SYMPATHOLYTIC

AGENTS

BY
LUBOGO PATRICK
Department of Pharmacology
School of Health Sciences
Soroti University
 SYMPATHOLYTIC AGENTS
• Sympatholytic drugs reduce BP by inhibiting or
blocking the sympathetic nervous system
1. α1 adrenergic receptor antagonist (α1 Blockers)

2. β adrenergic receptor antagonist (β Blockers)

3. Combined α1 and β Blockers

4. Centrally Acting Sympatholytic Drugs

 α1-Blockers
• Availability of drugs that selectively block α 1 adrenergic receptors
without affecting α2 adrenergic receptors adds another group of
antihypertensive agents
• Prazosin, terazosin, & doxazosin are α1-blockers available for the
treatment of hypertension
• Phenoxybenzamine & phentolamine are nonselective α
adrenergic receptor blocker
 Phenoxybenzamine, an irreversible α blocker (α1 > α2), is used in the
treatment of catecholamine-producing tumors (pheochromocytoma)
 Phentolamine, a reversible competitive α blocker can also be used in short-
term control of hypertension in patients with pheochromocytoma
 Phentolamine also may be useful for the treatment of hypertensive crises
following abrupt clonidine withdrawal of clonidine or that may result from
the ingestion of tyramine-containing foods during the use of nonselective
MAO inhibitors
 Pharmacological Effects
• Initially, α1 blockers reduce arteriolar resistance and increase
venous capacitance
• This causes a sympathetically mediated reflex increase in heart rate
and plasma renin activity
• During long-term therapy, vasodilation persists, but cardiac output,
heart rate, and plasma renin activity return to normal
• Renal blood flow is unchanged during therapy with an α 1 blocker
• The α1 blockers cause a variable amount of postural hypotension,
depending on the plasma volume
• Retention of salt and water occurs in many patients during
continued administration, and this attenuates the postural
hypotension
• The α1 blockers reduce plasma concentrations of triglycerides and
total LDL cholesterol and increase HDL cholesterol
 Therapeutic Uses
• α1-blockers are not recommended as monotherapy for hypertensive
patients

• α1-blockers may be considered as add-on therapy to other

agents (e.g., as fourth or fifth line) when hypertension is not
adequately controlled

• In addition, they may have a specific role in the antihypertensive

regimen for elderly men with benign prostatic hyperplasia

• Consequently, they are used primarily in conjunction with thiazide

diuretics, β blockers, and other antihypertensive agents

• Combination therapy with a thiazide is recommended to minimize

potential edema resulting from the α1-blocker’s tendency to cause
sodium & water retention

• β Blockers enhance the efficacy of α1 blockers

 Adverse effects
• The use of α1-blockers is often curtailed by complaints of :

 transient dizziness, palpitations, postural hypotension

& syncope following the first dose

 orthostatic hypotension with chronic use

• Due to their ability to cross blood–brain barrier, α 1-

blockerscan also cause asthenia, vivid dreams &
depression

• In addition, priapism may occur

 β-blockers
• Contemporary guidelines refrain from supporting the use of β-
blockers as first-line antihypertensive agents

• However, the role of β-blockers in patients with specific select

comorbidities is well-established such as coronary artery
disease, HF with reduced ejection fraction (HFrEF), or
recent myocardial infraction (MI)

• The hemodynamic effects & antiarrhythmic properties of β-

blockers also make them desirable for hypertensive patients
who suffer from ischemic conditions including acute coronary
syndromes
 Locus & Mechanism of Action
• Antagonism of β adrenergic receptors affects the regulation of
the circulation through a number of mechanisms, including a
reduction in myocardial contractility and heart rate (i.e.,
cardiac output)
• Antagonism of β1 receptors of the juxtaglomerular complex
reduces renin secretion and RAS activity
 This action likely contributes to the antihypertensive action
• Some members of this large, heterogeneous class of drugs
have additional effects unrelated to their capacity to bind to β
adrenergic receptors e.g.
 labetalol and carvedilol are also α1 blockers
 nebivolol promotes endothelial cell–dependent vasodilation via
activation of NO production
 Pharmacodynamic Differences
• β blockers vary in their selectivity for the β 1 receptor subtype,
presence of partial agonist or ISA, and vasodilating capacity
• While all of the β blockers are effective as antihypertensive agents,
these differences influence the clinical pharmacology and spectrum
of adverse effects of the various drugs
• The antihypertensive effect resides in antagonism of the β 1 receptor,
while major unwanted effects result from antagonism of β 2 receptors
(e.g., peripheral vasoconstriction, bronchoconstriction,
hypoglycemia)
• Standard therapies are β1 blockers without intrinsic
sympathomimetic activity (e.g., atenolol, bisoprolol, metoprolol)
• They produce an initial reduction in cardiac output (mainly β 1) & a
reflex-induced rise in peripheral resistance, with little or no acute
change in arterial pressure
 Pharmacodynamic Differences
• In patients who respond with a reduction in BP, peripheral
resistance gradually returns to pretreatment values or less
• Generally, persistently reduced cardiac output and possibly
decreased peripheral resistance account for the reduction in arterial
pressure
• Nonselective β blockers (e.g., propranolol) have stronger adverse
effects on peripheral vascular resistance by also blocking β 2
receptors that normally mediate vasodilation
• Vasodilating β blockers (e.g., carvedilol, nebivolol) may be preferred
in patients with peripheral artery disease
• Drugs with intrinsic sympathomimetic activity (e.g., pindolol) are not
recommended for the treatment of hypertension or any other
cardiovascular disease because they actually increase night-time
mean heart rate due to their direct partial agonistic activity
 Pharmacokinetic Differences
• Lipophilic β blockers (metoprolol, bisoprolol, carvedilol, propranolol)
with membrane-stabilizing properties appear to have more
antiarrhythmic efficacy than the hydrophilic compounds (atenolol,
nadolol, labetalol)
• Many β blockers have relatively short plasma half-lives & require
more than once-daily dosing (metoprolol, propranolol, carvedilol), a
significant disadvantage in the treatment of hypertension
 They should generally be prescribed in sustained-release forms

• Bisoprolol & nebivolol have t1/2 values of 10–12 h & thus achieve
sufficient trough levels at once-daily dosing
• Hepatic metabolism of metoprolol, carvedilol & nebivolol is CYP2D6
dependent
 The relevance is probably greatest in case of metoprolol, for which
CYP2D6 poor metabolizers show 5-fold higher drug exposure and 2-fold
higher heart rate decreases than the majority of extensive metabolizers
 Adverse Effects & Precautions
• Adverse effects include bradycardia, heart block, heart failure,
dyspnea, bronchospasm, fatigue, dizziness, lethargy,
depression, hyper-/hypoglycemia, hyperkalemia &
hyperlipidemia
• These drugs should be avoided in patients with reactive airway
disease (e.g. asthma) or with SA or AV nodal dysfunction or in
combination with other drugs that inhibit AV conduction, such as
verapamil
• The risk of hypoglycemic reactions may be increased in diabetics
taking insulin, but type 2 diabetes is not a contraindication
• Sudden discontinuation of β blockers can produce a withdrawal
syndrome that is likely due to upregulation of β receptors during
blockade, causing enhanced tissue sensitivity to endogenous
catecholamines—leads to rebound hypertension & can exacerbate
the symptoms of CAD
 Drug should be tapered gradually over 10–14 days prior to discontinuation
 Therapeutic Uses
• The β blockers provide effective therapy for all grades of
hypertension

 Marked differences in their pharmacokinetic properties should be

considered; once-daily dosing is preferred for better compliance

• The combination of a β blocker, a diuretic, and a

vasodilator is effective for patients who require a third
antihypertensive drug

• β Blockers (i.e., bisoprolol, carvedilol, metoprolol, or

nebivolol) are highly preferred drugs for hypertensive patients
with conditions such as MI, ischemic heart disease, or
congestive heart failure & may be preferred for younger
patients with signs of increased sympathetic drive
 Combined α1 and β Blockers
• Carvedilol is a nonselective β blocker with α1-antagonist
activity
 Carvedilol is approved for the treatment of hypertension &
symptomatic heart failure
 The drug dissociates slowly from its receptor, explaining why the
duration of action is longer than the short t1/2 (2.2 h) and why its effect
can hardly be overcome by catecholamines
 Carvedilol undergoes oxidative metabolism and glucuronidation in the
liver; the oxidative metabolism occurs via CYP2D6
 As with labetalol, the long-term efficacy and side effects of carvedilol in
hypertension are predictable based on its properties as a β and α 1
blocker
 Carvedilol reduces mortality in patients with congestive heart failure
 Due to the vasodilating effect, carvedilol is a β blocker of choice in
patients with peripheral artery disease
 Combined α1 and β Blockers
• Labetalol is an equimolar mixture of four stereoisomers
 One isomer is an α1 blocker, another is a nonselective β
blocker with partial agonist activity, and the other two
isomers are inactive

 Labetalol has efficacy and adverse effects that would be

expected with any combination of an α1 and a β blocker

 FDA-approved for eclampsia, preeclampsia,

hypertension, and hypertensive emergencies

 Main indication for labetalol is hypertension in

pregnancy
 Centrally Acting Sympatholytic Drugs
• These include:
1. Methyldopa
2. Clonidine & Moxonidine
3. Reserpine
 Methyldopa
• Methyldopa is a centrally acting antihypertensive agent
• It is a prodrug that exerts its antihypertensive action via an
active metabolite
• Methyldopa’s adverse effect profile limits its current use
largely to treatment of hypertension in pregnancy, where it
has a record for safety
• Methyldopa (α-methyl-3,4-dihydroxy-l-phenylalanine) is an
analogue of DOPA
• It is metabolized by the L-aromatic amino acid decarboxylase
in adrenergic neurons to α-methyldopamine, which then is
converted to α-methylnorepinephrine, the pharmacologically
active metabolite
 Methyldopa
• α-Methylnorepinephrine is stored in the secretory vesicles of
adrenergic neurons, substituting for norepinephrine (NE), such
that the stimulated adrenergic neuron now discharges α-
methylnorepinephrine instead of NE

• α-Methylnorepinephrine acts in the CNS to inhibit

adrenergic neuronal outflow from the brainstem, probably
via acting as an agonist at presynaptic α2 adrenergic
receptors in the brainstem, attenuating NE release and
thereby reducing the output of vasoconstrictor adrenergic
signals to the peripheral sympathetic nervous system
 Pharmacokinetics of Methyldopa
• Methyldopa is a prodrug
• Cpmax occurs 2–3 h following an oral dose
• The drug is eliminated with a t1/2 of about 2 h
• Methyldopa is excreted in the urine primarily as the sulfate
conjugate (50%–70%) and as the parent drug (25%)
• The t1/2 of methyldopa is prolonged to 4–6 h in patients with renal
failure
 Patients with renal failure are more sensitive to the
antihypertensive effect of methyldopa
• Despite its rapid absorption & short t 1/2, the peak effect of
methyldopa is delayed for 6–8 h & the duration of action of a single
dose is usually about 24 h
 This permits once- or twice-daily dosing
 Therapeutic uses of Methyldopa
• Methyldopa is the drug of choice for treatment of
hypertension during pregnancy based on its effectiveness
and safety for both mother and fetus

• The usual initial dose of methyldopa is 250 mg twice daily

 There is little additional effect with doses greater than 2 g/d

• Administration of a single daily dose of methyldopa at bedtime

minimizes sedative effects, but administration twice daily is
required for some patients
 Adverse Effects of Methyldopa
• Transient sedation
• Hepatotoxicity; potentially serious toxic effect of methyldopa
• Hemolytic anemia
• Peripheral edema
• Orthostatic hypotension
• Depression occurs occasionally
• Dryness of the mouth
• Other adverse effects include diminished libido,
parkinsonian signs & hyperprolactinemia that may become
sufficiently pronounced to cause gynecomastia &
galactorrhea
• Methyldopa may precipitate severe bradycardia & sinus
arrest
 Clonidine & Moxonidine
• These drugs stimulate α2A adrenergic receptors in the
brainstem, resulting in a reduction in sympathetic outflow from
the CNS
• The hypotensive effect correlates directly with the decrease in
plasma concentrations of NE
• At doses higher than those required to stimulate central α 2A
receptors, these drugs can activate α 2B receptors on vascular
smooth muscle cells
 This effect accounts for the initial vasoconstriction that is seen when overdoses
of these drugs are taken and may be responsible for the loss of therapeutic
effect that is observed with high doses

• A major limitation in the use of these drugs is the paucity of

information about their efficacy in reducing the risk of cardiovascular
consequences of hypertension
 Pharmacological properties
• The α2 adrenergic agonists lower arterial pressure by effects
on both cardiac output and peripheral vascular resistance

• In the supine position, when the sympathetic tone to the

vasculature is low, the major effect is a reduction in heart rate
and stroke volume

• However, in the upright position, when sympathetic outflow to

the vasculature is normally increased, these drugs reduce
peripheral vascular resistance
 This action may lead to postural hypotension

• The decrease in cardiac sympathetic tone leads to a reduction

in myocardial contractility and heart rate that could promote
congestive heart failure in susceptible patients
 Therapeutic Uses
• Adding clonidine to other antihypertensive agents may be
used for individuals with resistant hypertension

• Clonidine may be effective in reducing early morning

hypertension in patients treated with standard
antihypertensives

• Clonidine has been used in hypertensive patients for the

diagnosis of pheochromocytoma

• The failure of clonidine to suppress the plasma

concentration of NE to less than 500 pg/mL 3 h after an
oral dose of 0.3 mg of clonidine suggests the presence of
such a tumor
 Adverse Effects
• Sedation & xerostomia are prominent adverse effects

• Orthostatic hypotension & erectile dysfunction may be

prominent in some patients

• Less-common CNS side effects include sleep disturbances

with vivid dreams or nightmares, restlessness, and
depression

• Cardiac effects related to the sympatholytic action of these

drugs include symptomatic bradycardia & sinus arrest

• Sudden discontinuation of clonidine and related α2 adrenergic

agonists may cause a withdrawal syndrome leading to
rebound hypertension
 Reserpine
• Reserpine is an alkaloid extracted from the root of
Rauwolfia serpentina

• Reserpine was the first drug found to interfere with the

function of the SNS in humans, and its use began the
modern era of effective pharmacotherapy of hypertension

• Reserpine is both centrally-acting and peripherally-acting

sympatholytic drug
 Mechanism of Action
• Reserpine binds tightly to adrenergic storage vesicles in central &
peripheral adrenergic neurons
• The interaction inhibits the vesicular catecholamine transporter
VMAT2, so that nerve endings lose their capacity to
concentrate and store NE and dopamine
 Catecholamines leak into the cytoplasm, where they are metabolized
 Consequently, little or no active transmitter is released from nerve endings,
resulting in a pharmacological sympathectomy
• Recovery of sympathetic function requires synthesis of new storage
vesicles, which takes days to weeks after discontinuation of the drug
• Because reserpine depletes amines in the CNS as well as in the
peripheral adrenergic neuron, it is probable that its antihypertensive
effects are related to both central and peripheral actions
• Both cardiac output and peripheral vascular resistance are reduced
during long-term therapy with reserpine
 Toxicity
• Most adverse effects of reserpine are due to its effect on the
CNS
• Sedation & inability to concentrate or perform complex
tasks are the most common adverse effects
• More serious is the occasional psychotic depression that
can lead to suicide
• Orthostatic hypotension
• Nasal congestion, fluid retention & peripheral edema &
• Diarrhea & increased gastric secretion leading to
exacerbation of peptic ulcer disease
• Contraindications include hypersensitivity, peptic ulcer
disease or ulcerative colitis, history of mental depression
or electroconvulsive therapy
 Therapeutic Uses
• Reserpine at low doses, in combination with diuretics, is
effective in the treatment of hypertension, especially in
the elderly

• Several weeks are necessary to achieve maximum effect

• However, with the availability of newer drugs that have proven

life-prolonging effects and are well tolerated, the use of
reserpine has largely diminished, and it is no longer
recommended for the treatment of hypertension
Very Important note
FINAL EXAM WILL COVER ALL
INFORMATION IN THIS
PRESENTATION AS WELL AS ANY
ADDITIONAL INFORMATION
MENTIONED DURING THE LECTURE

Best Wishes