Antihypertensive agents

Centrally Acting Sympatholytics

The sympathetic adrenergic nervous system plays a major role in the regulation of
arterial pressure.

Mechanism of action:

The mechanism of the central hypotensive action for methyldopa is attributed to its
transport into the CNS via an aromatic amino acid transport mechanism, where it is
decarboxylated and hydroxylated into alpha-methylnorepinephrine (Fig. 24.7) (9). This
active metabolite of methyldopa decreases total peripheral resistance, with little
change in cardiac output and heart rate, through its stimulation of central inhibitory
alpha-2-adrenoceptors.
A reduction of plasma renin activity can also contribute to the hypotensive action of
methyldopa. Postural hypotension and sodium and water retention are also effects
related to a reduction in blood pressure.
Therapeutic Applications (Methyldopa)

This drug is used in the management of moderate to severe hypertension and is

reserved for patients who fail to achieve blood pressure goals with stage 2 drugs.
Methyldopa is also co administered with diuretics and other classes of antihypertensive
drugs, permitting a reduction in the dosage of each drug and minimizing adverse effects
while maintaining blood pressure control. Methyldopa has been used in the
management of hypertension during pregnancy without apparent substantial adverse
effects on the fetus and also for the management of pregnancy-induced hypertension
(i.e., preeclampsia) (5).
Method of synthesis

i. 4-hydroxy-3-methoxy phenylacetone is taken as starting material.

ii. It undergoes reaction with ammonium chloride followed by reaction with potassium cyanide to α-amino nitrile
compound.
iii. On reacting with sulfuric acid, we get methyldopa as final product.
The overall mechanism of action for the centrally active sympatholytics, clonidine,
guanabenz, and guanfacine, appears to be stimulation of alpha2-adrenoceptors and specific
binding to nonadrenergic imidazoline I-1 receptors in the CNS (mainly in the medulla
oblongata), causing inhibition of sympathetic output (sympatho inhibition) (19,20). This
effect results in reduced peripheral and renovascular resistance and leads to a decrease in
systolic and diastolic blood pressure. Through the use of imidazoline and a2-adrenergic
antagonists, specific I1 receptors have recently been characterized in CNS control of blood
pressure (21). The I-1 receptors are pharmacologically distinct from a2-receptors, because
they are not activated by catecholamines but characterized by their high affinity for 2-
iminoimidazolines(or 2-aminoimidazolines) and low affinity for guanidines (21)
Medicinal Uses
Clonidine, guanabenz, and guanfacine are used in the management of mild to
moderate hypertension or when stage 2 drugs have been ineffective in
achieving blood pressure goals (1,6).

They have been used as monotherapy or to achieve lower dosages in

combination with other classes of antihypertensive agents. The centrally acting
sympatholytics are generally reserved for patients who fail to respond to
therapy with a stage 1 drug (e.g., diuretics, b-adrenergic blocking agents, ACEIs,
or ARBs). Clonidine, guanabenz, and guanfacine can be used in combination
with diuretics and other stage 1 hypotensive agents, permitting a reduction in
the dosage of each drug, which minimizes adverse effects while maintaining
blood pressure control.
Adrenergic Neuron Blocking Agents

Reserpine, guanethidine are two drugs with similar mechanisms of action involving
norepinephrine storage granules. These drugs are transported into the adrenergic
neurons by uptake-1, where they bind to the storage vesicles and prevent release of
neurotransmitter in response to a neuronal impulse. Reserpine, guanethidine, and
guanadrel are orally active antihypertensives that actually replace norepinephrine in
the storage vesicles, resulting in a slow release in the amount of norepinephrine
that is present.

Mechanism of Action (9)

Reserpine acts to replace and deplete the adrenergic neurons of their stores of
norepinephrine by inhibiting the active transport Mg-ATPase responsible for
sequestering norepinephrine and dopamine within the storage vesicles. The
norepinephrine and dopamine that are not sequestered in vesicles are destroyed by
MAO. As a result, the storage vesicles contain little neurotransmitter, adrenergic
transmission is dramatically inhibited, and sympathetic tone is decreased, leading to
vasodilation. Reserpine has the same effect on epinephrine storage in the adrenal
medulla. Reserpine readily enters the CNS, where it also depletes the stores of
norepinephrine and serotonin. The CNS neurotransmitter depletion led to the use
of reserpine in treating certain mental illnesses.
Medicinal uses of Reserpine

This drug is used the management of mild to moderate hypertension, but because of
very significant CNS adverse effects and its cumulative action in the adrenergic
neurons, reserpine is rarely used. Reserpine and related Rauwolfi a alkaloids have been
used in the symptomatic treatment of agitated psychotic states, such as schizophrenic
disorders, although other antipsychotic agents have generally replaced reserpine
and the alkaloids.
Mechanism of Action Guanethidine is an adrenergic neuronal blocking agent
that produces a selective block of peripheral sympathetic pathways by
replacing and depleting norepinephrine stores from adrenergic nerve
endings, but not from the adrenal medulla (6,9). It prevents the release of
norepinephrine from adrenergic nerve endings in response to sympathetic
nerve stimulation. The chronic administration of guanethidine results
in an increased sensitivity of these effector cells to catecholamines.
Following the oral administration of usual doses of guanethidine, depletion of
the catecholamine stores from adrenergic nerve endings occurs at a very
slow rate, producing a more gradual and prolonged fall in systolic blood
pressure than in diastolic pressure. Associated with the decrease in blood
pressure is an
increase in sodium and water retention and expansion of
plasma volume (edema). If a diuretic is not administered
concurrently with guanethidine, tolerance to the antihypertensive
effect of the guanethidine during prolonged
therapy can result.