PHARMACOLOGY OF DRUGS

ACTING ON SYMPATHETIC
NERVOUS SYSTEM
SYMPATHETIC DRUGS
A. SYMPATHOMIMETICS/ADRENERGICS
1. Direct Sympathomimetics
2. Indirect Sympathomimetics and Mixed Agents
B. SYMPATHOLYTICS/ADRENERGIC
BLOCKERS/ANTIADRENERGICS
1. Centrally acting antiadrenergics
2. Peripheral presynaptic antiadrenergics
3. Peripheral postsynaptic antiadrenergics
a. -blockers
b. -blockers
Direct sympathomimetics

 NE, Epinephrine and

Dopamine are
endogenous
sympathetic agonists
 Binds to 1, 2, 1, or 2
adrenergic receptors
where they “turn on”
second messengers
Alpha-1 activation
Alpha-2 and Beta receptor activation
The Alpha Receptors
Postsynaptic Alpha1 Receptors on
Vascular Smooth Muscle
Effects of alpha 1 receptor activation
on different tissues and systems
Presynaptic Alpha2 Receptors
 Alpha2 receptors also exist presynaptically
associated with nerve terminals
 Activation of these receptors inhibits the release of
NE
 NE acts at presynaptic alpha2 receptors to inhibit its own
release.
Alpha-2 receptor activation
Drugs affecting alpha receptors
The Beta receptors
Effect of Beta1 Receptor Activation
on the Heart
SELECTIVE BETA2 AGONISTS

Bronchodilation and decrease in airway resistance

Effect of Beta2 Receptor Activation
on Smooth Muscle
 Leads to vascular and
nonvascular smooth
muscle relaxation
 Drugs that activate the
beta2 receptor can be
used to treat as
asthma (by relaxing
airway smooth muscle)
and premature labor
(by relaxing uterine
smooth muscle).
 SYMPATHOMIMETICS ACTING
AT BETA RECEPTOR SYSTEMS
 Dopamine and Dobutamine
 Used in Congestive heart failure and cardiogenic
shock
 Activate the myocardial beta1 receptor and thus
increase the force of contraction of the failing
heart
 This will result in an increase in cardiac output
 These drugs are reserved for use in the acute
management of heart failure
DOPAMINE

 D1-activation leads to vasodilation of renal,

splanchnic, coronary, cerebral, and other
resistance vessels
 In renal vasculature, may induce natriuresis
 Dopamine activates 1 receptors in the heart
 USES OF SELECTIVE BETA2
AGONISTS
1. Airways dysfunction; bronchial asthma,
chronic bronchitis, emphysema
In airways dysfunction, beta2 selective agonists
relax airways thus decreasing airways resistance
2. Premature labor
In premature labor, the beta2 selective agonists
relax uterine smooth muscle.
Drugs that relax uterine smooth muscle are
referred to as tocolytic agents
 Direct Sympathomimetics
I. Catecholamines II. Non-catecholamines
 Epinephrine  Longer half-lives
 Norepinephrine  Phenylephrine &
 Isoproterenol Methoxamine
 Dobutamine  Marketed as nasal and
 Dopamine ophthalmic decongestants
 Metabolized by COMT  Metaproterenol, Albuterol,
and MAO Bitolterol, Terbutaline,
 Short duration of action Isoetharine, Salmeterol,
Salbutamol
 Clinically used to treat
anaphylaxis, cardiac  Bronchodilators
arrest, heart failure and  Ritodrine
shock  Uterine relaxant
INDIRECT-ACTING SYMPATHOMIMETICS

Displace stored catecholamine

Inhibit the reuptake of

released transmitter by
interfering with the action of
NET.
Indirect acting agonists
 Amphetamine
 Methamphetamine
 Useful in narcolepsy,
hyperkinetic syndrome of
children, attention deficit
disorder (ADHD)
 Modafinil
 psychostimulant
Mixed sympathomimetics

 Displace NE from presynaptic terminals and

bind to adrenergic receptors
 Ephedrine – clinically used to treat narcolepsy
 Mephentermine & Metaraminol – Treatment of
hypotension
 Phenylpropanolamine
 Decongestant in oral OTC drugs
 OTC appetite suppressants, but was removed from the
market due to hemorrhagic stroke in young women
 CATECHOLAMINE REUPTAKE
INHIBITORS
 Atomotexine
 Used in ADHD
 Reboxetiline
 Sibutramine
 The only appetite suppressant approved by FDA
 Duloxetine
 antidepressant
 Cocaine
 THERAPEUTIC USES OF
SYMPATHOMIMETICS
 CARDIOVASCULAR APPLICATIONS
 Acute hypotension – NE, Phenylephrine, and
methoxamine
 Shock
 Cardiogenic shock and AHF
 Chronic orthostatic hypotension
 Emergency management of complete heart block
and cardiac arrest
 Local vasoconstriction
 Epinephrine – applied topically in nasal packs or gingival
string
 THERAPEUTIC USES OF
SYMPATHOMIMETICS
 PULMONARY APPLICATIONS
 Therapy of bronchial asthma
 ANAPHYLAXIS
 Epinephrine
 OPHTHALMIC APPLICATIONS
 Phenylephrine – mydriatic
 Apraclonidine and brimonidine – lower IOP,
approved for treating glaucoma
 THERAPEUTIC USES OF
SYMPATHOMIMETICS
 GENITOURINARY APPLICATIONS
 Relax pregnant uterus
 CNS APPLICATIONS
 In mood elevation
 Treatment of narcolepsy (Modafinil)
 In ADHD (methylphenidate)
 THERAPEUTIC USES OF
SYMPATHOMIMETICS
 ADDITIONAL THERAPEUTIC USES
 Treatment of diarrhea in diabetics with autonomic
neuropathy
 Clonidine diminish craving for narcotics and
alcohol during withdrawal and may facilitate
cessation of cigarette smoking
 Clonidine diminish menopausal hot flushes
 Tizanidine, an 2-agonist, used as muscle
relaxant
Case Study
A 46-year-old woman sees her physician
because of palpitations and headaches. She
enjoyed good health until 1 year ago when
spells of cardiac palpitations began. These
became more severe and were eventually
accompanied by throbbing headaches and
drenching sweats. Physical examination
reveals a blood pressure of 150/90 mm Hg
and heart rate of 88 bpm.
During the physical examination, palpation of
the abdomen elicits a sudden and typical
episode, with a rise in blood pressure to
210/120 mm Hg, heart rate to 122 bpm, and
facial pallor. This is accompanied by severe
headache and profuse sweating.
 What is the likely cause of her episodes?

 What caused the blood pressure and heart

rate to rise so high during the examination?
 What treatments might help this patient?
 SYMPATHOLYTICS /
ADRENERGIC BLOCKERS
MECHANISMS
1. Decreasing the sympathetic outflow from
the brain
2. Suppressing NE release from presynaptic
neurons
3. Blocking post-synaptic adrenergic receptors
 Presynaptic Adrenergic Blockers
 Centrally acting antiadrenergics
 Clonidine
 Guanabenz
  - methyldopa
 Peripheral Presynaptic anti-adrenergics
 Guanethidine
 Guanadrel
 Bretylium
 Reserpine
Mechanism of action
 Actions of Presynaptic Adrenergic
Blockers
 These drugs stimulate alpha2 receptors
 decrease sympathetic outflow to the heart and
blood vessels
 The decrease in sympathetic tone results
in a decrease in peripheral vascular
resistance
 Clonidine and guanabenz are active drugs
 Methyldopa is a prodrug which must first
be converted to α-methylnorepinephrine
 APPLICATIONS OF ALPHA-2
AGONISTS
 Used clinically to treat hypertension
 In male erectile dysfunction (limited
usefulness)
 Under study;
 Use in Raynaud’s phenomenon
 Treatment of DM type 2
 Treatment of psychiatric depression
SELECTIVE ALPHA1-ANTAGONISTS
 Prazosin and Prazosin analogs
 Terazosin, Doxazosin, Trimazosin
 Reversible antagonists
 CARDIOVASCULAR EFFECTS
 Relaxes arterial and venous smooth muscle
as well as nonvascular smooth muscle.
 Decreases peripheral vascular resistance
and venous return.
 Decreases systemic arterial blood pressure
without a significant increase in heart rate.
SELECTIVE ALPHA1-ANTAGONISTS

 OTHER EFFECTS
 Miosis and nasal stuffiness
 Decrease resistance to the flow of urine
 Phenoxybenzamine blocks H1, Ach, and SE
receptors as well as alpha receptors
SELECTIVE ALPHA1-ANTAGONISTS
 CLINICAL USES
 Treatment of Hypertension
 Treatment of urinary retention due to
prostatic hyperplasia (Benign prostatic
hypertrophy)
 SIDE EFFECTS
 Orthostatic hypotension
 Nasal stuffiness
 Inhibition of ejaculation
 Syncope - Prazosin
SELECTIVE ALPHA1-ANTAGONISTS
 Prazosin and Prazosin analogs (terazosin,
doxazosin, trimazosin)
NON-SELECTIVE ALPHA BLOCKERS
 Phentolamine
 Competitive antagonist
 Used in erectile dysfunction – in combination
with papaverine (a non-specific smooth muscle
relaxant)
 Phenoxybenzamine
 Irreversibly blocks alpha receptors
 Used clinically in pheochromocytoma
Other uses of alpha blockers
 In peripheral vascular disease
 Ocassionally , in Raynaud’s phenomenon
 Chronic hypertension*
 Hypertensive emergencies
 Prazosin family

* With limited application

SOME ADVERSE EFFECTS COMMONLY
OBSERVED WITH ALPHA BLOCKERS

 Orthostatic hypotension
 Tachycardia
 Vertigo
 Sexual dysfunction
 BETA ADRENERGIC RECEPTOR
BLOCKERS
 These drugs are
competitive
antagonists of the
beta adrenergic
receptors
 Beta blockers are
either selective for
the beta1 receptor
or nonselective
beta1 and beta2
antagonists
NON SELECTIVE BETA BLOCKERS
 PROPRANOLOL is the prototype beta blocker
as well as the prototype of a nonselective
beta blocker
 Blocks myocardial beta1 receptors which is
a major site of therapeutic action
 Cardiovascular effects:
a. Decreases force and rate of myocardial contraction
b. Decreases renin secretion
c. Decreases blood pressure
 Blocks beta2 receptors
Cardiovascular Effects of -blockers
EFFECTS OF BETA BLOCKERS
 In the eye
 Reduce intraocular pressure
 Used therapeutically in glaucoma
 In the respiratory tract
 Increase airway resistance (beta-2)
 Selective beta-1 blockers do not exhibit this effect
 Atenolol is the prototype drug of selective beta-1
blockers
 Should be avoided by patients with COPD/asthma
 Endocrine effects of Beta blockers

 Non-selective beta blockers are contraindicated in

diabetic patients
 This is because catecholamines utilize the beta2 receptor
to promote glycogenolysis and mobilize glucose
 Selective beta1 blockers should be used with
caution in patients with diabetes
 In addition all beta blockers mask the tachycardia
associated with hypoglycemia
 As a result, the diabetic patient is deprived of one of the
earliest physiologic responses to hypoglycemia
EFFECTS OF BETA BLOCKERS
 Not related to beta blockade
 Intrinsic sympathomimetic activity
 Observed in partial beta agonist (e.g. Pindolol)
 Sometimes desired to prevent the untoward effects like
exacerbation of asthma or excessive bradycardia
 Local anesthetic action (“membrane-stabilizing”
action)
 Due to blockade of sodium channel
 Not used topically in the eye
 Sotalol (non-selective beta blocker) lacks local
anesthetic action
 CV USES OF BETA BLOCKERS
 Hypertension
 Ischemic heart disease
 Supraventricular tachyarrhythmias
 Heart failure
 Other CV disorders
 obstructive myopathy
 aortic aneurysm
OTHER USES OF BETA BLOCKERS
 Glaucoma (see table 10-3 in the next slide)
 Hyperthyroidism – Propranolol
 Neurologic disease
 In migraine headaches (Propranolol)
 Reduce certain tremors
 Reduce somatic manifestations of anxiety
(e.g. performance anxiety or “stage fright”) –
low doses of propranolol given prophylactically
 Symptomatic treatment of alcohol withdrawal –
Propranolol
OTHER USES OF BETA BLOCKERS
 Miscellaneous
 Diminish portal vein pressure in cirrhosis
 Decrease bleeding (first episode) from
esophageal varices –Nadolol and Propranolol
 Prevent rebleeding in esophageal varices
(nadolol + isosorbide mononitrate)
 In infantile hemangiomas – Propranolol
SUMMARY OF BETA RECEPTOR BLOCKERS
 Nonselective α1, β1, β2 blockers
 Labetalol –Used in hypertension
 Nonselective β1, β2 blockers
 Propranolol – Used in hypertension,Glaucoma,
Migraine, Hyperthyroidism, Angina pectoris,
Myocardial infarction
 Timolol – For glaucoma and hypertension
 Pindolol – For hypertension
 β1 specific
 Metoprolol, Atenolol, Acebutolol – For hypertension
 Clinical toxicity of Beta blockers

 Bradycardia
 CNS effects
 Include mild sedation, vivid dreams, and rarely,
depression
 Beta blockers with low lipid solubility are
associated with a lower incidence of CNS adverse
effects than compounds with higher lipid solubility
 Clinical toxicity of Beta blockers

 Worsening of preexisting asthma and other

forms of airway obstruction
 Associated with 2 receptor blockade
 Exacerbation of hypoglycemic episodes in
diabetic patients