Download 20.b) SYMPATHETIC NERVOUS SYSTEM, ALFA AND BETA

20.b) SYMPATHETIC NERVOUS SYSTEM, ALFA AND BETA SYMPATHOMIMETICS
(CLASSIFICATION ACCORDING TO SELECTIVITY, THERAPEUTIC USES, SIDE EFFECTS)
Major effects mediated by α and β adrenoceptors
Receptor
α1
Agonist
Epi ≥ NE >> Iso
Tissue
Vascular smooth muscle
Responses
Contraction
GU smooth muscle
Contraction
Liver
Glycogenolysis;
gluconeogenesis
Intestinal smooth muscle
Hyperpolarization
relaxation;
and
Increased contractile force;
arrhythmias
α2
Epi ≥ NE >> Iso
β1
Iso > Epi = NE
Heart
Pancreatic islets (β cells)
Decreased insulin secretion
Platelets
Aggregation
Nerve terminals
Decreased release of NE
Vascular smooth muscle
Juxtaglomerular cells
Contraction
Increased renin secretion
Heart
β2
Iso > Epi >> NE
Increased force and rate of
contraction and AV nodal
conduction velocity
Smooth muscle (vascular, Relaxation
bronchial, GI, and GU)
Skeletal muscle
Glycogenolysis; uptake of K+
Liver
β3
Iso = NE > Epi
Adipose tissue
Glycogenolysis;
gluconeogenesis
Lipolysis
Classification of adrenergic receptor agonists (sympathomimetic amines) or drugs that
produce sympathomimetic-like effects
Adrenergic Agonists
Direct-acting
Selective
Non-selective
Mixed-acting
Indirect-acting
Ephedrine
α, β and releasing agent
Releasing
agents
α-1 Phenylephrine
α-1α-2 Oxymetazoline
α-2 Clonidine
β-1β-2 Isoproterenol
Amphetamine
β-1 Dobutamine
α, β Epinephrine
Tyramine
β-2 Terbutaline
α, β Norepinephrine
*Not actually sympathetic drugs but produce sympathomimetic-like effects.
*Uptake
inhibitor
*MAO/
COMT
Inhibitor
s
Cocaine
Pargyline
Entacapone
ADRENERGIC AGONISTS
The adrenergic drugs affect receptors that are stimulated by norepinephrine or epinephrine.
Some adrenergic drugs act directly on the adrenergic receptor either by activating the receptor
or by blocking the action of norepinephrine and epinephrine. Other drugs act indirectly by
altering the release of norepinephrine by the adrenergic neuron.
DIRECT-ACTING ADRENERGIC AGONISTS
A. EPINEPHRINE
Synthesized from tyrosine in the adrenal medulla and released into the blood stream.
At low doses, beta effects on the vascular system predominate at high doses, alpha effects are
strongest.
1. Actions:
Cardiovascular:
Heart: Cardiac output increases. Increased oxygen demands on the myocardium. Cardiac
efficiency is reduced; it can also cause dysrhythmias.
Vessels: constriction of arterioles in the skin, mucous membranes, and viscera (α effects),
dilates vessels going to liver and skeletal muscle
(β2 effects). Blood pressure: increase in systolic BP, coupled with a slight decrease in diastolic
pressure.
Respiratory: Bronchodilation by acting directly on bronchial smooth muscle (β2 action) - it
relieves all known allergic - or histamine – induced bronchoconstriction. Life saving in
anaphylactic shock. Epinephrine rapidly relieves the dyspnea and increases the tidal volume.
2. Metabolism: conversion of energy stores (glycogen and fat) to freely available fuels (glucose
and FFA). Hyperglycemia, Lipolysis.
3. Biotransformation:
Two enzymatic pathways - COMT and MAO. The final metabolites found in the urine are
metanephrine and vanillylmandelic acid.
4. Therapeutic uses:
a. Bronchospasm: acute asthma and anaphylactic shock;
b. Glaucoma: reduce intraocular pressure in open-angle glaucoma. It reduces the production
of aqueous humour.
c. Anesthetics: prolong the action of local anesthetics, presumably by decreasing local blood
flow;
d. Nasal decongestion: vasoconstriction of mucous membranes.
5. Pharmacokinetics: Rapid onset but brief duration of action. Administered subcutaneously,
by inhalation, or topically to the eye. Oral administration is ineffective (catecholamines are
inactivated by the intestine).
6. Adverse effects:
a. CNS disturbances: Anxiety, fear, tension, headache, and tremor.
b. Hemorrhage: Cerebral hemorrhages as a result of the vasopressor effects, causing a marked
elevation of blood pressure.
c. Cardiac arrhythmias: particularly if the patient is receiving digitalis.
d. Pulmonary edema
7. Interactions:
a. Hyperthyroidism: Enhanced cardiovascular actions in patients with hyperthyroidism. The
mechanism appears to involve increased production of adrenergic receptors in the
hyperthyroid individual.
b. Cocaine: In the presence of cocaine, ADR produces exaggerated cardiovascular actions. Due
to the ability of cocaine to prevent re-uptake of catecholamines.
B. NOREPINEPHRINE
Actions:
1. Cardiovascular:
a. Vasoconstriction: Intense vasoconstriction  ↑ peripheral resistance (α1 effect). Both
systolic and diastolic BP increase.
b. Baroreceptor reflex: In vivo, little if any cardiac stimulation is noted (NOR induces a reflex
increase in vagal activity by ↑baroreceptor activity). Bradycardia counteract the local actions
of NOR on the heart.
c. Effect of atropine pretreatment: If atropine (blocks the transmission of vagal effects) is
given before NOR  NOR stimulates the heart and produces tachycardia.
2. Therapeutic uses:
- Shock, however, dopamine is better (it does not reduce blood flow to the kidney as does
NOR). Never used for asthma.
- Vasoconstrictor agent with local anesthetics.
C. ISOPROTERENOL
1. Actions:
a. Cardiovascular: increase heart rate and force of contraction, causing increased cardiac
output. Dilates the arterioles of skeletal muscle (β2)  decrease in peripheral resistance.
It may increase systolic BP slightly, but it greatly reduces mean arterial and diastolic BP.
b. Pulmonary: bronchodilation (β2 action), rapidly alleviates an acute attack of asthma, when
taken by inhalation. Action lasts about one hour.
c. Other effects: Actions on β receptors, slight increase in blood sugar, increased lipolysis.
2. Therapeutic uses: Bronchodilator in asthma. Stimulation of the heart, treatment of
atrioventricular block or cardiac arrest.
3. Administration: Absorbed systemically, but by the sublingual mucosa it is more
reliably absorbed; parenterally or as an inhaled aerosol.
It is a marginal substrate for COMT and is stable to MAO action
4. Adverse Effects: Palpitations, tachycardia, headache, and flushing are common. Cardiac
ischemia and arrhythmias may occur, particularly in patients with underlying coronary artery
disease.
D. DOPAMINE
1. Actions:
a. Cardiovascular actions: stimulatory effect on β1 receptors of heart. Very high doses –
activation of α receptors on the vasculature  vasoconstriction.
b. Renal and visceral actions: Dilates renal and splanchnic arterioles by activating
dopaminergic receptors, thus increasing blood flow to the kidneys and other viscera.
2. Therapeutic uses:
a. Shock: continuous infusion. It raises the blood pressure. Increased blood flow to the kidney
enhances the glomerular filtration rate and causes sodium diuresis.
b. Congestive heart failure
3. Adverse effects:
Excessive sympathomimetic activity. Nausea, vomiting, tachycardia, anginal pain, arrhythmias,
headache, hypertension, and peripheral vasoconstriction may be encountered during
dopamine infusion. Dopamine is rapidly metabolized to homovanilic acid, and its adverse
effects are therefore short-lived.
E. DOBUTAMINE
1. Actions: synthetic drug increases cardiac contractility and output.
2. Therapeutic uses: Used to increase cardiac output in congestive heart failure. It increases
cardiac output with little change in heart rate - not significantly elevation of oxygen demands
of the myocardium - a major advantage over other sympathomimetic drugs.
3. Adverse effects:
a. Cardiovascular: Caution in atrial fibrillation (it increases AV conduction.
b. Other: The same as ADR. Tolerance may develop on prolonged use.
F. PHENYLEPHRINE
Actions: synthetic drug
1. Cardiovascular effects: Vasoconstrictor raises both systolic and diastolic BP. No effect on
the heart itself but induces reflex bradycardia. Often used topically on the nasal mucous
membranes and in ophthalmic solutions for mydriasis.
2. Therapeutic uses: Nasal decongestant. To raise blood pressure and to terminate episodes
of supraventricular tachycardia.
3. Adverse effects: Hypertensive headache and cardiac irregularities.
G. METHOXAMINE
Direct-acting synthetic non-selective adrenergic drug, binds primarily to α receptors, with α1
receptors favored over α2.
It BP, vasoconstriction. Increase in total peripheral resistance. Used clinically to relieve
attacks of paroxysmal supraventricular tachycardia.
H. CLONIDINE
Used in essential hypertension to lower blood pressure because of its action on the CNS.
Minimize the symptoms that accompany withdrawal from opiates or benzodiazepines.
Acts centrally to produce inhibition of sympathetic vasomotor centers.
I. METAPROTERENOL
It is not a catecholamine, it is resistant to methylation by COMT.
Administered orally or by inhalation. Bronchodilator.
J.  2 AGONISTS - SHORT ACTING
TERBUTALINE: Used as a bronchodilator and to reduce uterine contractions in premature
labor.
RITODRINE: Used to relax the uterine contractions of premature labor.
ALBUTEROL, SALBUTAMOL: Used to relieve bronchospasm.
K.  2 AGONISTS – LONG-ACTING
CLENBUTEROL, REPROTEROL, PROCARTEROL, FORMOTEROL, SALMETEROL
Bronchodilators. 1 dose by metered dose inhaler provides bronchodilation for 12 hours.
Adverse effects of selective β2 agonists:
- tachycardia, dysrhythmias
- tremor
- peripheral vasodilation
INDIRECT - ACTING ADRENERGIC AGONISTS
A. AMPHETAMINE
Actions: marked central stimulatory action (not only NOR release, but also the release of 5-HT
and dopamine in CNS), - increase of NOR release, - MAO inhibitor, - uptake inhibitor.
Increase blood pressure. Peripheral actions are mediated primarily through the cellular release
of stored catecholamines. Absorbed orally, penetrates into brain, plasma T0.5 about 12 hours,
excreted in urine.
Use and function:
- CNS stimulant in narcolepsy, used in attention-deficit/hyperactivity disorder.
- Appetite suppressant
Adverse effects: Hypertension, tachycardia, insomnia, acute schizophrenia-like psychosis (with
hallucination and stereotyped behavior) in overdose. Loss of appetite. Euphoria and
excitement. Psychological dependence and tolerance develops!
MIXED - ACTION ADRENERGIC AGONISTS
A. EPHEDRINE
A plant alkaloid, also made synthetically. It is not a catechol and so it is a poor substrate for
COMT and MAO »»» long duration of action.
Excellent absorption orally and penetrates into CNS.
Actions:
a. Cardiovascular: ↑ systolic and diastolic BP by vasoconstriction and cardiac stimulation.
b. Pulmonary: Bronchodilation, is less potent than epinephrine or isoproterenol and produces
its action more slowly. Therefore used prophylactically in chronic treatment of asthma.
c. Skeletal muscle: ↑ contractility and improves motor function in Myasthenia gravis
(particularly when used with anticholinesterases).
d. CNS: Mild stimulation. Increases alertness, decreases fatigue, prevents sleep.
Therapeutic uses:
- Asthma
- nasal decongestant
- to raise blood pressure.
- milder form of inhibition in intoxication with local anesthetics
Adverse effects:
- Vasoconstriction in pulmonary vessels after long-term administration.
- Other similar to amphetamine, but less pronounced.
Contraindicated if MAO inhibitors are given !
Tolerance, tachyphylaxis develops!
B. METARAMINOL
Direct effects on vascular  adrenergic receptors. Indirectly acting agent that stimulates the
release of norepinephrine. The drug has been used in the treatment of hypotensive states;
relieve attacks of paroxysmal atrial tachycardia, shock. Given parenterally as a single injection.
It enhances cardiac activity and produces mild vasoconstriction.
Marisa Clemente
Lippincott’s 65-79
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)