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Drugs for hypertension/vascular tone (ABCD) (Other vasodilators…
Drugs for hypertension/vascular tone
(ABCD)
RAAS inhibitors
Angiotensin receptor (AT1) antagonists
Losartan
(-sartans)
NOT ATI receptor but ATII type 1 receptor antagonist
No effects on bradykinin metabolism and are therefore more selective blockers of angiotensin: also more complete effects on AT system due to other enzymes except ACE that generate ATII,
cough and angio-oedema less
Prolonged inhibition of ATII type 1 receptors causes vasodilation
There are 2 types of ATII receptors
ATII type 1 receptors: vasoconstrict
ATII type 2 receptors: vasodilate
Inhibit ATII type 1, negative feedback, increased ATII, drugs dont inhibit ATII type 2 receptors, vasodilate
ACE Inhibitors
(Angiotensin-Converting Enzyme Inhibitor),
Captopril
(-prils)
Bradykinin receptor antagonist icatibant reduces hypotensive effect of captopril
NSAIDs may impair hypotensive effect of ACE inhibitors
ACE inhibitors principally lower BP by decreasing peripheral VR: CO and HR not changed: no reflex sympathetic activation so can be used in ischaemic heart disease (unlike direct vasodilators)
No correlation between plasma renin activity and antihypertensive response, therefore renin profiling not necessary
Clinical use
Hypertension
Cardiac failure
Following myocardial infarction
Renal insufficiency
Toxicity
Severe hypotension, acute renal failure, hyperkalaemia
In conditions in which glomerular filtration is critically dependent on angiotensin II-mediated
efferent
vascular tone (such as a post-stenotic kidney, or patients with heart failure and severe depletion of circulating volume), ACE inhibition can induce acute renal failure
Dry cough sometimes accompanied by wheezing and angio- oedema: due to bradykinin and substance P
Contraindicated in pregnancy
First trimester: increased teratogenicity
Second and third trimester: fetal hypotension, anuria,
renal failure: sometimes death
Amniotic fluid is derived from fetal urine. If fetal urine production is affected, then no amniotic fluid produced
Inhibits ATI to ATII converting enzyme peptidyl dipeptidase (removes 2 AA)
Inhibits bradykinin (potent vasodilator) degradation, increasing bradykinin conc
Hypotensive actions of captopril result from both inhibition of renin-angiotensin system and stimulation of kallikrein-kinin system
Renin inhibitors
Aliskiren
Produces dose dependent reduction in plasma renin activity, AI, AII and aldosterone concentrations
Reduction in BP similar to that produced by ACEI and diuretics; also safety and tolerability similar
Prevents rise in renin activity produced by ACEI, ARBs and diuretics (AII inhibits secretion of renin from renal cortex in negative feed back loop)
Antihypertensive Therapy (ABCD)
ACEI, ATII type1-R ant.
β-blocker
Ca-blocker
Diuretic
Calcium blocker
Non dihydropyridine:
Verapamil, Diltiazem
Dihydropyridine:
Nifedipine
(-dipines)
Lowering BP: Verapamil=diltiazem=nifedipine
Vasodilator: Nifedipine>diltiazem>verapamil
Cardiac depressant:
Verapamil
>diltiazem>Nifedipine (Think of Vera Heart)
Toxicity
Excessive inhibition of calcium influx produce cardiac depression including cardiac arrest, bradycardia, AV block and heart failure: but are rare
•Patients receiving β-blockers more sensitive to cardiodepressant effects of calcium channel blockers.
•Most types of smooth muscle relaxed by calcium channel blockers but vascular smooth muscle appears to be most sensitive
•Minor side effects include flushing, dizziness, nausea, constipation and peripheral oedema: constipation common with verapamil.
Other vasodilators
Prazosin (α-1 blocker)
used primarily in men with hypertension and prostatic hyperplasia
Hydralazine
Dilates
arterioles
not veins
Increases cGMP and is also a NO donor leading to dilation of smooth muscle
Tachphylaxis (rapidly diminishing response to successive doses of a drug, rendering it less effective) to antihypertensive effects develops rapidly: benefits of combination therapy now recognized: used as second line therapy in severe hypertension with β-blockers and diuretics
Combination of hydralazine with nitrates effective in heart failure: especially in african american with hypertension and heart failure
Minoxidil
Dilates
arterioles
not veins
Opens K+ channels in smooth muscle stabilizing
membrane making contraction less likely (when K+ channel open, Ca2+ cannot enter)
Sweating and hypertrichosis (excessive hair growth) is common
Now used topically as stimulant for hair growth in male pattern baldness
Sildenafil
Increases cGMP by inhibiting its breakdown by PDE5.
PDE5 is primarily distributed in arterial wall smooth muscle of lungs and penis
Used in ED (erectile dysfunction) and pulmonary hypertension
In ED relaxes intimal cushions in helicine arteries leading to vasodilation and increased blood flow to corpus cavernosum
In PH relaxes pulmonary arteries leading to decreased PR and reduces workload of right ventricle
Contraindicated if taking nitrates, hepatic
impairment, renal dysfunction and hypotension
Ca2+ calmodulin complex activates myosin light chain kinase (MLCK) to active form. Adenylyl cyclase activated by beta2 agonist converts ATP to cAMP, deactivating MLCK by phosphorylation. Guanylyl cyclase activated by nitric oxide converts GTP to cGMP, deactivating MLCK by activating protein kinase G which phosphorylates/deactivates MLCK. When myosin light chain kinase is activated, it phosphorylates myosin light chain, leading to contraction
RAAS
Angiotensinogen converted to angiotensin I via renin (JGA)
Angiotensin I converted to angiotensin II via ACE (lungs, kidney)
Angiotensin II: Aldosterone, ADH, arteriolar vasoconstriction, sympathetic
Even in low renin hypertensive states, ACE-I lower BP
Drugs to avoid in certain diseases
Congestive heart failure: Ca2+ blockers
Asthma/COPD: β blockers
Diabetes: β blockers
Pregnancy: ACE-I