol
• Esmolol
• BB mechs

Answer 7

• 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

Question 8

Beta blocker classification

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

Answer 8

• 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

Question 9

Beta blocker adverse effects

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

Answer 9

• 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

Question 10

Alpha-1 adrenergic receptor blockers

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

Answer 10

• 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

Question 11

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

Answer 11

• 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)

Question 12

Angiotensin II receptor antagonists (ARBs)

• Drugs
• Mech
• ARBs vs. ACE-Is

Answer 12

• 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)

Question 13

Renin inhibitors

• Drug
• General
• Renin
• Use
• Effects
• Adverse events
• Doses > 300 mg

Answer 13

• 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

Question 14

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/…

Answer 14

• 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

Question 15

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

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

Answer 15

• 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 ↑

Question 16

Central alpha-2 agonists

• Drugs
• Mech
• Methyl-dopa
• Clonidine
• Moxonidine

Answer 16

• 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

Question 17

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

Answer 17

• 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

Question 18

Adrenergic neural terminal inhibitors

• Drugs
• Mech
• Use

Answer 18

• 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”)

Question 19

Ganglionic blockers

• Drugs
• Mech
• Use
• Adverse effects
  
  • SNS
  • PNS

Answer 19

• 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

Question 20

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

Answer 20

• 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”

Question 21

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

Answer 21

• 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

Question 22

Antihypertensive drugs for treatment of hypertensive emergency/urgency

• CNS emergencies
• Cardiac emergencies
• Renal emergencies

Answer 22

• 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

Question 23

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/…

Answer 23

• 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

Question 24

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…

Answer 24

• 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).

Question 25

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

Answer 25

• 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

Question 26

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

• Labetalol
• Enalaprilat
• Diazoxide

Answer 26

• 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

Question 27

Antihypertensive drugs for special populations

• Heart Failure
• Post-MI
• High coronary disease risk
• Diabetes
• Chronic kidney disease
• Recurrent stroke prevention

Answer 27

• 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

Question 28

Antihypertensive drugs for special populations:
Hypertension in elderly

• Pharmacological treatment
• Recommended therapeutic goals
• Drugs that lower BP
• Treatment of HTN in very elderly (>80yo)

Answer 28

• 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

Question 29

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 –>

Answer 29

• 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

Question 30

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

Answer 30

• 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

Question 31

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

Answer 31

• 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

Question 32

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

Answer 32

• 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

Question 33

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

Answer 33

• 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

Question 34

Non-Compliance and Pharmacotherapy of Hypertension

Answer 34

• 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