http://medsouls4you.blogspot.

com

Antihypertensives

Learning Objectives
Differentiate between angiotensin-converting enzyme inhibitors and
angiotensin-receptor blockers
Explain drug strategy for treating hypertension using calcium-channel
blockers, drugs altering sympathetic activity, and direct-acting
vasodilators
Answer questions about indications for use of antihypertensive drugs
Describe modifications of hypertension treatment in comorbid
conditions
Apply knowledge of treatment of pulmonary hypertension

DRUG STRATEGY
l
l
l
l

TPR
CO
body fluid volume
BP may result in homeostatic regulation:
Reflex tachycardia ( sympathetic activity)
Edema ( renin activity)

Clinical Correlate
Current recommendations are to use
thiazide diuretics, ACEIs, or long-acting
CCBs as first-line therapy. These drugs
are considered equally effective.

THIAZIDE DIURETICS (See Chapter 1)

Thiazide diuretics are commonly used in the management of hypertension.

http://medsouls4you.blogspot.com

91

Section III

http://medsouls4you.blogspot.com

Cardiac and Renal Pharmacology

ANGIOTENSIN-CONVERTING ENZYME INHIBITORS (ACEIs)

AND ANGIOTENSIN-RECEPTOR BLOCKERS (ARBs)
Inhibited by aliskiren
renin (kidney)
Angiotensinogen
Angiotensin I
Bradykinin
(from liver)
Angiotensinconverting
Blocked by
enzyme
ACE inhibitors
(plasma)
Angiotensin II
AT-1 receptors
blocked by
losartan

Adrenal cortex

Aldosterone
secretion

AT-1
receptors

inactivation

Blood vessels

Vasoconstriction

Figure III-2-1. The Angiotensin System

92

Drugs:
ACEIs: captopril, lisinopril (and other prils)
Block formation of angiotensin II
Resulting in prevention of AT1-receptor stimulation
aldosterone, vasodilation
ACEIs prevent bradykinin degradation
ARBs: losartan (and other sartans)
Block AT1 receptors
Same results as ACEIs on BP mechanisms
ARBs do not interfere with bradykinin degradation
Renin inhibitor: Aliskiren
Blocks formation of angiotensin I
Same results as ACEIs on BP mechanisms
Aliskiren does not interfere with bradykinin degradation
Uses:
Mild-to-moderate hypertension (all)
Protective of diabetic nephropathy (ACEI/ARBs)
CHF (ACEI/ARBs)
Side effects:
Dry cough (ACEIs)
Hyperkalemia
Acute renal failure in renal artery stenosis
Angioedema
Contraindication: pregnancy

http://medsouls4you.blogspot.com

http://medsouls4you.blogspot.com
Chapter 2
CALCIUM-CHANNEL BLOCKERS (CCBs)
l
l
l
l

VERAPAMIL

Ca2+-channel blockers

DILTIAZEM

Antihypertensives

Bridge to Physiology

Block L-type Ca2+ channels in heart and blood vessels

Results in intracellular Ca2+
Causes CO (verapamil and diltiazem), TPR (all CCBs)
Drugs: verapamil, diltiazem, dihydropyridines (dipines, prototype:
nifedipine)

Heart

Blood vessel
DIPINEs

Vasodilators may have specificity.

l

Arteriolar: Ca2+-channel blockers,

hydralazine, K+-channel openers

Venular: nitrates

Both arteriolar and venular: the rest

Orthostatic (postural) hypotension

results from venular dilation (not
arteriolar) and mainly results from
1 blockade or decreased sympathetic
tone.

Figure III-2-2. Cardiac or Vascular Selectivity of

Major Ca2+-Channel Blockers

Uses:
Hypertension (all drugs)
Angina (all drugs)
Antiarrhythmics (verapamil, diltiazem)
Side effects:
Reflex tachycardia (dipines)
Gingival hyperplasia (dipines)
Constipation (verapamil)

DRUGS ALTERING SYMPATHETIC ACTIVITY

l

blockers
Mechanism (See ANS section)
Side effects:
Cardiovascular depression
Fatigue
Sexual dysfunction
LDLs and TGs
Cautions in use:
Asthma
Vasospastic disorders
Diabetics (alteration of glycemia and masking of tachycardia due to
hypoglycemic events)
1 blockers
arteriolar and venous resistance
Reflex tachycardia
Drugs: prazosin, doxazosin, terazosin
Uses:
Hypertension
BPH: urinary frequency and nocturia by the tone of urinary
sphincters

http://medsouls4you.blogspot.com

93

Section III

http://medsouls4you.blogspot.com

Cardiac and Renal Pharmacology

DIRECT-ACTING VASODILATORS

Clinical Correlate
Cyanide Poisoning
Sodium nitrite or amyl nitrite can
be used in cyanide poisoning. It
promotes formation of methemoglobin
(MetHb), which binds CN ions,
forming cyanomethemoglobin. This
prevents the inhibitory action of CN on
complex IV of the electron transport
chain. Cyanomethemoglobin is then
reconverted to methemoglobin by
treatment with sodium thiosulfate,
forming the less toxic thiocyanate
ion (SCN). MetHb is converted to
oxyhemoglobin with methylene blue.

Drugs Acting Through Nitric Oxide

l

Clinical Correlate
A hypertensive emergency occurs
when hypertension is severe enough
to cause end-organ damage. Most
commonly, nitroprusside, labetalol,
or the D1 agonist fenoldopam is given
intravenously as therapy.

94

Side effects:
First-dose syncope
Orthostatic hypotension
Urinary incontinence
Advantage: good effect on lipid profile ( HDL, LDL)
2 agonists: clonidine and methyldopa (prodrug)
2 stimulation:
in sympathetic outflow
TPR but also HR
Uses:
Mild-to-moderate hypertension (both)
Opiate withdrawal (clonidine)
Hypertensive management in pregnancy (methyldopa)
Side effects:
Positive Coombs test (methyldopa)
CNS depression (both)
Edema (both)
Drug interactions:
Tricyclic antidepressants antihypertensive effects of 2 agonists

Hydralazine
TPR via arteriolar dilation
Use: moderate-to-severe hypertension
Side effects:
SLE-like syndrome and slow acetylators
Edema
Reflex tachycardia
Nitroprusside
TPR via dilation of both arterioles and venules
Use: hypertensive emergencies (used IV)
Side effect: cyanide toxicity (co-administered with nitrites and thiosulfate;
see Clinical Correlate)

Drugs Acting to Open Potassium Channels

l

Drugs: minoxidil and diazoxide

Open K+ channel, causing hyperpolarization of smooth muscle
Results in arteriolar vasodilation
Uses:
Insolinoma (diazoxide)
Severe hypertension (minoxidil)
Baldness (topical minoxidil)

http://medsouls4you.blogspot.com

http://medsouls4you.blogspot.com
Chapter 2

Antihypertensives

Side effects:
Hypertrichosis (minoxidil)
Hyperglycemia ( insulin release [diazoxide])
Edema
Reflex tachycardia

INDICATIONS FOR USE OF ANTIHYPERTENSIVE DRUGS

IN COMORBID CONDITIONS
Table III-2-1. Use of Antihypertensive Drugs in Comorbid Conditions
Indication

Suitable Drug(s)

Angina

Beta blockers, CCBs

Diabetes

ACEIs, ARBs

Heart failure

ACEIs, ARBs, beta blockers

Post-MI

Beta blockers

BPH

Alpha blockers

Dyslipidemias

Alpha blockers, CCBs, ACEIs/ARBs

Chronic kidney disease

ACEI, ARBs

Clinical Correlate
Chronic (preexisting) hypertension
in pregnancy is often treated with
methyldopa or labetalol, while
preeclampsia (new-onset hypertension
in pregnancy) is treated with labetalol
or hydralazine.

TREATMENT OF PULMONARY HYPERTENSION

l

Bosentan
Endothelin (ET)-1 is a powerful vasoconstrictor through ET-A and -B
receptors
Bosentan is an ETA receptor antagonist
Administered orally
Side effects are associated with vasodilation (headache, flushing,
hypotension, etc.)
Contraindication: pregnancy
Prostacyclin (PGI2): epoprostenol
Administered via infusion pumps
Sildenafil
Inhibits type V PDE
cGMP
Pulmonary artery relaxation
pulmonary hypertension

http://medsouls4you.blogspot.com

95