Unit 2: Drugs Used in Hypertension Flashcards
Diuretics: Classification
Thiazide Diuretics
Loop (high-ceiling) diuretics
Potassium-sparing diuretics
Diuretics
Action: Deplete sodium stores
Effect: Lowers BP during rest, exercise, regardless of posture; prevents sodium retention; reduces plasma and extracellular fluid volume; decrease peripheral resistance; enhances effects of other hypotensive drugs and takes care of the compensatory effect; well tolerated;
Thiazide diuretics
Initial drug of choice for hypertension
Cheap
Thiazide Diuretics: Drugs
Hydrochlorothiazide
Hydrochlorothiazide: Mechanism
Mechanism: Reduces blood volume; reduces arterial peripheral resistance; some have direct vasodilating effects
Thiazide Toxicities
Hypokalemia
Dehydration, hyperglycemia, hyperuricemia
Increase levels of LDL cholesterol, total cholesterol and TG
Thiazide contraindications
Ineffective when GFR is low
Loop (high-ceiling) diuretics: Drugs
Furosemide, ethacrynic acid, bumetanide, torsemide
Loop (High-ceiling) diuretics: Diuresis
Produce much greater diuresis than thiazides
Reserved for patients with a low GFR
Loop (high-ceiling) diuretics: adverse effects
Dehydration, hyperglycemia, hyperuricemia
Hearing-loss
Potassium sparing diuretics: Drugs
Spironolactone
Triamterene
Amiloride
Potassium-Sparing Diuretics: Features
Poor diuresis (modest hypotensive effect) Conserves K (combination with thiazides)
Potassium-Sparing Diuretics: Toxicity
Hyperkalemia
Potassium-Sparing Diuretics: C/I
K supplements
ACE inhibitorso
angiotensin II receptor blockers
Sympatholytics: Sites of Action
Decrease outflow of SNS activity from the brain
Antagonism of alpha or beta adrenergic receptors
Availability of neurotransmitter released from adrenergic neurons
Blockade of SNS neurotransmission at the level of autonomic ganglia
Centrally acting sympatholytics: Drugs
Methyldopa
Clonidine
Methyldopa: MOA
Decreases SNS outflow from brainstem
Must first be converted (metabolite)
- Alpha-methyl norepinephrine
Methyldopa: Therapeutic Use
Treatment of essential hypertension
Methyldopa: Side Effects and Toxicity
Bradycardia, diarrhea, failure of ejaculation
Edema
Postural hypotension but less than with reserpine or other; reduces BP in supine and standing position
- Venous pooling
Effects on the dopaminergic system (sedation, drowsiness, vertigo, EPS)
Lactation
Dry mouth and decrease in saliva
Idiosyncratic reactions
Methyldopa: What causes lactation
high prolactin in plasma
Methyldopa: What are the symptoms of dry mouth
Pain in the salivary glands
Difficulty swallowing
Methyldopa: What are the idiosyncratic reactions
Drug fever
Liver damage
Hemolytic anemia
Methyldopa: Pharmacokinetics
Excreted through the kidney primarily
Absorbed well from GIT
Clonidine: Mechanism
Decrease in Central sympathetic outflow
Alpha2 agonist
- stimulate alpha2 receptors in vasomotor centers of brainstem
Clonidine: Use
Treatment of essential hypertension
Analgesia
Withdrawal from opioids, alcohol, tobacco
Migraine; Tourette’s syndrome
Clonidine: Pharmacological Effects
Bradychardia
- Decreased sympathetic nerve activity
Decreased tone thus decrease in CO
Decreased SNS to vessels causing vasodilation
- Occurs with reduction of PR, especially when patient upright
Light orthostatic hypotension
Clonidine: Side effects
Similar to those seen with methyldopa
Bradycardia
Fluid and sodium retention
Occasionally impotence or postural hypotension
Sudden withdrawal
- Hypertensive crisisClonidine: Pharmacokinetics
Absorbed well from GIT
Largely excreted by kidney
Adrenoreceptor Antagonists
Propranolol
Beta-blockers
- Timolol
- Nadolol
- Metoprolol
- Atenolol
Combined beta and alpha blockade
- Labetalol
- CarvedilolPropranolol: Mechanism
Beta-adrenergic blocking agent
Decreases CO via beta1 blockade
Beta1 blockade inhibits renin production by juxtaglomerular cells in kidney
- decreases cascade
Propranolol: Use
Mild-Moderate hypertension Reduce morbidity and mortality in HF Supraventricular and ventricular arrhythmias CHF Migraines Decrease remodeling
Propranolol: Side Effects
HF Rebound hypertension from sudden continuation AV block Hypotension Exacerbation of asthmatic symptoms
Propranolol: Toxicity
May be detrimental to diabetics
- Masks tachycardia which usually signals hypoglycemia intensified hypoglycemic response because of suppression of glycogenolysis
Elevated TG
Decreased HDL-cholesterol
Diminished exercise tolerance
- Skeletal muscle needs vasodilation
- Blocked beta-2 does not allow vasodilation
Metoprolol: type of drug (what is it preferred for as well)
Selective beta-1 blockade
Preferred for patients with asthma or diabetes
Beta blockers with “Intrinsic Sympathomimetic Activity”
Less effect on resting HR and CO
Less likely to cause decrease in HDL/LDL
Labetalol
Combined beta and alpha receptor blockade
- Predominance of beta blockade (3:1)
Lowers BP without much alteration of HR or CO
Pheochromocytoma and hypertensive emergencies
Carvedilol
Combined beta and alpha receptor blockade
Adrenoreceptor Antagonists (alpha blockers)
Prazosin
Prazosin: Mechanism
Blocks postsynaptic alpha adrenoreceptors in arterioles and venules
Allows NE to act on presynaptic alpha2 receptor negative feedback on its own release
Less reflex tachycardia than non-selective alpha-blockers
Block of presynaptic alpha2 “auto-receptors” by nonselective blockers allows more NE release following nerve stimulation
Prazosin: Use
Essential hypertension
- Could be increased by combination
Dilates both resistance and capacitance vessels (decreases both afterload and preload)
- BP reduced more in upright than supine
Prazosin: Side effects
Well tolerated
“First-dose phenomenon”
- Postural hypotension and syncope occurring shortly after the first dose
First dose should be given at bedtime
Dizziness, palpitations, lassitude, headache
Adrenergic Neurons (presynaptic)
Reserpine
Guanethidine
Reserpine: Mechanism
Depletion of catecholamines
Depletion of serotonin in CNS and PNS
Crosses the BBB
Antagonizes the uptake and binding of NE by storage granules
NE then metabolized by MAO in neuron
Once NE depleted, sympathetic discharge is decreased
Reserpine: Use
Antihypertensive agent
Once used as an antipsychotic
Reserpine: Side Effects
Sedation Parkinson's like symptoms Nightmares Depression GIT (Increase tone, motility and secretion) Severe diarrhea Miosis, flushing, congestion Orthostatic hypotension
Guanethidine: Mechanism
Taken up by adrenergic neuron and replaces NE in vesicle
Concentrated in vesicle where it displaces NE and causes gradual NE depletion
Prevents release of NE from vesicles
Primarily peripheral
- Doesn’t cross BBB
Guanethidine: Use
Moderately severe to severe hypertension
Guanethidine: Side effects
Postural hypotension
Dizziness
Intestinal cramping and diarrhea
Ejaculatory failure
MAO inhibitors: Effects
Produce severe postural hypotension
No longer used for hypertension, but sometimes used for action on the CNS
MAO: Mechanism
Related to formation of false neurotransmitter
- Tyramine - Octopamine replaces NE - Octopamine is ineffective in stimulating alpha receptors
Drugs acting on Autonomic Ganglia
Mecamylamine (hypertensive emergency)
Vasodilators
Hydralazine Minoxidil Diazoxide (Hyperstat IV) Nitroprusside Fenoldopam
Hydralazine: Mechanism
Relaxation of vascular smooth muscle is major effect (arteriole effect greater than effect on veins)
Causes reflex cardiac stimulation
Increases renin secretion (due to stimulation of sympathetic and decrease in BP)
Sodium and water retention
Affects preload the most due to effect on arteries
Hydralazine: Use
Hypertensive emergency
Essential hypertension
Hydralazine: Side effects
Headache, palpitation, anorexia, nausea, dizziness, sweating
Myocardial stimulation
Drug fever, urticaria, skin rash
Drug-induced lupus-like syndrome occurs in 10-20% of patients receiving prolonged therapy with high doses
Minoxidil: Mechanism
Direct vasodilator
Like hydralazine, it dilates arterioles but not veins
Minoxidil: Use
More reflex sympathetic stimulation and sodium and water retention than hydralazine
Used in combination with a beta-blocker and a diuretic
Minoxidil: Side Effects
Tachycardia, palpitations, angina and edema when doses of beta-blockers and diuretics are inadequate
Minoxidil: other uses
Rogaine for hair growth
Diazoxide: mechanism
Arteriolar dilator used for hypertensive emergencies
Structurally related to diuretics but is devoid of diuretic activity
Hypotensive effects greater if given with a beta-blocker to prevent reflex tachycardia
Nitroprusside:Mechanism
Decrease pre-load and after-load
- Dilates both arterioles and venules resulting in decreased peripheral resistance and venous return
Parenterally administered
Complex of iron, cyanide groups and a nitroso moiety; metabolized to cyanide
Solutions are light sensitive
Sodium thiosulfate used to prevent or treat cyanide poisoning during infusion
Nitroprusside: Use
Hypertensive emergency and severe cardiac failure
Fenoldopam: Mechanism
Dopamine receptor agonist
Fenoldopam: Administration
Continuous IV infusion
Fenoldopam: Use
Hypertensive emergency
Calcium Channel Blockers (vasodilators):Mechanism
Calcium antagonists
Inhibits calcium influx in arterial smooth muscle causing dilation of peripheral arterioles and reduction of blood pressure
Inhibits movement of calcium through channels in myocardial and specialized conducting tissues of the heart
Calcium Channel Blockers: Agents
Verapamil
Diltiazem
Nifedipine
Amlodipine
Cardioactive CCB: Drugs
Verapamil
Diltiazem
Vasoactive CCB (Dihydropyridines): Drugs
Nifedipine
Amlodipine
CCB: Drug Interactions
Do not use with beta-blocker (additive effect)
Grape fruit juice (can increase serum level of calcium channel blockers)
Digoxin
- Levels will be increased with verapamil
- Verapamil will cause a prolongation of AV conduction velocity
- Digoxin does as well
CCB: Use
Treatment of hypertension
Treatment of angina
Antiarrhythmic
Can be vasogenic to decrease stroke
Actions of Angiotensin II
Vasoconstriction
Release of aldosterone
- From the adrenal cortex
Alteration of cardiac and vascular structure (remodeling)
Actions of aldosterone
Regulation of blood volume and blood pressure
Sodium and water retention
Pathologic cardiovascular effects
involved in remodeling
Renin: What does it do?
Catalyzes the formation of angiotensin I from angiotensinogen
regulation of renin release
Angiotensin- converting enzyme (kinase II): Action
catalyzes the conversion of angiotensin I (inactive) into angiotensin II (highly active)
Regulation of blood pressure by the RAA system: operation
Help regulate blood pressure in the presence of hemorrhage, dehydration, or sodium depletion
Regulation of blood pressure by the RAA system: how it acts
Constricts renal blood vessels
Acts on the kidney to promote retention of sodium and water and excretion of potassium
Angiotensin- Converting Enzyme Inhibitors: Mechanism
Reducing levels of angiotensin II
Increasing levels of bradykinin
Captopril (ACE Inhibitor): Mechanism
Prevents formation of angiotensin II and reduces blood levels of aldosterone
Inhibition of the enzyme (ACE; kinase II) also inhibits inactivation of the vasodilator bradykinin
- Can cause increase in prostaglandins
- Increase in bradykinin
- Can cause dry cough
Captopril: Use
Hypertension Heart failure Myocardial infarction Diabetic and nondiabetic nephropathy Prevention of MI, stroke, and death in patients at high cardiovascular risk
Captopril: Adverse effects
First-dose hypotension Fetal injury Cough Angioedema Hyperkalemia Rash/ Dysguesia Renal failure Neutropenia
Captopril: Drug Interactions
Diuretics
- Can increase possibility of first-dose hypertension
Antihypertensive agents
Drugs that raise potassium levels
Lithium
Nonsteroidalanti- inflammatory drugs
- will counter the effectiveness of many antihypertensives
- prostaglandins cause dilation of the renal vessels
Other ACE Inhibitors
Enalapril
Angiotensin II Receptor Blockers [ARB]: Drugs
Losartan
Candesartan
Olimesartan
Valsartan
Losartan: Mechanism
Competitive receptor antagonist of angiotensin II
Lower BP almost as effectively as ACEI with fewer side effects such as cough
Losartan: Pharmacologic effects
Block access of angiotensin II Cause dilation of arterioles and veins Prevent angiotensin II from inducing pathologic changes in cardiac structure Reduce excretion of sodium and water No inhibition of Kinase II Do not increase levels of bradykinin
Renin Inhibitors
Aliskiren
Aldosterone Antagonists
Spironolactone
Eplerenone
Spironolactone: Mechanism
Blocks aldosterone receptors
Binds with receptors for other steroid hormones
Spironolactone: Therapeutic uses
Hypertension
Heart failure
Spironolactone: Adverse effects
Hyperkalemia Gynecomastia Menstrual irregularities Impotence Hirsutism Deepening of the voice
Eplerenone: Mechanism
Selective blockade of aldosterone receptors
Eplerenone: Therapeutic
Hypertension
HF
Eplerenone: Pharmacokinetics
Absorption is not affected by food
Eplerenone: Adverse effects
Hyperkalemia
Eplerenone: Drug interactions
Inhibitors of CYP3A4
Drugs that raise potassium levels
Caution when combined with lithium
Stage I hypertension: Drug of choice
Thiazide diuretics
Stage II hypertension drug of choice
Combination of ACEI, ARB, CCB, beta-blocker and a diuretic
Don’t use these drugs if you have:
chronic kidney disease
bilateral renal stenosis
Which hypertension drug is most effective on African Americans
Diuretics
