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Flashcards in 25 Pharmacology of Antihypertensive Drugs Deck (34):
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

  • 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

2

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

3

Diuretics

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

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...

  • 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

5

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

6

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

7

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

8

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

9

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
    • 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

10

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

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

  • 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)

12

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)

13

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

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/...

  • 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

15

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 ↑

16

Central alpha-2 agonists

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

  • 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

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

  • 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

18

Adrenergic neural terminal inhibitors

  • Drugs
  • Mech
  • Use

  • 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")

19

Ganglionic blockers

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

  • 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

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

  • 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
  • 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”

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

  • 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

22

Antihypertensive drugs for treatment of hypertensive emergency/urgency

  • CNS emergencies
  • Cardiac emergencies
  • Renal emergencies

  • 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

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/...

  • 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

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...

  • 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).

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

  • 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

26

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

27

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

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)

  • 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

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 -->

  • 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

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

  • 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

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

  • 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

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

  • 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

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

  • 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

34

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