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Pharmacology > Antihypertensives > Flashcards

Antihypertensives Flashcards

1
Q

Monotherapy for antihypertensives

A

when BP is <20/10mm Hg above goal

  • ACEI or ARB, long-acting or
  • DHP CCB, long-acting or
  • Thiazide diuretic
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2
Q

antihypertensive combination therapy

A

when BP >20/10 mm Hg above goal

• Long-acting ACEI or ARB
plus long-acting DHP CCB

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3
Q

What hypertensive drugs are best for older individuals or african americans

A

DHP CCB (longacting) or thiazide diuretic

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4
Q

Angiotensin Converting Enzyme Inhibitors (ACEIs)

A

Captopril - 2-3 times daily dosing
Enalapril - 1 or 2 x daily
Lisinopril

3 chemical classes - Sulfhydrl-containing, Dicarboxylate-containing, and Phosphorus-containing

mostly prodrugs

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5
Q

ARBs Class Properties

A

Losartan
CYP2C9 and 3A4 metabolism
Renal/biliary excretion
Dosing: 1-2x daily

Valsartan
inactive metabolites, half-life longer in elderly
Dosing: 1x daily

Competitive inhibitors of AT1 receptor - Sustained receptor block even with increased levels of ANGII

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6
Q

ACEIs / ARBs lower blood pressure through what effects?

A

Decreased PVR - inhibiting AngII vasoconstriction action

↓ Mean SBP and DBP and ↑compliance of large arteries

increased Na+ and water excretion and decreasing aldosterone secretion
-this enhances efficacy of diuretics

vasodialation of afferent and efferent renal arteriole

They do not cause reflex tachycardia

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7
Q

Risk factors for hyperkalemia:

A
  • renal insufficiency,
  • diabetes,
  • elderly,
  • K+-sparing drugs
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8
Q

ACEIs Effects

A

Inhibit formation of AngII

Do not inhibit non-ACE AngII producing pathways

block conversion of AngI to AngII

Both ACEIs and ARBs increase Ang(1-7) levels

increase levels of bradykinin &raquo_space; vasodilation

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9
Q

ARBs Effects

A

Reduce activation or AT1 receptors
Permit activation of AT2 receptors

Block ANGII action at AT1 receptors

ARBs stimulate renin release →..→ ↑AngII formation; Block AngII effects

Both ACEIs and ARBs increase Ang (1-7) levels

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10
Q

ACE inhibitors and ARBs therapeutic uses

A

Hypertension - initial therapy, alone or in combination
=> start low dose
=> initial drop in BP, especially in patient with diuretic-induced volume depletion or CHF

Left ventricular hypertrophy regression reported with ACEIs, ARBs (and CCBs)

Post-MI for patients at high risk of subsequent CV events

HF with reduced ejection fraction - with loop diuretic – prolongs survival

chronic kidney disease - initial therapy, may slow disease progression

Diabetes mellitus – lower protein excretion and delay or slow the
rate of diabetic nephropathy progression

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11
Q

Adverse effects of ACEIs / ARBs

A

Hypotension
=> first few doses, vol depleted patients

Reduced GFR
=> relaxed efferent arteriole, may be severe in patients with reduces intrarenal perfusion pressure

Hyperkalemia
-reduced aldosterone secretion leads to impaired urinary K+ excretion

Cough
-Increased kinins may induce
bronchial irritation and cough

Angioedema
-related to elevated levels of bradykinin

Enteropathy - only seen with Olmesartan, characterized by severe chronic diarrhea and weight loss

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12
Q

contraindications of ACE inhibitors and ARB

A

Angioedema

Hypersensitivity / Anaphylaxis

Absolutely contraindicated in all trimesters of pregnancy - reduced renal function leads to oligohydramnios

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13
Q

Drug-Drug Interactions of ACEI and ARB

A

Concomitant ACEI-ARB therapy is NOT RECOMMENDED – possible increase risk of mortality in high-risk patients

aliskiren - enhanced hyperkalemia and hypotensive effects

potassium sparing druges - diuretics and NSAIDS

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14
Q

Aliskiren

A

Direct Renin Inhibitor

CYP3A4 metabolism; Excreted mainly unchanged in feces

once daily dosing

Potent competitive inhibitor of renin -> decreased ang I, II and aldosterone

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15
Q

Uses of Aliskiren

A

hypertension - not for initial treatment, monotherapy or combination therapy

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16
Q

Adverse Effects of Aliskiren

A

Symptomatic hypotension in volume or salt-depleted patients

Acute kidney injury and hyperkalemia in patients with low blood flow or deteriorating renal function

Angioedema

Contraindicated in pregnancy

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17
Q

Drug-Drug Interactions of Aliskiren

A

Other antihypertensive agents - use caution

Strong CYP3A4 inhibitors - use caution

p-glycoprotein inhibitors - increases systemic levels of drug

itraconazole and cyclosporine should be avoided

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18
Q

Why is use of Aliskiren in combination with ACEI or ARB not recommended?

A

Increased risk of hyperkalemia / hypotension

Does not lower the risk of cardiovascular event

Contraindicated in patients with diabetes mellitus taking an ACEI or ARB:
↑incidence of renal impairment, hypotension, and hyperkalemia

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19
Q

L-TYPE CALCIUM CHANNEL BLOCKERS (CCBs)

A 
Non-DHP 
=> Verapamil
=> Diltiazem 
DHP - oral 
=> Nifedipine
=> Amlodipine
DHP - I.V. 
=> Nicardipine
=> Clevidipine
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20
Q

Pharmacokinetics of CCBs

A

general class properties

Good oral absorption but reduced bioavailability

High plasma protein binding, p-glycoprotein substrates

CYP-mediated metabolism, esp. CYP3A4; t½ vary between 1.3 – 64 hours

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21
Q

Non-Dihydropyridines

A

Verapamil - 20-35% bioavailability, Oral 1-2 h, I.V. 1-5 min ~90% protein binding, CYP3A4, (and others) half-life: 4.5-12h

Diltiazem - 40% bioavail, Oral 30-60 min, I.V. 3 min, 75% protein binding, CYP3A4 metabolism, half-life 3 to 4.5 h

Used for angina prophylaxis, hypertension, rate control in atrial fibrillation, SVT treatment and prophylaxis

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22
Q

Dihydropyridines

A

Nifedipine (oral) – bioavail 40-77%, 20 min onset, >90% protein binding, CYP3A4 with half-life 2-5 hrs.

Amlodipine (oral) – 64-90% bioavail, 24-48 h onset, >90% protein binding, CYP3A4 30-50 h halflife

Nicardipine (I.V.) – onset in minutes, >95% protein binding, CYP3A4, 2C8, 2D6 with plasma halflife: α 3min, β 45 min, terminal 14h

Clevidipine (I.V.) – onset in 2-4 minutes, >99.5% protein binding, metabolism by tissue esterases and halflife I min

used for prophylaxis of angina and treatment of hypertension

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23
Q

Nifedipine

A

Dihydropyridine

Nifedipine extended release appears to cause less reflex tachycardia than the immediate release formulation

takes it from 3x daily to 1x daily

suppress premature
contractions in preterm labor

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24
Q

Amlodipine

A

Dihydropyridine

Amlodipine has slow absorption, minimal peaks and troughs, and prolonged effect.
It causes less reflex tachycardia, possible due to lower peaks and long t½

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25
Q

Why shouldn’t short half life DHP CCBs be used for hypertension?

A

They can cause:

Rapid drop in blood pressure

Oscillations in blood pressure control

Concurrent surges in sympathetic reflex activity.

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26
Q

MOA of L-type Voltage Gated Ca2+ Channels

A

Normal:
L-type Ca2+ channels have long, large, high threshold

Dominant type in vascular smooth muscle, cardiac myocytes, SA and AV nodal tissue

They mediate entry of EC Ca2+ and induce Ca2+-induced Ca2+ release → contraction of smooth muscle and cardiac muscle and stimulate SA node conduction

Drug Action:

CCBs bind to a site on the main poreforming (α1) subunit of the Ca2+ channel → block Ca2+ entry

Blocks smooth muscle contraction and drug binding reduces frequency of opening in response to depolarization and a decrease in transmembrane calcium current:

long-lasting smooth muscle relaxation, reduction in contractility through the heart and decreases SA node pacemaker rate and AV cconduction velocity.

CCBs bind more effectively to open channels and inactivated channels

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27
Q

What are the dose-dependent effects of calcium-channel blockers:

verapamil and diltiazem

Dihydropyridines

A

Verapamil / Diltiazem:
=> Decrease the channel’s rate of recovery
=>channel block is enhances as the frequency of stimulation increases
=> Depress rate of the sinus node pacemaker (automaticity)
=> Slow AV conduction

Dihydropyridines (DHPs)
=> potent vasodilators with reflex tachy and positive iontropy
=> does not affect the channels rate of recovery
=> does not affect conduction through the AV node

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28
Q

what are calcium antagonists’ cardiac and vascular effects?

A

Slow heart rate, Slow AV conduction and Reduce myocardial contractility

↓ peripheral arterial resistance => ↓ afterload => ↓O2 consumption

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29
Q

What are CCBs therapeutic uses and effects?

A

Hypertension
=> used for initial or add-on therapy; decrease BP by relaxation of arterioles and decreased SVR

Hypertensive emergency
=> DHP CCB plus labetalol or esmolol to prevent reflex tachycardia
=> Nicardipine: potent, long acting → duration ≤8 hours
=> Clevidipine: 1-minute t½ → duration 5-15 min

Angina - initial or add-on therapy - decreased PVR increases coronary blood flow and increases O2 delevery to myocardium.

Supraventricular tachyarrhythmias
=> verapamil/diltiazem, slow automaticity & slow conduction through AV node

Raynaud phenomenon
=> Long-acting DHP CCB may reduce intensity of attacks

Subarachnoid hemorrhage
=> to reduce incidence and severity of ischemic deficits

Migraine
=> Verapamil may prevent migraine

Tocolytic
=> Nifedipine (for 48 hours only) to suppress premature
contractions in preterm labor (24-34 weeks)

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30
Q

how is the CCB treatment different for different type/stages of angina?

A

Variant angina => CCBs first line

Exertional angina => BB plus DHP and CCB
=> Non-DHP act on the double product (HR x SBP) →↓ O2 demand

Unstable angina /acute coronary syndrome:
=> DHP CCB when combined with BB
=> Non-DHP only for paitents who do not tolerate BB

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31
Q

Adverse Effects of CCBs

A

non-DHP: bradycardia and worsening cardiac output, constipation (especially verapamil)

DHP: peripheral edema caused by vasodilation which increased capillary pressure and permeability leading to the edema.

Both – GERD aggravation

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32
Q

Contraindications of Verapamil and Diltazem

A

Increased risk of AV block and/or severe depression of ventricular function

=> I.V. verapamil + I.V. beta blocker

verapamil or diltiazem in patients with ventricular dysfunction,. SA or AV nodal conduction disturbances and SBP below 90 mm Hg

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33
Q

Contraindications of Nifedipine

A

immediate-release is not for use in patients with acute or unstable angina and STEMI because it may precipitate or aggravate myocardial infarction

short-acting formulations are not appropriate in the long-term treatment of angina or hypertension

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34
Q

Drug interactions of CCBs

A

Verapamil + digoxin → digoxin toxicity
=> verapamil blocks P-gp

Verapamil + quinidine → excessive hypotension
=> CYP3A4, P-gp inhibition, PD effects

CYP- and P-gp mediated interactions

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35
Q

Verapamil

A

Non-DHP CCB

In addition to hypertension and angina:
Supraventricular tachyarrhythmias and migrane

when given with digotoxin can lead to digitoxin toxicity and given with quinidine can cause hypotension

Diltiazem - also a Non-DHP CCB that is used for Supraventricular Tachyarrhythmias

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36
Q

Beta Blockers

A

competitive antagonists of norepinephrine and epinephrine (or inverse agonists)

the amino nitrogen favors interaction with β receptors

βArs regulate numerous functional responses, including heart rate and contractility, smooth muscle relaxation and multiple metabolic events

β-Adrenergic receptors (β1β2β3) are GsPCRs which means they activate adenylyl cyclase and increase cAMP and PKA

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37
Q

Name the effects of stimulating Beta R in the heart, skeletal muscle, hepatic vasculature and the renal system.

A

SA node - increased HR; in atria, AV node, his-purkinje system all increase automaticity and conduction velocity and in the ventricles contractility, conduction, automaticity and rate of idioventricular pacemakers.
All Beta1

Skeletal muscle and hepatic vasculature beta 2 vasodilation predominates

Renal jextaglomerular apparatus => beta receptor activation induces renin release causing activation of RAAS system

Blocking cardiac β1 adrenergic receptors → slows heart rate
and AV conduction
Blocking renal β1 adrenergic receptors → inhibits renin release

BBs reduce cardiac output and lower blood pressure in patients with hypertension

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38
Q

Propranolol

A

non-selective beta blocker - first gen
(also, nadolol, penbutolol, pindolol, pimolol) (not starred)

highly lipid soluble and plasma protein binding, halflife 3-5 hours and <90 absorption

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39
Q

Beta1 Selective beta blockers

A

Esmolol and Metaprolol (also acebutolol, atenolol, bisoprolol – not starred)

esmolol - low lipid solubility, 9 minute halflife, 55% protein binding

metaprolol - moderate lipid solubility, 100% absorbed, 3 to 7 hour halflife with low protein binding.

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40
Q

Non-selective β blockers with additional actions or ‘third generation’

A

Carteolol – highly intrinsic agonist activity, Low lipid solubility, and 85% absorption, 85 % bioavil, 6 hr halflife, and 23-30% protein binding.

Carvedilol – ++ membrane stabilizing, Moderate lipid solubility, >90 absorption, ~30 bioavil, 7-10 half-life, 98% protein binding

Labetalol – has membrane stabalizing and intrinsic agonist activity, Low lipid solubility, >90 extent of absorption, ~33% bioavail, ~5 hr halflife, and ~50 protein binding

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41
Q

Additional Actions of Carteolol

A

Nitric oxide production and beta2 receptor agonism

42
Q

Additional Actions of Labetalol

A

alpha 1 receptor antadonism

43
Q

Additional Actions of Carvedilol

A

alpha 1 receptor antagonism, Ca2+ entry blockade, antioxidant activity

44
Q

therapeutic uses of beta blockers

A

Hypertension

Hypertensive emergencies - labetalol, esmolol (other classes of vasodilators)

Intraoperative tachy, hypertension - propranolol, metoprolol, esmolol

Ischemic heart disease (angina)

Congestive heart failure

Certain arrhythmias

Hyperthyroidism

Glaucoma

45
Q

How do Beta blockers effect an individual with a “normal” heart?

A

β receptor blockade has relatively little effect on the normal heart of an individual at rest but has profound effect during exercise or stress

At these points sympathetic control of the heart is dominant.

They do not usually cause hypotension in health peeps with normal BP

46
Q

Effects of Beta Blockers in ischemic heart disease?

A

they reduce myocardial O2 consumption in ischemia heart disease, such as for the treatment of exertional angina

Shown to improve survival in patients who have had an MI

47
Q

What cautions should be considered with beta blockers in regards to the treatment of angina?

A

↑End-diastolic volume and ↑Ejection time which tend to increase myocardial O2 requirement

Use nitrates to counterbalance

48
Q

how do beta blocker treat CHF?

A

Thought to decrease unstable tachyarrhythmias and reduce remodeling (decrease LV chamber size and increase LV EF, and decrease stress in the myocardium)

attenuation of sustained sympathetic activation => inhibit maladaptive proliferative cell signaling in the myocardium, reduce catecholamine-induced cardiomyocyte toxicity and decrease myocyte apoptosis.

most patients respond favorly to BB but they can precipitate acute decompensation of cardiac function.

bisoprolol, carvedilol, metoprolol and
nebivolol&raquo_space;> shown to reduce mortality

49
Q

how do beta blocker treat arrhythmias?

A

Class II antiarrhythmics

Reduce HR and decrease intracellular Ca2+ overload which inhibit afterdepolarization-mediated automaticity

increase AV nodal conduction time (PR interval) and prolong AV nodal refractoriness

BBs are useful in terminating re-entrant arrhythmias involving the AV node and in
controlling ventricular response in atrial fibrillation or flutter.

BBs can prevent recurrent infarction and sudden death in patients recovering from
acute myocardial infarction

propranolol - some Na+ channel blocking effects at high concentrations

50
Q

how do beta blocker treat hyperthyroidism?

A

Hyperthyroidism increases the basal metabolic rate and enhanced organ sensitivity to catecholamines

BBs ameliorate symptoms – palpitations, tachycardia, tremulousness, anxiety, heat intolerance

Controll pulse rate, hypertension and atrial fibrillation

thyroid storm can cause SVT and sudden death => thyrotoxicosis

51
Q

how do beta blocker treat Glaucoma:?

A

beta 2 receptors in eye - ciliary body, epithelium and blood vessels

decrease intraocular pressure by decreasing production of aqueous humor and decreasing ocular blood flow (decrease ultrafilatration)

Nasolacrimal drainage ⇒ BBs potentially can cause adverse cardiovascular and pulmonary effects in susceptible patients

little to no effect on pupil size or accommodation, no blurred vision or night blindness.

52
Q

Why are beta blockers useful for situational or performance anxiety?

A

Sympathetic manifestations may include palpitations, tightness in the chest, breathlessness, muscular tension, trembling, flushing, sweating, dry mouth

Low dose of propranolol taken an hour before decreases somatic manifestations of anxiety

53
Q

Adverse Effects of Beta blockers

A

Excessive bradycardia

peripheral vascular insufficiency
=> Block β2-mediated peripheral vasodilation

asthma/copd exacerbation
=> Block β2-mediated bronchodilation

delayed recovery from insulin-induced hypoglycemia
=> Inhibit β2-mediated hepatic glycogenolysis / gluconeogenesis and blunt perception of symptoms (beta1 may be less likely to do this)

Decrease insulin sensitivity and Increase plasma VLDL and agents decrease HDL
=> both selective and non-selective BB

Decrease release of free fatty acids from adipose tissue (an exercising muscles energy source)
=> Block β-mediated activation of hormone-sensitive lipase in fat cells

Fatigue; insomnia; nightmares and decreased libido

54
Q

Beta Blockers Withdrawal Syndrome

A

Nervousness, tachycardia, increased BP, increased intensity of angina, and increased risk of sudden cardiac death

may be because of upregulation or supersensitivity of beta adrenoceptors

55
Q

Name the selective alpha 1 blockers?

A

Prazosin

Terazosin

Doxazosin

56
Q

Name the nonselective alpha blockers?

A

phenoxybenzamine

phentolamine

57
Q

Pharmacokinetics of alpha 1 blockers

A

Terazosin and Doxazosin have largely replaces prazosin because they can be given once daily while prazosin is given 2-3 times daily.

P/T undergo hepatic metabolism, Dox is hepatic CYP3A4, 2D6 and 2C19

All have high bioavil, terazosin is 100%

58
Q

MOA of alpha 1 blockers

A

“-osin”

Block the activation of GqPCR and the activation of PLC metabolic pathway.

predominant receptor subtype in most arteries and veins with the effect of vasoconstriction.

Selective competitive antagonists of α1 ARs:

reduce arteriolar resistance and increases venous capacitance which decreases preload

59
Q

MOA of nonselective alpha blockers

A
  • Phenoxybenzamine: irreversible αAR block
  • Phentolamine: competitive αAR antagonist

reduce arteriolar resistance and increases venous capacitance which decreases preload

60
Q

What are the cardiovascular effects of alpha blockers?

A

Reduction of blood pressure by reduces PVR

Orthostatic hypotension “first dose effect” by blocking contraction of veins and arterioles in the legs which enhances venous pooling and inability to maintain BP in upright position.

Tachycardia - low in alpha 1 selective, reflex event through the a2R block of nonselective alpha blockers

61
Q

Non-Cardiac Effects of Alpha Blockers

A

Miosis (unopposed muscarinic effect)

Nasal stuffiness (blcoked vasoconstriction of nasal mucosa vasculature)

decreases resistance to urine flow - because of smooth muscle relaxation

62
Q

What are the effects of long term therapy with selective alpha 1 blockers?

A

Persistence of vasodilation and retention of salt and water

some patient may continue to experience orthostatic hypotension

63
Q

Therapeutic uses of selective alpha 1 blockers

A

“-osin”

Hypertension (mild-moderate) refractory to first-line agents – as an add on to diuretic, BB etc..
=> less protective in reducing CV morbidity/mortality

Urinary retention due to benign prostatic hyperplasia
=>blocking α1 receptors relaxes smooth muscle of the bladder neck and prostate, which improves urine flow

64
Q

Therapeutic Uses of Phenoxybenzamine

A

Hypertension / sweating treatment in pheochromocytoma

=> BB may be added (after alpha blocker) to reverse the cardiac effects of excessive catecholamines

65
Q

Therapeutic Uses of Phentolamine

A

• Diagnosis of pheochromocytoma
=> historic use

• Extravasation management
=> pressor, blocks local blood flow around injection site, this reverses it.

• Local anesthesia reversal (dental use)
=> reversal of the vasocontrictive effect

66
Q

Effects / Drug Interactions of Selective Alpha-1 Blockers

A
  1. Orthostatic hypotension / syncope: first dose effect
    => Reflex increase in PVR is blocked; venous return and cardiac output are reduced
  2. Mild, infrequent AEs: dizziness, palpitations, headache, tiredness,
  3. Intraoperative floppy iris syndrome
    • no benefit in discontinuing a-blocker before surgery
  4. Nasal congestion, rhinorrhea

Drug interactions: Sympathomimetic agents; other alpha blockers; other drugs affecting blood pressure

67
Q

Adverse Effect of Phenoxybenzamine and Phentolamine

A

nonselective alpha blockers

Orthstatic hypotension with reflex tachy, cardiac arrhythmias, or ischemic cardiac events
=> Slow titration

Reversible ejaculation impairment

Cancer risk with Phenoxybenzamine so long term use is not recommended

GI effects in phentolamine include upper abdominal pain, nausea, vomiting, diarrhea
=> stimulates GI smooth muscle (muscarinic) and acid secretion (histamine release)

68
Q

What populations should be considered with use of nonselective alpha blocker use?

A

Use with caution in patients with CV disease and renal impairment

Drug Interactions - high potential so avoid drugs that enhance hypotensive effects or increase BP

69
Q

Alpha-2 Adrenergic Agonists

A

CENTRALLY ACTING SYMPATHOLYTICS

Clonidine
Methyldopa

70
Q

Pharmacokinetics of Clonidine

A

70-80% bioavailability with low plasma protein binding

hepatic metabolism with enterohepatic circulation with renal excretion

half life is 12-16 hours, 30 min to 1 hr onset and twice daily dosing

71
Q

Pharmacokinetics of Methyldopa

A

~42% bioavailability due to being a substrate of COMT and metabolism in gut and liver.

low protein binding

Renal excretion, half life about 2 hours, onset 4-6 hours.

2-3 times dosing

72
Q

MOA of alpha 2 agonists

A

Alpha-2 agonists reduce sympathetic outflow from CNS

activate alpha 2 adrenergic R in brainstem

act on postsynaptic α2 adrenoceptors, inhibiting the activity of those neurons, and / or act on postsynaptic α2 reducing
norepinephrine release

α2-Adrenergic receptors are GiPCRs which inhibit adenylyl cyclase and decrease cAMP and activity levels of PKA.

located on presynaptic and potsynaptic sites centrally and located peripherally.

73
Q

Clonidine MOA specific

A

Directly activates α2 receptors

Alpha-2 agonists lower BP by decreasing heart rate, relaxing capacitance vessels, and reducing peripheral vascular resistance

74
Q

Methyldopa MOA specific

A

Taken up into presynaptic vesicles =. Converted to active methylnorepinephrine => Replaces NE in secretory vesicle
false transmitter

Alpha-2 agonists lower BP by decreasing heart rate, relaxing capacitance vessels, and reducing peripheral vascular resistance

75
Q

CNS and therapuetic effects of Alpha-2 Agonists

A

Sympatholytic effects => reduce sympathetic outflow to hear and vasculature and stimulate parasympathetic outflow

Does not effect sensitivity to baroreceptor or the baroreceptor effect or renal blood flow/ GFR

↓ PVR
↓ HR, myocardial contractility
↓ renal vascular resistance
↑vagal tone

Spinal effect for pain relief => epidural clonidine

patient supine - ↓ heart rate and ↓ stroke volume

patient upright - ↓ vascular resistance

76
Q

Therapeutic Uses of Clonidine

A

Refractory hypertension => add-on after ACEI/ARB, diuretic and CCB

ADHD with 12-hour extended release

Pain management - epidural

Glaucoma - topical

off-label use for menopausal hot flashes, substance withdrawal (opioids, alcohol, smoking) and reduction of catecholamine-induced symptoms

77
Q

Therapuetic uses of Methyldopa

A

Management of hypertension in pregnancy

What else can you give to a hypertensive pregnant patient?

78
Q

Side Effects of Alpha-2 Agonists

A

Most commonly are sedation and dry mouth
=> dose dependent

others => bradycardia, orthostatic hypotension, sexual dysfunction, CNS depression, and vivid drease

79
Q

Adverse effects specific to methyldopa

A

Parkinsonism, hyperprolactinemia

Hepatotoxicity Hemolytic anemia
=> autoimmune Abs to Rh antigen

Lupus-like syndrome

80
Q

In what situation should you proceed with caution when it comes to alpha 2 agonist use?

A

Cardiovascular disease like bradycardia, coronary insufficiency, recent MI or conduction disturbances

Severe bradycardia or sinus arrest can occur in patients with SA nodal dysfunction or AV nodal block

Epidural clonidine should be avoided in patients with predisposition for hypotension or respiratory depression

81
Q

For what reasons should abrupt discontinuation of Clonidine/Methyldopa be avoided?

A

Because of withdrawal syndrome

sudden discontinuation of alpha 2 agonist leads to a catecholamine surge
=> headache, apprehension, tremors, abdominal pain, sweating, and tachycardia

and Rebound hypertension
=> BP could rise to levels higher than warranted treatment in the first plase
=> typically 18-36 hours after discontinuation

CLONIDINE SHOULD BE GRADUALLY TAPERED

82
Q

Can you give alpha 2 agonists with beta blockers?

A

Yes, alpha 2 agonists may enhance AV blocking effects of BB but BB may enhance rebound hypertension effect of alpha 2 agonist withdrawal

Withdraw the beta blocker several days before clonidine withdrawal
=> both drugs need to be tapered down, starting with BB and then clonidine
=> BP should be monitored.

83
Q

Hydralazine

A

Direct vasodilator - decrease BP by decreasing systemic vascular resistance

Can be IV or Oral, high protein binding with extensive first pass effect and excretion in the urine. 
t½: 2-8 h (oral)
O: 20-30 min
D: 8 h (oral)
D: 1-4 h (I.V.)

Relaxes vascular smooth muscle (mechanism not
defined)

Dilates arterioles but not veins

add-on drug for refractory hypertension

84
Q

Hydralazine - pharmacogenomics and N-AT 2

A

N-Acetyltransferase 2 (NAT2)

Slow acetylators may be more subject to adverse effects and are at risk of developing antinuclear antibodies and lupus-like syndrome

Fast acetylators have greater first-pass metabolism and may be prone to inaduate therapeutic response to standard doses

85
Q

Therapeutic uses for Hydralazine

A

Heart failure with reduced ejection fraction
− Hydralazine + isosorbide dinitrate
=> patients unresponsive to ACEI and BB
=> evidence of benefit in African-Americans

Hypertensive emergency in pregnancy and postpartum

Also - Lebetolol or methyldopa

Hypertension

86
Q

Effect and MOA for vasodilators

A

Relaxing the smooth muscle of arterioles =>
↓ SVR and ↓ MAP => Compensatory responses
=> mediated by baroreceptors, SNS, renin, ANG II, and aldosterone

works best when given with other anti-HTN to oppose cardiovascular responses (reflex tachy and/or salt and water retention)

does not cause orthostatic hypotension or sexual dysfunction

87
Q

What other drugs do you give with vasodilators and why?

A

Diuretics to counter salt and water retention

Beta blockers to counter reflex tachycardia

88
Q

Minoxidil

A

Vasodilator - oral, decrease SVR and BP

add-on drugs for refractory hypertension

Oral, 90% bioavail, hepatic meta by glucuronidation and excreted in the urine

half life 4 hours, onset 30 min and duration is 3 days

MOA - Active metabolite mediates opening of KATP channels in smooth muscle membranes of arterioles → hyperpolarization → relaxation of smooth muscle
=> dilates arterioles but not veins

89
Q

Minoxidil - adverse effects

A

Reflex tachycardia and fluid
retention can be severe

Hypertrichosis - because of this it is also used as a stimulant for hair growth

90
Q

Adverse Effects of Hydralazine

A

Lupus-like syndrome – high dose, prolonged time, slow acetylators
=> arthralgia, myalgia, skin, rashes, fever

Rare:
Peripheral Neuropathy
Drug fever

91
Q

Vasodilators Common Class Adverse Effects

A

Headache, nausea, anorexia, palpitations, sweating, flushing

Reflex tachycardia

Salt / fluid retention

Angina exacerbation in patients with ischemic heart disease

Development of congestive heart failure

Beta blocker and diuretic should be co-administered to counteract these compensatory effects

92
Q

Nitroprusside - pharmocokinetics and MOA

A

Parenteral Vasodilator

nitroprusside is taken up by red blood cells => NO + cyanide

cyanide is detoxified by way of sulfur in the mitochondria. This process is saturable and too much cyanide => toxicity

t½ elimination:
Nitroprusside, circulatory: ~2 min
Thiocyanate, renal elimination: ~3 days

t½ elimination:
Nitroprusside, circulatory: ~2 min
Thiocyanate, renal elimination: ~3 days

Activates guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme → ↑ intracellular cGMP → vascular smooth muscle relaxation

Dilates arterial and venous vessels

93
Q

Therapeutic uses of Nitroprusside

A

Parenteral Vasodilator

Acute hypertension

Acute decompensated heart failure

Controlled hypotension during surgery

94
Q

Adverse effects of Nitroprusside

A

Parenteral Vasodilator

Excessive blood pressure lowering

Cyanide accumulation
=> Metabolic acidosis, arrhythmias, excessive hypotension, death

Methemoglobinemia reported

ANtidote:

  1. Sod. nitrite f/b sod. thiosulfate → sulfur donor → cyanide metabolism
  2. Hydroxycobalamin → cyanocobalamin (nontoxic vitamin B12)
95
Q

Fenoldopam - pharm and MOA

A

Fenoldopam - Parenteral Vasodilator

Hepatic methylation, glucuronidation, sulfation; renal excretion

t½: ~5 minutes; O: 10 min; D: 1 hour

Vasodilators decrease BP by decreasing systemic vascular resistance

Dopamine D1 agonist → relaxation of vascular smooth muscle + natriuresis / diuresis
=> GsPCR → ↑ cAMP

Dilates peripheral arterioles

96
Q

Therapeutic Uses of Fenoldopam

A

Severe hypertension - Rx up to 48 hours

short-term use in patients with renal compromise and pediatric patients
=> because D1 agonism increases renal blood flow

97
Q

Adverse effects of fenoldopam

A

parental vasodilator

hypotension

reflex tachy

headache and flushing

increases intraocular pressure&raquo_space; contraindication in glaucoma patients

98
Q

Reserpine - kinetics, MOA and Effects

A

Sympathetic nerve terminal blockers

Oral, crosses BBB, hepatic metabolism with half-life 50 to 100 hours and duration of several weeks

MOA - blocks VMAT 2 irreversibly
=> depletion of neurotransmitter centrally and peripherally (degraded in the cytoplasm on account of being unable to be stored in vesicles)

Put simple - blocks neutrotransmitter reuptake

Effects => ↓ cardiac output + ↓ peripheral vascular resistance

99
Q

Adverse effects and contraindications of Reserpine

A

AEs => orthostatic hypotension, sexual dysfunction, dyspepsia, depression, sedation and Parkinsonism

Contraindicated in patients with history of depression, active peptic ulcer, ulcerative colitis, cardiac arrhythmias, bradycardia and parkinson’s disease

100
Q

Ganglion-blocking Agents

A

No longer used clinically due to intolerable toxicities

Mecamylamine and Trimethaphan

competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia

Reduce blood pressure by decreasing cardiac output and
peripheral resistance

101
Q

Adverse Effects associated with ganglion blockers - Mecamylamine and Trimethaphan

A

Trimethaphan and Mecamylamine

Adverse effects:
− Sympathoplegia: excessive orthostatic hypotension
− Parasympathoplegia: constipation, urinary retention, precipitation of glaucoma, blurred vision / mydriasis, dry mouth
− Sexual dysfunction: and decreased libido, impotence (both erection and ejaculation)
− CNS: altered mental status, choreiform movements, convulsions, fatigue, orthostatic dizziness, paresthesia, sedation

Pharmacology (23 decks)

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