Antihypertensives Flashcards
Monotherapy for antihypertensives
when BP is <20/10mm Hg above goal
- ACEI or ARB, long-acting or
- DHP CCB, long-acting or
- Thiazide diuretic
antihypertensive combination therapy
when BP >20/10 mm Hg above goal
• Long-acting ACEI or ARB
plus long-acting DHP CCB
What hypertensive drugs are best for older individuals or african americans
DHP CCB (longacting) or thiazide diuretic
Angiotensin Converting Enzyme Inhibitors (ACEIs)
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
ARBs Class Properties
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
ACEIs / ARBs lower blood pressure through what effects?
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
Risk factors for hyperkalemia:
- renal insufficiency,
- diabetes,
- elderly,
- K+-sparing drugs
ACEIs Effects
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 »_space; vasodilation
ARBs Effects
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
ACE inhibitors and ARBs therapeutic uses
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
Adverse effects of ACEIs / ARBs
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
contraindications of ACE inhibitors and ARB
Angioedema
Hypersensitivity / Anaphylaxis
Absolutely contraindicated in all trimesters of pregnancy - reduced renal function leads to oligohydramnios
Drug-Drug Interactions of ACEI and ARB
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
Aliskiren
Direct Renin Inhibitor
CYP3A4 metabolism; Excreted mainly unchanged in feces
once daily dosing
Potent competitive inhibitor of renin -> decreased ang I, II and aldosterone
Uses of Aliskiren
hypertension - not for initial treatment, monotherapy or combination therapy
Adverse Effects of Aliskiren
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
Drug-Drug Interactions of Aliskiren
Other antihypertensive agents - use caution
Strong CYP3A4 inhibitors - use caution
p-glycoprotein inhibitors - increases systemic levels of drug
itraconazole and cyclosporine should be avoided
Why is use of Aliskiren in combination with ACEI or ARB not recommended?
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
L-TYPE CALCIUM CHANNEL BLOCKERS (CCBs)
Non-DHP => Verapamil => Diltiazem DHP - oral => Nifedipine => Amlodipine DHP - I.V. => Nicardipine => Clevidipine
Pharmacokinetics of CCBs
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
Non-Dihydropyridines
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
Dihydropyridines
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
Nifedipine
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
Amlodipine
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
Why shouldn’t short half life DHP CCBs be used for hypertension?
They can cause:
Rapid drop in blood pressure
Oscillations in blood pressure control
Concurrent surges in sympathetic reflex activity.
MOA of L-type Voltage Gated Ca2+ Channels
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
What are the dose-dependent effects of calcium-channel blockers:
verapamil and diltiazem
Dihydropyridines
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
what are calcium antagonists’ cardiac and vascular effects?
Slow heart rate, Slow AV conduction and Reduce myocardial contractility
↓ peripheral arterial resistance => ↓ afterload => ↓O2 consumption
What are CCBs therapeutic uses and effects?
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)
how is the CCB treatment different for different type/stages of angina?
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
Adverse Effects of CCBs
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
Contraindications of Verapamil and Diltazem
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
Contraindications of Nifedipine
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
Drug interactions of CCBs
Verapamil + digoxin → digoxin toxicity
=> verapamil blocks P-gp
Verapamil + quinidine → excessive hypotension
=> CYP3A4, P-gp inhibition, PD effects
CYP- and P-gp mediated interactions
Verapamil
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
Beta Blockers
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
Name the effects of stimulating Beta R in the heart, skeletal muscle, hepatic vasculature and the renal system.
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
Propranolol
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
Beta1 Selective beta blockers
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.
Non-selective β blockers with additional actions or ‘third generation’
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
Additional Actions of Carteolol
Nitric oxide production and beta2 receptor agonism
Additional Actions of Labetalol
alpha 1 receptor antadonism
Additional Actions of Carvedilol
alpha 1 receptor antagonism, Ca2+ entry blockade, antioxidant activity
therapeutic uses of beta blockers
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
How do Beta blockers effect an individual with a “normal” heart?
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
Effects of Beta Blockers in ischemic heart disease?
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
What cautions should be considered with beta blockers in regards to the treatment of angina?
↑End-diastolic volume and ↑Ejection time which tend to increase myocardial O2 requirement
Use nitrates to counterbalance
how do beta blocker treat CHF?
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»_space;> shown to reduce mortality
how do beta blocker treat arrhythmias?
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
how do beta blocker treat hyperthyroidism?
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
how do beta blocker treat Glaucoma:?
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.
Why are beta blockers useful for situational or performance anxiety?
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
Adverse Effects of Beta blockers
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
Beta Blockers Withdrawal Syndrome
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
Name the selective alpha 1 blockers?
Prazosin
Terazosin
Doxazosin
Name the nonselective alpha blockers?
phenoxybenzamine
phentolamine
Pharmacokinetics of alpha 1 blockers
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%
MOA of alpha 1 blockers
“-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
MOA of nonselective alpha blockers
- Phenoxybenzamine: irreversible αAR block
- Phentolamine: competitive αAR antagonist
reduce arteriolar resistance and increases venous capacitance which decreases preload
What are the cardiovascular effects of alpha blockers?
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
Non-Cardiac Effects of Alpha Blockers
Miosis (unopposed muscarinic effect)
Nasal stuffiness (blcoked vasoconstriction of nasal mucosa vasculature)
decreases resistance to urine flow - because of smooth muscle relaxation
What are the effects of long term therapy with selective alpha 1 blockers?
Persistence of vasodilation and retention of salt and water
some patient may continue to experience orthostatic hypotension
Therapeutic uses of selective alpha 1 blockers
“-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
Therapeutic Uses of Phenoxybenzamine
Hypertension / sweating treatment in pheochromocytoma
=> BB may be added (after alpha blocker) to reverse the cardiac effects of excessive catecholamines
Therapeutic Uses of Phentolamine
• 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
Effects / Drug Interactions of Selective Alpha-1 Blockers
- Orthostatic hypotension / syncope: first dose effect
=> Reflex increase in PVR is blocked; venous return and cardiac output are reduced - Mild, infrequent AEs: dizziness, palpitations, headache, tiredness,
- Intraoperative floppy iris syndrome
• no benefit in discontinuing a-blocker before surgery - Nasal congestion, rhinorrhea
Drug interactions: Sympathomimetic agents; other alpha blockers; other drugs affecting blood pressure
Adverse Effect of Phenoxybenzamine and Phentolamine
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)
What populations should be considered with use of nonselective alpha blocker use?
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
Alpha-2 Adrenergic Agonists
CENTRALLY ACTING SYMPATHOLYTICS
Clonidine
Methyldopa
Pharmacokinetics of Clonidine
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
Pharmacokinetics of Methyldopa
~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
MOA of alpha 2 agonists
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.
Clonidine MOA specific
Directly activates α2 receptors
Alpha-2 agonists lower BP by decreasing heart rate, relaxing capacitance vessels, and reducing peripheral vascular resistance
Methyldopa MOA specific
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
CNS and therapuetic effects of Alpha-2 Agonists
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
Therapeutic Uses of Clonidine
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
Therapuetic uses of Methyldopa
Management of hypertension in pregnancy
What else can you give to a hypertensive pregnant patient?
Side Effects of Alpha-2 Agonists
Most commonly are sedation and dry mouth
=> dose dependent
others => bradycardia, orthostatic hypotension, sexual dysfunction, CNS depression, and vivid drease
Adverse effects specific to methyldopa
Parkinsonism, hyperprolactinemia
Hepatotoxicity Hemolytic anemia
=> autoimmune Abs to Rh antigen
Lupus-like syndrome
In what situation should you proceed with caution when it comes to alpha 2 agonist use?
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
For what reasons should abrupt discontinuation of Clonidine/Methyldopa be avoided?
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
Can you give alpha 2 agonists with beta blockers?
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.
Hydralazine
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
Hydralazine - pharmacogenomics and N-AT 2
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
Therapeutic uses for Hydralazine
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
Effect and MOA for vasodilators
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
What other drugs do you give with vasodilators and why?
Diuretics to counter salt and water retention
Beta blockers to counter reflex tachycardia
Minoxidil
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
Minoxidil - adverse effects
Reflex tachycardia and fluid
retention can be severe
Hypertrichosis - because of this it is also used as a stimulant for hair growth
Adverse Effects of Hydralazine
Lupus-like syndrome – high dose, prolonged time, slow acetylators
=> arthralgia, myalgia, skin, rashes, fever
Rare:
Peripheral Neuropathy
Drug fever
Vasodilators Common Class Adverse Effects
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
Nitroprusside - pharmocokinetics and MOA
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
Therapeutic uses of Nitroprusside
Parenteral Vasodilator
Acute hypertension
Acute decompensated heart failure
Controlled hypotension during surgery
Adverse effects of Nitroprusside
Parenteral Vasodilator
Excessive blood pressure lowering
Cyanide accumulation
=> Metabolic acidosis, arrhythmias, excessive hypotension, death
Methemoglobinemia reported
ANtidote:
- Sod. nitrite f/b sod. thiosulfate → sulfur donor → cyanide metabolism
- Hydroxycobalamin → cyanocobalamin (nontoxic vitamin B12)
Fenoldopam - pharm and MOA
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
Therapeutic Uses of Fenoldopam
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
Adverse effects of fenoldopam
parental vasodilator
hypotension
reflex tachy
headache and flushing
increases intraocular pressure»_space; contraindication in glaucoma patients
Reserpine - kinetics, MOA and Effects
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
Adverse effects and contraindications of Reserpine
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
Ganglion-blocking Agents
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
Adverse Effects associated with ganglion blockers - Mecamylamine and Trimethaphan
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
