Intro to antihypertensive agents Flashcards
Hypertension and Cardiovascular Disease
Approximately 29-31% of US adults have hypertension
76.4 million Americans (> 20 years old)
Most common reason for office visits of nonpregnant adults
Only 50.1% of those with hypertension are considered controlled (less than 140/90 mmHg)
Hypertension associated with serious adverse effects:
- Renal failure, coronary disease, heart failure, stroke, dementia
Blood pressure calc and drug strategies
BP = CO * SVR
BP – blood pressure
CO – cardiac output
SVR – systemic vascular resistance
Drug Strategies:
Reduce cardiac output and blood pressure is reduced
Reduce systemic vascular resistance and blood pressure is reduced
Compensatory responses may include:
Reflex tachycardia (increased sympathetic activity)
Edema (increased renin activity)
Lifestyle modifications to prevent and manage hypertension
weight reduction adopt DASH eating plan Dietary sodium reduction physical activity moderation of alcohol consumption
Sites of action of the major classes of antihypertensive drugs
diuretics
agents that block the production or action of angiotensin
direct vasodilators
sympathoplegic agents (those that alter sympathetic function)
Initial monotherapy options for patients with chronic kidney disease
ACE inhibitr
Angiotensin receptor blocker (ARB)
Initial monotherapy options for patients without CKD
Black- thiazide diuretic, calcium channel blocker
Nonblack- thazide diuretic, ACE inhibitor, ARB, CCB
Diuretics- basics
Increase the rate of urine flow and sodium excretion
Used to adjust the volume and/or composition of body fluids in a variety of clinical situations including (but not limited to):
Edematous states: heart failure, kidney disease and renal failure, liver disease (cirrhosis)
Nonedematous states: hypertension, nephrolithiasis (kidney stones), hypercalcemia, and diabetes insipidus
Diuretics: Molecular Targets
Specific membrane transport proteins
- Sodium/potassium/chloride cotransporter (loop diuretics)
- Sodium/chloride cotransporter (thiazide diuretics)
- Sodium channels (potassium-sparing diuretics)
Enzymes
- Carbonic anhydrase (carbonic anhydrase inhibitors)
Hormone receptors
- Mineralocorticoid receptor (potassium-sparing diuretics)
Carbonic Anhydrase Inhibitors
Prototype: acetazolamide
MOA: inhibits the membrane-bound and cytoplasmic forms of carbonic anhydrase
Results in: ↓ H+ formation inside PCT cell ↓ Na+/H+ antiport ↑ Na+ and HCO3- in lumen ↑ diuresis
Urine pH is increased and body pH is decreased
Other agents: brinzolamide, dorzolamide, methazolamide
Therapeutic Use:
Rarely used as antihypertensives due to low efficacy as single agents and development of metabolic acidosis
Used for glaucoma, acute mountain sickness, and metabolic alkalosis
ADRs: acidosis, hypokalemia, renal stones, paresthesias (with high doses), sulfonamide hypersensitivity
Loop Diuretics
Prototypes: furosemide and ethacrynic acid
MOA: inhibit the luminal Na+/K+/2Cl- cotransporter (NKCC2) in the TAL of the loop of Henle
Results in:
↓ intracellular Na+, K+, Cl- in TAL
↓ back diffusion of K+ and positive potential
↓ reabsorption of Ca2+ and Mg2+
↑ diuresis
Ion transport is virtually nonexistent
Among the most efficacious diuretics available
Diuretic activity tied to secretion rates (act at luminal side of tubule)
t1/2 correlated to kidney function – 0.5-2 hrs (healthy) vs. 9 hrs (end stage renal disease) for furosemide
Therapeutic Use:
Edema, heart failure, hypertension, acute renal failure, anion overdose, hypercalcemic states
ADRs: hypokalemia, alkalosis, hypocalcemia, hypomagnesemia, hyperuricemia, ototoxicity, sulfonamide hypersensitivity (not all)
Thiazide Diuretics
Prototype: hydrochlorothiazide (HCTZ)
MOA: cause inhibition of the Na+/Cl- cotransporter (NCC) and block NaCl reabsorption in the DCT
Results in:
↑ luminal Na+ and Cl- in DCT
↑ diuresis
Enhance the reabsorption of Ca2+ in both DCT and PCT
Largest class of diuretic agents
Therapeutic Use:
Hypertension, mild heart failure, nephrolithiasis (calcium stones), nephrogenic diabetes insipidus
ADRs: hypokalemia, alkalosis, hypercalcemia, hyperuricemia, hyperglycemia, hyperlipidemia, sulfonamide hypersensitivity
More hyponatremic effects than loop diuretics
Use with caution in patients with diabetes mellitus
Potassium-sparing diuretics: Mineralocorticoid Receptor (MR) Antagonists
Spironolactone and eplerenone
Therapeutic Use: hyperaldosteronism, adjunct to K+-wasting diuretics, antiandrogenic uses (female hirsutism), heart failure (reduces mortality)
Do not require access to the tubular lumen to induce diuresis
ADRs: hyperkalemia, acidosis, and antiandrogenic effects
Potassium-sparing diuretics: Na+ channel ENaC Inhibitors
Amiloride and triamterene
Therapeutic Use: adjunct to K+-wasting diuretics and lithium-induced nephrogenic diabetes insipidus (amiloride)
ADRs: hyperkalemia and acidosis
Mineralocorticoid Receptor (MR)
Nuclear hormone receptor responsible for regulating the expression of multiple gene products Natural agonists include mineralocorticoids – a class of steroid hormones that influence salt and water balance Examples include aldosterone, deoxycorticosterone, and glucocorticoids (cortisol) Also known as the aldosterone receptor
Major effects of Ang II
vasoconstriction –> PRESSOR (rapid)
Increase Na+ reabsorption in prox tubule, relase of aldosterone from adrenal cortex, renal vasoconstriction –> PRESSOR (slow)
Vascular and Cardiac Hypertrophy and Remodelling
Pharmaceutical Strategies for Inhibition of the Renin-Angiotensin-Aldosterone System
Aldosterone Receptor (MR) Antagonists
ACE Inhibitors
Angiotensin II Receptor Blockers (ARBs)
Renin Inhibitors
β-Blockers
Angiotensin-Converting Enzyme (ACE) Inhibitors
Prototypes: captopril, enalapril, lisinopril
MOA: inhibit the conversion of angiotensin I to the more active angiotensin II; also prevent degradation of bradykinin and other vasodilator peptides
Therapeutic Use:
Hypertension, heart failure, left ventricular dysfunction, prophylaxis of future cardiovascular events (e.g., MI, CAD, stroke) and nephropathy (+/- diabetes)
Benefits of ACE Inhibitors in HTN
Lowers peripheral vascular resistance, and mean, diastolic, and systolic BP
Cardiac function in patients with uncomplicated hypertension is little changed
Stroke volume and cardiac output may increase slightly with sustained treatment
Baroreceptor function and cardiovascular reflexes are not compromised
Responses to postural changes and exercise are little impaired
Evidence that ACE inhibitors are superior in treating HTN in patients with diabetes
Improve endothelial function & reduce CV events more so than CCBs or diuretic and β-blocker combination
ADRs of ACE Inhibitors
Hypotension
* Cough
* Angioedema
* Hyperkalemia – avoid K+-sparing diuretics
* Acute renal failure – particularly in patients with renal artery stenosis
Fetopathic potential (teratogen) – CI in pregnancy
Proteinuria
Skin rash
Dysgeusia (altered sense of taste)
Rare: neutropenia, glycosuria, hepatotoxicity
DDIs: antacids, capsaicin, NSAIDs, K+-sparing diuretics, digoxin, lithium, allopurinol
Renal Considerations with ACE Inhibitors
ACE inhibitors prevent/delay the progression of renal disease in type 1 diabetics and in patients with nondiabetic nephropathies (results mixed in type 2 diabetics)
ACE inhibitors vasodilate efferent arterioles > afferent arterioles
Reduces back pressure on the glomerulus and reduces protein excretion
ACE inhibitors usually improve renal blood flow and Na+ excretion rates in CHF
In rare cases, ACE inhibitors can cause a rapid decrease in GFR, leading to acute renal failure (ARF)
Can occur anytime during therapy, even after months or years of uneventful ACE inhibitor treatment
Risk Factors for ACE Inhibitor Induced Acute Renal Failure
MAP insufficient for adequate renal perfusion
Poor cardiac output
Low systemic vascular resistance
Volume depletion (diuretic use)
Renal vascular disease
Bilateral renal artery stenosis
Stenosis of dominant or single kidney
Afferent arteriolar narrowing (HTN, cyclosporin A)
Diffuse atherosclerosis in smaller renal vessels
Vasoconstrictor agents
NSAIDs
Cyclosporine
All cause renal hypoperfusion
Angiotensin II Receptors
G-protein coupled receptors
Two receptor subtypes (AT1 and AT2)
AT1 receptors
Major subtype in adults
Gq → PLC → IP3 + DAG → smooth muscle contraction
AT2 receptors
Activation causes production of nitric oxide and bradykinin
Smooth muscle dilation
Angiotensin II Receptor Blockers (ARBs)
Prototypes: losartan and valsartan
MOA: selectively block AT1 receptors, which leads to:
↓ contraction of vascular smooth muscle
↓ aldosterone secretion
↓ pressor responses
↓ cardiac cellular hypertrophy and hyperplasia
No effect on bradykinin metabolism
Therapeutic Use:
Hypertension, diabetic nephropathy, HF, HF or left ventricular dysfunction after AMI, and prophylaxis of cardiovascular events
ADRs: similar to ACE inhibitors but less cough and edema; CI during pregnancy
ACE Inhibitors VS. ARBs
ARBs reduce activation of AT1 receptors more effectively than do ACE inhibitors
ARBs permit activation of AT2 receptors
ACE inhibitors increase the levels of a number of ACE substrates, including bradykinin
Unknown whether or not these pharmacological differences result in significant differences in therapeutic outcomes
Aliskiren: A Direct Renin Inhibitor
MOA: inhibits renin and blocks the conversion of angiotensinogen to angiotensin I
Does not increase bradykinin
Rise in plasma renin levels but decreased plasma renin activity (ACE inhibitors, ARBs, and diuretics raise plasma renin levels and activity via feedback loop)
Studies show effectiveness comparable to ACEIs and ARBs
ADRs: similar to ACE inhibitors and ARBs; CI in pregnancy
2 types of calcium channel blockers
All CCBs bind to L-type Ca2+ channels. But the two classes bind to different sites, resulting in different effects on vascular versus cardiac tissue.
Non-dihydropyridines:
Prominent cardiac effects, but also act at vascular tissues
Verapamil > Diltiazem
Dihydropyridines (DHPs):
Predominantly arteriolar vasodilation effects
Amlodipine, Clevidipine, Felodipine, Isradipine, Nicardipine, Nifedipine, Nisoldipine
Calcium Channel Blockers: Therapeutic Use
Hypertension
Most useful when combined with another agent to counteract the reflex cardiovascular responses
Hypertensive emergencies
Parenteral formulations
Angina
Reduction of O2 demand makes particularly useful
Calcium Channel Blockers: ADRs
Generally very well tolerated
Excessive vasodilation – dizziness, hypotension, headache, flushing, nausea
Diminished by long-acting formulations and long t1/2 agents
Constipation (esp., verapamil), peripheral edema, coughing, wheezing, pulmonary edema
CI: use of verapamil/diltiazem with a b-blocker (potential for AV block)
Verapamil/diltiazem should not be used in patients with ventricular dysfunction, SA or AV nodal conduction defects and systolic BP less than 90 mmHg
Potassium Channel Openers: MOA
Increased potassium permeability stabilizes the smooth muscle cell membrane at resting potential, reducing the probability of contraction
Potassium Channel Openers
Diazoxide
-Arteriolar vasodilation
-Diminishing use in hypertensive emergencies due to ADRs:
Excessive hypotension can cause stroke and MI
Hyperglycemia
Minoxidil
Arteriolar vasodilation
Therapeutic Use: severe hypertension and baldness (topical)
ADRs:
Headache, sweating, hypertrichosis
Reflex tachycardia & edema – must be used with β-blocker & diuretic to avoid these effects
Fenoldopam
D1 dopamine receptor agonist
Renal afferent arteries contain dopamine receptors—activation increases blood flow to the kidneys
For hypertensive emergencies & post-operative hypertension
ADRs: tachycardia, headache, and flushing
Should be avoided in patients with glaucoma due to increases in intraocular pressure
Hydralazine
MOA: releases nitric oxide from endothelium
- Dilates arterioles, but not veins
Therapeutic Use:
- First-line oral therapy for hypertension in pregnancy, with methyldopa
- Combination with nitrates is effective in patients with heart failure
- Parenteral formulation useful in hypertensive emergencies
ADRs:
- Can induce fluid and sodium retention
- Headache, nausea, anorexia, sweating, flushing, palpitations
- Reflex tachycardia can provoke angina in patients with ischemic heart disease
- Lupus-like syndrome (reversible on drug withdrawal)
Nitroprusside and Organic Nitrates
Prototype organic nitrate: nitroglycerin
MOA:
- Dilates both arterial and venous vessels—decreases total peripheral resistance and venous return
- Decreases both preload & afterload
- Mainly relaxation of large veins ® ¯ venous return ® ¯ preload ® ¯ O2 demand (major effect), smaller ¯ in afterload
Therapeutic Use: used to treat hypertensive emergencies, heart failure, & angina (nitrates)
ADRs:
- Nitroprusside: excessive hypotension, cyanide poisoning
- Nitrates: orthostatic hypotension, syncope, throbbing headache
β-blocker Use in Hypertension
No longer 1st line treatment for hypertension, except when concomitant with a compelling indication:
- Heart failure
- Recent MI
- Reduced left ventricular function
Predispose to diabetes, particularly when combined with thiazide
Relative CI: asthma
Less stroke protection than other antihypertensives
β-blockers with α-blocking Activity: Labetalol
Selective a1 blocker Nonselective b1 & b2 blocker Partial agonist at b2 Therapeutic Use: IV for severe hypertension Acceptable option for hypertension during pregnancy
β-blockers with α-blocking Activity: Carvedilol
Nonselective b-blocker + a1-blocker
Also has antioxidant properties
β-blockers with Vasodilating Activity
Non-selective vasodilating β-blockers
- Carteolol, carvedilol, labetalol
β1-selective vasodilating β-blockers
- Betaxolol, nebivolol
These drugs produce peripheral vasodilation through a variety of mechanisms: ↑ NO Activate β2-receptors Block of α1-receptors Block Ca2+ entry Open K+ channels Antioxidant activity Antiproliferative effects
Esmolol
beta 1-selective
Very rapid onset & short duration of action
Used as IV infusion for peri-operative tachycardia and hypertension, hypertensive emergencies, arrhythmias
Used in electroconvulsive therapy
alpha 1-Selective Receptor Blockers
MOA: prevent vasoconstriction of both arteries and veins
↓ total peripheral resistance, ↓ venous return, ↓ preload
Usually do not ↑ heart rate or cardiac output
Do not ↑ NE release (no 2 block)
Favorable effects on lipids (↓ LDL & triglycerides; ↑ HDL)
Relaxes smooth muscle in the prostate
Therapeutic Use: 3rd or 4th line treatment of essential hypertension; added to other agents from different classes in refractory cases; also used in men with concurrent HTN and BPH
ADRs: postural hypotension & syncope, especially with initial doses; usually given at bedtime to minimize hypotensive effects
Clonidine
An a2-adrenergic receptor agonist
IV - increase BP (peripheral a2B) followed by decreased BP (central a2A)
Oral - decreased BP (decreased C.O., preload)
Patch - same as oral
Therapeutic Use:
Essential hypertension (rarely used)
Adjunct for narcotic, alcohol, & tobacco withdrawal (unlabeled)
ADRs:
Dry mouth, sedation, impotence, depression
*** Sudden withdrawal causes hypertensive crisis
Methyldopa
False neurotransmitter concept:
- Converted to methyl-NE
- Stored in vesicles instead of NE
- Released & acts as a centrally acting α2-agonist
- Decreases central sympathetic outflow & decreases blood pressure
Therapeutic Use: only used to treat hypertension in pregnancy because of its safety
ADRs (many): sedation, dry mouth, sexual dysfunction, postural hypotension, anemia
