Medical Pharmacology Topics
| Preliminary Outline |
Antihypertensives |
Several drug classes are used to treat hypertension: diuretics, sympatholytics, vasodilators, calcium blockers, angiotensin converting enzyme (ACE) inhibitors, and angiotensin receptor antagonists.
A "stepping up" approach is used in the treatment of hypertension. Some patients may only need nonpharmacological approaches like weight control and sodium/alcohol restrictions. If the nonpharmacological aproach is not succesful, a drug is added to the treatment, either a diuretic, beta blocker, calcium blocker or ACE inhibitor. If further treatment is needed, a second drug from a different class may be added, or one drug may be substituted for another from a diferent class. A third and fourth drug may be added as needed.
Sympatholytics and Vasodilators
Sympatholytics are useful in treating hypertension because they induce vasodilation, and include guanethidine, clonidine, prazosin, labetalol, propanolol and metropolol. Guanethidine is a rarely used adrenergic receptor blocker, and can increase rening levels.
Clonidine is a an a-agonists but also acts on the CNS to decrease SNS activity, thus reducing vasoconstriction. It also decreases plasma renin levels.
Prazosin is an a-receptor antagonist, thus preventing vasoconstriction. Labetalol is both an alpha and beta blocker.
Propanolol and metoprolol are a beta blockers, and is not well understood how they lower blood pressure in hypertensive patients, while having no pressor effect on normal individuals (may be related to their blocking of renin secretion).
The calcium blockes include verapamil, diltiazem and nifedipine. These agents are not first line drugs because of their many side effects, among them headache, dizziness, alterations of heart rate, flushing and congestive heart failure. Nifedipine has a greater vasodilator effect, and thus a greater reflex tachycardia. Verapamil has good vasodilator activity and little reflex tachicardia because of its negative ionotropic action on the myocardium. Other vasodilators used to treat hypertension are hydralazyne and nitroprusside.
Inhibitors of Angiotensin Activity
Decreased renal function and/or increased sympathetic activity increase renin secretion. Renin cleaves angiotensinogen (synthsozed in the liver) to yield angiotensin I. In turn, angiotensin I is converted in the lungs to angiotensin II by angiotensin converting enzyme (ACE). The same reaction breaks down bradykinin. Bradykinin mediates vasodilation through prostaglandings (?).
Angiotensin II alters peripheral resistance, renal function and cardiovascular structure. Angiotensin is a direct vasoconstrictor, resulting in a rapid pressor response. It will also act directly to increase Na reabsorption in the proximal tubule and release aldosterone from the adrenal cortex, resulting in a slow pressor response. Angiotensin II also plays a rele in long-term vascular and cardiac remodeling and hypertrophy.
An ACE inhibitor will decrease angiotensin II and aldosterone levels, increase renin and bradykinin levels, and decrease blood pressure. In addition, ACE inhibition enhaces the response to diuretics (blunted homeostatic release of aldosterone), are potassium sparing (also due to decreased aldosterone) and seem to delay the development of diabetic nephropathy.
Examples of ACE inhibitors are captopril, enalapril and lisinopril. They ae metabolized in the liver and excreted in the urine. Enalapril is a prodrug rapidly absorbed orally that must be de-esterified to the active agent, enalaprilat (has poor oral absorption). Adverse effects of ACE inhibitors include allergic rash, fever, loss of taste, hypotension, cough, angioedema (0.1-0.2%), teratogenicity, fetal mortality, and hyperkalemia.
Angiotensin II receptor antagonists like losartan, are selective competitive inhibitors of the angiotensin receptor type 1 (AT1), which mediates vasoconstriction and aldosterone secretion. Slow dissociation kinetics make these agents act like "unsurmountable" antagonists. This is a clinical advantage, since there will be sustained recepyor blockade even with increased endogenous levels of angiotensin II, and the effects on blood pressre are sustained even after missed doses.
Angiotensin II antagonists have little effect on blood pressure when plasma renin levels are already low. Otherwise, these agents compleately block the action of angiotensin II, while ACE inhibitors may not (angiotensin from other sources). The antagonists do not affect bradykinin levels, do not produce cough and have a lower incidence of angioedema than ACE inhibitors. Adverse effects include teratogenicity, acute renal failure (especially when coadministered with other vasodilatorlike nitroprusside and hyperkalemia..
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to "Vasodilators" or take a quiz: [Q1].
Need more practice? Answer the review questions below.
Questions:
1- List 6 classes of drugs that are used to treat hypertension.
2- Explain the "stepping up" approach to the treatment of hypertension.
3- Why are sympatholitics useful in the treatment of hypertension?
4- List 6 sympatholytics used to treat hypertension.
5- What is the mechanism of action of clonidine?
6- What is the mechanisms of action of prazosin?
7- What is the mechanisms of action of labetalol?
8- What is the mechanisms of action of propanolol ad metoprolol?
9- List 3 calcium blockers.
10- What are the adverse effects of calcium blockers?
11- What are the effects of nifedipine?
12- What are the effects of verapamil?
13- List 2 vasodilators used to treat hypertension, other than calcium blockers.
14- What are the physiological triggers to increase renin secretion?
15- What is the function of renin?
16- What is the function of angiotensin converting enzyme?
17- What is the function of bradykinin?
18- What is the function of angiotensin II?
19- What are the effects of an ACE inhibitor?
20- List 3 ACE inhibitors.
21- What are the important pharmacokinetic characterstics of enalapril?
22- What are the adverse effects of ACE inhibitors?
23- List 1 angiotensin antagonits.
24- What is the mechanism of action of angiotensin antagonist?
25- What is the clinical importance of the slow dissociation kinetics of angiotensin antagonists?
26- What are the effects of angiotensin antagonists and how they relate to renin secretion and the effects of ACE inhibitors?
27- What are the adverse effects of angiotensin antagonists?
Continue scrolling to answers below (after sponsor).
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Answers:
1- List 6 classes
of drugs that are used to treat hypertension.
diuretics
sympatholytics
vasodilators
calcium blockers
ACE inhibitors
angiotensin blockers
2- Explain the "stepping
up" approach to the treatment of hypertension.
Some patients may only need nonpharmacological approaches like weight control
and sodium/alcohol restrictions. If the nonpharmacological aproach is not succesful,
a drug is added to the treatment, either a diuretic, beta blocker, calcium blocker
or ACE inhibitor. If further treatment is needed, a second drug from a different
class may be added, or one drug may be substituted for another from a diferent
class. A third and fourth drug may be added as needed.
3- Why are sympatholitics
useful in the treatment of hypertension?
induce vasodilation
4- List 6 sympatholytics
used to treat hypertension.
guanethedine
clonidine
prazosin
labetalol
propanolol
metroprolol
5- What is the mechanism
of action of clonidine?
a-agonist, but also acts in the CNS to decrease SNS
activity, thus reducing vasodilation and decreasing renin secretion
6- What is the mechanisms
of action of prazosin?
a-antagonist, prevent vasoconstriction
7- What is the mechanisms
of action of labetalol?
a- and b-antagonist, prevents
vasoconstriction and has other unknown effects thru b receptors still not clear
8- What is the mechanisms
of action of propanolol ad metoprolol?
beta blockers, and is not well understood how they lower blood pressure in hypertensive
patients, while having no pressor effect on normal individuals (may be related
to their blocking of renin secretion)
9- List 3 calcium
blockers.
verapamil
diltiazem
nifedipine
10- What are the
adverse effects of calcium blockers?
headache
dizziness
alterations of heart rate
flushing
congestive heart failure
11- What are the
effects of nifedipine?
has a greater vasodilator effect, thus a greater refex tachycardia
12- What are the
effects of verapamil?
has good vasodilator activity and little reflex tachycardia because of its negative
ionotropic action on the myocardium.
13- List 2 vasodilators
used to treat hypertension, other than calcium blockers.
hydralazyne
nitroprusside
14- What are the
physioklogical triggers to increase renin secretion?
decreased renal function
increased sympathetic activity
15- What is the
function of renin?
cleaves liver-synthesized angiotensinogen to yield angiotensin I
16- What is the
function of angiotensin converting enzyme?
Angiotensin I is converted in the lungs to angiotensin II by angiotensin converting
enzyme (ACE). The same reaction breaks down bradykinin.
17- What is the
function of bradikinin?
mediates vasodilation through prostaglandins
18- What is the
function of angiotensin II?
Alters peripheral resistance, renal function and cardiovascular structure. Is
a direct vasoconstrictor, resulting in a rapid pressor response. It will also
act directly to increase Na reabsorption in the proximal tubule and release
aldosterone from the adrenal cortex, resulting in a slow pressor response. Also
plays a role in long-term vascular and cardiac remodeling and hypertrophy.
19- What are the
effects of an ACE inhibitor?
decrease angiotensin II and aldosterone levels
increase renin and bradikinin levels
decrease blood pressure
enhances the response tu diuretics (because of blunted aldosterone release
spares potassium
delays development of diabetic nephropathy
20- List 3 ACE inhibitors.
captopril
enalapril
lisinipril
21- What are the
important pharmacokinetic characterstics of enalapril?
Is a prodrug rapidly absobed orally, that must be de-esterified to the active
agent, enalaprilat, which has poor oral availability.
22- What are the
adverse effects of ACE inhibitors?
allergic rash
fever
loss of taste
hypotension
cough
angioedema (0.1-0.2%)
teratogenicity
fetal mortality
hyperkalemia
23- List 1 angiotensin
antagonits.
Losartan
24- What is the
mechanism of action of angiotensin antagonist?
selective competitive inhibitors of angiotensin II receptor type 1 (AT1), which
mediates vasoconstriction and aldoseterone secretion. Slow dissociation kinetics
make these agents act like "unsurmountable" antagonists.
25- What is the
clinical importance of the slow dissociation kinetics of angiotensin antagonists?
there will be sustained receptor blockade even with increased endogenous levels
of angiotensin II, and the effects on blood pressre are sustained even after
missed doses.
26- What are the
effects of angiotensin antagonists and how they relate to renin secretion and
the effects of ACE inhibitors?
compleately block the action of angiotensin, lowering blood pressure
do not affect bradykinin, have lower incidece of angioedema
have little effect on blood pressure if renin levels are already low
27- What are the
adverse effects of angiotensin antagonists?
teratogenicity
acute renal failure especially if coadministered with vasodilators
hyperkalemia
Diuretics
Thiazides