Pharmacology

Pharmacology of Hypertension
Diuretics (↓vascular Na+)
Class Drug MOA AE Uses Effects
Hydrochlorothiazide -Hypokalemia
Early DCT -> inhibit Na+- -HTN (1 line)
st
-Metabolic alkalosis
Thiazides Cl- symporter & weak -Mild-mod HTN; normal renal + cardiac function
Indapamide -Gout -Initial ↓BP via ↓plasma vol, ↓CO, ↑PVR, ↓renal blood flow
inh of carb anhydrase -anti-HTN dose < diuretic dose
-Allergic rx -@6-8 wks, CO and vol normalize, ↓PVR, renal blood flow norm
TAL -> inhibit Na+-K+-2Cl- -Hypokalemia -Late ↓BP via cont’ Na+ excretion -> reversal of vessel stiffness
-Malignant hypertension; chronic kidney disease
Loop Furosemide symporter & weak inh -Metabolic alkalosis -Postural hypoTN negligible
(where thiazides are not effective)
of carb anhydrase -Allergic rx -Moderate anti-HTM effect; enhance effects of other anti-HTN
-Hyperkalemia agents
Late DCT, cortical CD -> -Used in combo w thiazides to counteract hypokalemia
K+ sparing Spironolactone -Metabolic acidosis
aldosterone R antagonist -Tx HTN due to hyperaldosteronism
-Sexual dysfunction

Sympatholytics (↓PRV, ↑venous pooling, inh cardiac function; mod-severe HTN)

Class Drug MOA Uses Adverse effects
-↓Sympathetic outflow from vasomotor centers (↓central adrenergic tone -> ↓CO, -CNS: drowsiness, depression, headache, asthenia (lack of energy),
Clonidine ↓HR, ↓PRV, decr venous tone, ↓renal vascular resistance = unchanged renal flow) xerostomia (oral dryness), sleep disorders, mental clouding,
-Moderate HTN effect depression
Centrally Clonidine: -2nd choice drug (w diuretic)
-CV: bradycardia, AV block
acting -α2 agonists in brainstem -> ↑sensitivity to baroR -> ↓sympathetic outflow -HTN preg (methyldopa)
-Heme: +ive Coomb’s test
Methyldopa -Imidazoline R agonist -> ↓sympathetic outflow
-Other: sexual dysfunction, skin (clonidine patch)
Methyldopa:
-False NT, clonidine-like effects in brainstem; works like NE in periphery (small extent) -HTN crisis (rebound HTN) on sudden withdrawal
-Selective inh of α1 -> dilation of resistance (arterioles) + capacitance (venules) -Postural hypotension (first dose)
-HTN (2nd choice)
α1-Blockers Prazosin -Slight ↑HR, ↑CO (compensatory mech), decr venous tone, ↓PRV -Dizziness, palpitations, nasal stiffness
-pts w BPH
-Moderate HTN effect -Sexual dysfunction, delayed ejaculation
Propranolol -↓CO (inh β1 R), inh renin rls (inh β1
β-Blockers
(β1,2 blocker) R); inh NE rls from presynaptic
-Not 1st line -Blocking β1 -> bradycardia
terminals (inh presynaptic β R);
-Improve morbidity and -Blocking β2 -> CI in asthma, peripheral vascular insufficiency, DM (if
↓central adrenergic tone (ing
Labetalol mortality post MI asthma, use Esmolol = selective β1 inh VS adding α inh helps
α/β-Blockers hypothalamic + bulbar β R)
(α/β blocker) -HTN emerg (labetalol) moderate reflex response to ↓CO)

Vasodilators (‘relax’ vascular SMm, ↓PRV w compensation via baroR -> sympathetic NS)
Class Drug MOA Uses Adverse effects Contraindications
-Rls NO -> guanylyl cyclase -> cGMP -> PKG pathway
-Compensatory hypertension
Nitroprusside -↓↓PRV, ↓↓venous return, ↓CO (due to ↓preload), -HTN emerg (IV) -CN accum: metabolic acidosis (give B12)
-To produce controlled hypoTN during
(arterioles ↑HR (compensatory mech); 1-10 min effect -Acute dissecting aortic aneurysm -Thiocyanate: mm spasm, convulsions
surg in pt w inadequate cerebral circ
and veins) -Metabolized to NO and CN -> thiocyanate (AE) -Severe heart failure (↓afterload) -Excessive hypoTN/reround HTN
-CVD
-Postural hypotension
Nitric oxide
-CNS: asthenia, headache, nausea, dizziness
releasers
-‘Relax’ arteriolar SMm (MOA uncertain) -CV: palpitations, sweating and flushing, reflex
-HTN (2 choice)
nd
-↓PRV, unchanged venous tone, ↑HR, ↑CO tachycardia, MI and angina (in risk pts as ↑HR = -Coronary artery disease
Hydralazine -Heart failure (w isosorbide
(compensatory mech), ↑renal blood flow ↑O2 demand) -Cerebrovascular disease
mononitrate in African Americans)
-Moderate HTN effect -Other: Lupoid syndrome (fever, serum sickness,
hemolytic anemia)
-Severe, drug-resistant HTN
-Open K+ channels (hyperpolarization) -> ‘relax’ -Na+/water retention (edema)
Minoxidil -Topically tx baldness (Rogaine) -CDV
arteriolar SMm -CNS: headache, sweating
K+ channel -Combo w loop diuretic + β-blocker
-↓PRV, unchanged venous tone, ↑HR, ↑CO (strong -CV: palpitations, angina, cardiac failure
openers
compensatory mech), ↑renal blood flow -HTN emerg (IV) -Other: hypertrichosis (excess hair) -CVD
Diazoxide
-High HTN effect -Hypoglycemia due to insulinoma -Hyperglycemia, allergy (diazoxide) -DM
Ca2+ Verapamil -Inh Ca2+ influx at vascular SMm and myocardium -HTN (1st line)
 Pharmacology
(non-dihydropyr)
Diltiazem -Dihydropyridines: peripheral vasodilatory effect;
channel
(non-dihydropyr) ↑HR, ↑CO, ↓PVR (more)
blockers -Most effective in black pts
Nifedipine -Non-dihydropyrydines: = anti-arrhythmic effect;
(see later -HTN emerg (Nicardipine)
(dihydropyridine) ↓HR, no effect on CO, ↓PVR (less)
lecture) Nicardipine -Moderate HTN effect
(dihydropyridine)
D1-dopamine -Peripheral D1 DA-R agonist -> dilation of renal -HTN emerg -CVD
-Reflex tachycardia, headache, flushing, ↑
receptor Fenoldopam arterioles and natriuresis (inh of Na+ reab) -Induce controlled hypotension -Glaucoma
intraocular P; ↓ serum K+
agonists -Does not cross BBB during surgery -Hypokalemic states

Inhibitors & antagonists of the renin-angiotensin system (RAS)

Class Drug MOA Uses Adverse effects Contraindications
-Pts w DM2; preg
-Competitive inh of renin -Dizziness, fatigue, diarrhea, hyperkalemia
Renin -Renal impairment being treated with
Aliskiren -Inh renin activity -> ↓angiotensin I, II, aldosterone, - HTN (2nd line just bc new drug) (when given with ACE inhibitors or angiotensin
inhibitors ACE inhibitors or angiotensin II receptor
↑plasma renin (due to loss of -ive short-loop fdbk) antagonists); severe hypotension; angioedema
antagonists (ARBs)
Captopril -Inh ACE (angiotensin converting enzyme) -> inh
Enalaprilat conversion of angiotensin I to angiotensin II ->
(IV emerg) relaxation of vascular SMm, ↓PVR and venous tone,
-Bilateral renal artery stenosis
unchanged HR and CO -HTN (1st line)
ACE -Severe stenosis of abdominal aorta
-Inactivates bradykinin -> ↑plasma bradykinin -HTN emerg (enalaprilat) -Hypotension, postural hypotension
inhibitors -Advanced renal insufficiency
-No sym reflex (use in ischemic heart disease) -Role in CHF, DM, chronic kidney d -Angioedema (immune response)
Enalapril -Hx of angioedema
-Interfere w short –ive loop feedback (no ATII to inh -Hyperkalemia (risk for arrhythmia)
-CVD
renin rls) -> ↑systemic renin (but no renin effect) -Dry, disturbing cough (due to bradykinin)
-Hypovolemic, hyperkalemic states
-Good HTN effect
-Pregnancy
Angiotensin -Competitive antagonism at angiotensin II R
-HTN (1st line)
II receptor Losartan -Prevent angiotensin II effect -> vasodilation, ↑
-Role in CHF, DM, chronic kidney d
antagonists salt/water secretion, no effect on bradykinin
Pharmacology
Pharmacology