AUTONOMIC DRUGS

Asst. Prof. Levent HACISÜLEYMAN

ANATOMIC
ASPECTS OF THE
AUTONOMIC
NERVOUS
SYSTEM
• The autonomic nervous system (ANS) is the major involuntary,
automatic portion of the nervous system and contrasts in several ways
with the somatic (voluntary) nervous system.
• The motor (efferent) portion of the ANS is the major neural pathway for
information transmission from the central nervous system (CNS) to the
involuntary effector tissues (smooth muscle, cardiac muscle, and
exocrine glands.
• Its 2 major subdivisions are the parasympathetic ANS (PANS) and the
sympathetic ANS (SANS).
• The parasympathetic preganglionic motor fibers originate in cranial
nerve nuclei III, VII, IX, and X and in sacral segments (usually S2–S4) of
the spinal cord.
• The sympathetic preganglionic fibers originate in the thoracic (T1–T12)
and lumbar (L1–L5) segments of the cord.
 NEUROTRANSMITTER ASPECTS OF THE ANS
• Acetylcholine (ACh) is the primary transmitter:
• in all autonomic ganglia
• at the synapses between parasympathetic postganglionic neurons and their effector cells
• at postganglionic sympathetic neurons to the thermoregulatory sweat glands
• at the somatic (voluntary) skeletal muscle neuromuscular junction
• The action of acetylcholine in the synapse is normally terminated by metabolism
to acetate and choline by the enzyme acetylcholinesterase in the synaptic cleft.
• Norepinephrine (NE) is the primary transmitter at the sympathetic postganglionic
neuron-effector cell synapses in most tissues.
• Dopamine may be a vasodilator transmitter in renal blood vessels, but
norepinephrine is a vasoconstrictor of these vessels.
• Outside the cleft, norepinephrine and dopamine can be metabolized by mono
amino oxidase (MAO) and catechol-O-methyltransferase (COMT) and the
products of these enzymatic reactions are excreted.
 ANS RECEPTORS
The major receptor systems in the ANS include cholinoceptors, adrenoceptors, and
dopamine receptors.
• Cholinoceptors (cholinergic receptors): these molecules respond to acetylcholine
and its analogs. Cholinoceptors are subdivided as follows:
• Muscarinic receptors:
• These receptors respond to muscarine (an alkaloid) as well as to acetylcholine.
• Muscarinic receptors are located primarily on autonomic effector cells (including heart,
vascular endothelium, smooth muscle, presynaptic nerve terminals, and exocrine
glands).
• All muscarinic receptors are G-protein coupled receptors.
• Nicotinic receptors:
• These receptors are located on Na+ -K+ ion channels and respond to acetylcholine and
nicotine by opening the channel.
• Nicotinic receptors are located in ganglia and in skeletal muscle end plates.
• Adrenoceptors (adrenergic receptors)
• adrenoceptors are divided into several subtypes:
• Alpha receptors:
• Alpha receptors are further divided into 2 major types, α1 and α2.
• Beta receptors:
• Beta receptors are divided into 3 major subtypes, β1, β2, and β3.
• Dopamine Receptors:
Direct effects of autonomic nerve activity on some organ systems

a Less important actions are

shown in brackets.
b Specific receptor type: α, alpha;
β, beta; M, muscarinic.
c Vascular smooth muscle in
skeletal muscle has sympathetic
cholinergic dilator fibers.
d Probably through presynaptic
inhibition of parasympathetic
activity.
e Probably M1, but M2 may
participate in some locations.
ACh, acetylcholine;
NE, norepinephrine.
 Cholinergic Drugs
• Drugs with acetylcholine-like effects (cholinomimetics) consist of 2 major
subgroups on the basis of their mode of action (ie, whether they act directly at
the acetylcholine receptor or indirectly through inhibition of cholinesterase).
Effects of cholinomimetics on major organ systems
DIRECT-ACTING CHOLINOMIMETIC AGONISTS
• This class comprises a group of choline esters (acetylcholine, methacholine,
carbachol, bethanechol) and a second group of naturally occurring
alkaloids (muscarine, pilocarpine, nicotine).
• Several clinical conditions benefit from an increase in cholinergic
muscarinic activity, including:
• Glaucoma (Glaucoma is the result of elevated pressure on eye due to the building up
of fluid the front part of the eye, which damages optic nerve) (topical pilocarpine).
• Sjogren’s syndrome (a disorder of immune system identified by its two most
common symptoms — dry eyes and a dry mouth) (oral pilocarpine).
• loss of normal PANS activity in the bowel and bladder such as bethanechol for
postoperative and postpartum functional urinary retention.
• Direct-acting nicotinic agonists are used:
• in smoking cessation (nicotine).
• to produce skeletal muscle paralysis (succinylcholine).
 INDIRECT-ACTING AGONISTS
• These drugs are acetylcholinesterase (AChE) inhibitors. As a result,
these drugs amplify acetylcholine effects.
• the indirect agents have muscarinic or nicotinic effects depending on
which organ system is under consideration.
• Their clinical uses are:
• Myasthenia: Neostigmine, Pyridostigmine, Physostigmine
• Alzheimer’s disease: Rivastigmine, galantamine, donepezil; tacrine (Lipid
soluble, enter CNS)
• Glaucoma: Echothiophate
• Toxicity: The spectrum of toxicity can be remembered with the aid of
the mnemonic DUMBBELSS (diarrhea, urination, miosis,
bronchoconstriction, bradycardia, excitation [of skeletal muscle and
CNS], lacrimation (the flow of tears), and salivation and sweating).
 Cholinoceptor Blockers

The cholinoceptor antagonists consist of 2 subclasses based on their spectrum

of action (ie, block of muscarinic versus nicotinic receptors).
 MUSCARINIC ANTAGONISTS
• Atropine is the prototypical nonselective muscarinic blocker.
This alkaloid is found in Atropa belladonna and many other
plants.
• Clinical Uses:
• CNS:
• Scopolamine is the standard therapy for motion sickness
• Benztropine, biperiden, and trihexyphenidyl are used in
parkinsonism
• Eye: Antimuscarinic drugs such as atropine, homatropine,
cyclopentolate, and tropicamide are used to cause mydriasis and
cycloplegia (pharmacological paralysis of the ciliary muscles, and it results
primarily in inhibition of accommodation) for eye exams or ocular
procedures.
• Bronchi
• Ipratropium is a quaternary antimuscarinic agent used by
inhalation to promote bronchodilation in asthma and chronic
obstructive pulmonary disease (COPD). (Although not as efficacious
as β agonists, ipratropium is less likely to cause tachycardia and
cardiac arrhythmias in sensitive patients). It has very few
antimuscarinic effects outside the lungs because it is poorly
absorbed and rapidly metabolized.
• Tiotropium is an analog with a longer duration of action.
• Aclidinium is a newer long-acting antimuscarinic drug.
• Gut: pirenzepine (M1-selective inhibitor) for the treatment of peptic
ulcer. Muscarinic blockers can also be used to reduce cramping and
hypermotility in transient diarrheas, but drugs such as diphenoxylate
and loperamide are more effective.
• Bladder: Oxybutynin, tolterodine, darifenacin, solifenacin for the
treatment of Overactive bladder (OAB), stress incontinence and to
reduce bladder spasms after urologic surgery.
• Cholinesterase inhibitor intoxication: Atropine, given parenterally in
large doses, reduces the muscarinic signs of poisoning with AChE
inhibitors.
 ANTIMUSCARINIC DRUG TOXICITIES
• Blockade of thermoregulatory sweating may result in hyperthermia.
• Salivation (dry mouth)and lacrimation are also reduced or stopped.
• tachycardia or arrhythmias.
• blurred vision and acute angle-closure glaucoma especially in the elderly.
• urinary retention, especially in men with prostatic hyperplasia.
• Constipation
• CNS toxicity includes sedation, amnesia, and delirium or hallucinations.
• Contraindications
• The antimuscarinic agents should be used cautiously in infants because of the
danger of hyperthermia.
• glaucoma, especially the closed-angle form
• in men with prostatic hyperplasia.
 NICOTINIC ANTAGONISTS
A. Ganglion-Blocking Drugs:
• Ganglionic blockers act by blocking the transmission at the sympathetic and
parasympathetic ganglia in the autonomic nervous system.
• These drugs were the first successful agents for the treatment of hypertension.
• Unfortunately, the adverse effects of ganglion blockade in hypertension are so
severe (both sympathetic and parasympathetic divisions are blocked) that patients
were unable to tolerate them for long periods.
• These drugs are still used in research.
B. Neuromuscular-Blocking Drugs (Nondepolarizing):
• These drugs prevent the action of ACh at the skeletal muscle end plate and their
effect is reversed by cholinesterase inhibitors.
• They are used for producing skeletal muscle relaxation that is important in surgery
and in mechanical ventilation of patients.
• rocuronium, vecuronium, atracurium, cisatracurium, mivacurium
 Sympathomimetics
• The sympathomimetics constitute a very
important group of drugs used for
cardiovascular, respiratory, and other
conditions.
 Sympathomimetics
• They are divided into subgroups:
• on the basis of their spectrum of action (α-, β-, or dopamine-receptor affinity)
• Epinephrine is a prototype agonist with effects at all α- and β-receptor types.
• phenylephrine (an α agonist)
• isoproterenol (β agonist)
• dopamine itself is a dopamine-receptor agonist
• or mode of action (direct or indirect).
• Sympathomimetic agonists directly activate their adrenoceptors
• or they may act indirectly to increase the concentration of endogenous catecholamine transmitter in the
synapse.
• Amphetamine derivatives and tyramine cause the release of stored catecholamines
• Cocaine and the tricyclic antidepressants inhibit reuptake of catecholamines by the norepinephrine
transporter (NET) and the dopamine transporter (DAT) in nerve terminals and thus increase the synaptic
activity of released transmitter.
• Blockade of metabolism (ie, block of catechol-O-methyltransferase [COMT] and monoamine oxidase
[MAO]) increases the stores of catecholamines and related molecules in adrenergic synaptic vesicles.
• The endogenous adrenoceptor agonists (epinephrine, norepinephrine, and dopamine) are catecholamines and are rapidly
metabolized by COMT and MAO. If used as drugs, these adrenoceptor agonists are relatively inactive by the oral route and
must be given parenterally.
ORGAN SYSTEM EFFECTS
• Central Nervous System:
• Catecholamines do not enter the CNS readily.
• Sympathomimetics that do enter the CNS (eg, amphetamines, cocaine) have a
spectrum of stimulant effects:
• reduction of fatigue
• Anorexia (lack or loss of appetite for food)
• Euphoria (a feeling of great happiness and excitement)
• Insomnia (a sleep disorder in which you have trouble falling and/or staying asleep)
• Repeated dosing of amphetamines results in the rapid development of
tolerance and dependence.
• Very high doses of amphetamines lead to:
• marked anxiety (a feeling of unease, such as worry or fear)
• Aggressiveness
• Paranoia *
• seizures
* a mental condition characterized by delusions of persecution, unwarranted jealousy, or exaggerated self-importance. It may be an aspect of chronic
personality disorder, of drug abuse, or of a serious condition such as schizophrenia in which the person loses touch with reality.
• Eye:
• The smooth muscle of the pupillary dilator responds to topical phenylephrine
and similar α agonists with contraction and mydriasis.
• Outflow of aqueous humor may be facilitated by nonselective α agonists, with
a subsequent reduction of intraocular pressure.
• Alpha2-selective agonists also reduce intraocular pressure by reducing
synthesis of aqueous humor.
• Bronchi:
• The smooth muscle of the bronchi relaxes markedly in response to β2
agonists, eg, isoproterenol and albuterol.
• Gastrointestinal Tract:
• Activation of either α or β receptors leads to relaxation of the smooth muscle.
• Alpha2 agonists may also decrease salt and water secretion into the intestine.
• Vascular System:
• Alpha1 agonists (eg, phenylephrine) contract vascular smooth muscle,
especially in skin and splanchnic blood vessels evoking a compensatory reflex
bradycardia.
• Alpha2 agonists—Alpha2 agonists (eg, clonidine) cause vasoconstriction
when administered intravenously or topically (eg, as a nasal spray), but when
given orally they accumulate in the CNS and reduce sympathetic outflow and
blood pressure.
• Beta agonists—Beta2 agonists (eg, albuterol, metaproterenol, terbutaline)
and nonselective β agonists (eg, isoproterenol) cause significant reduction in
arteriolar tone in the skeletal muscle vascular bed and can reduce peripheral
vascular resistance and arterial blood pressure.
• Dopamine—Dopamine causes vasodilation in the splanchnic and renal
vascular beds by activating D1 receptors. This effect can be useful in the
treatment of renal failure associated with shock.
• Heart:
• The β1 receptors predominate in some parts of the heart
• both β1 and β2 receptors mediate:
• increased rate of cardiac pacemakers
• increased atrioventricular node conduction velocity
• increased cardiac force.
• Metabolic and Hormonal Effects:
• Beta1 agonists increase renin secretion.
• Beta2 agonists increase insulin secretion. They also increase glycogenolysis in
the liver and the resulting hyperglycemia is countered by the increased insulin
levels.
• All β agonists appear to stimulate lipolysis via the β3 receptor.
 CLINICAL USES
1. Anaphylaxis:
• Epinephrine is the drug of choice for the immediate treatment of anaphylactic shock
(hypotension, bronchospasm, angioedema)
2. Central Nervous System:
• Methylphenidate and other amphetamine analogs are heavily used in attention
deficit hyperkinetic disorder (ADHD).
• Amphetamine is also used as a short-term treatment, along with a reduced calorie
diet and exercise for weight reduction.
• The drugs are abused or misused for the purpose of deferring sleep and for their
mood-elevating, euphoria-producing action.
3. Eye:
• The α agonists, especially phenylephrine and tetrahydrozoline, are often used to
reduce the conjunctival itching and congestion caused by irritation or allergy.
• Phenylephrine is also an effective mydriatic.
• α2 agonists (apraclonidine and brimonidine) are in current use for glaucoma by
reducing synthesis of aqueous humor.
4. Bronchi:
• β2-selective agonists, are drugs of choice in the treatment of acute asthmatic
bronchoconstriction.
• The short-acting β2-selective agonists (eg, albuterol, metaproterenol, terbutaline) are used
in the treatment of acute bronchospasm.
• Much longer-acting β2-selective agonists (eg, salmeterol, formoterol) are used in
combination with corticosteroids or antimuscarinic agents for prophylaxis in asthma or
chronic obstructive pulmonary disease (COPD)
5. Cardiovascular Applications:
• Norepinephrine is an effective agent in septic and cardiogenic shock when used properly.
Dobutamine and dopamine are also used.
• Epinephrine has been used in cardiac arrest by intravenous and direct intracardiac injection.
• Isoproterenol has been used for atrioventricular (AV) block.
• Alpha1 agonists (eg, pseudoephedrine, phenylephrine, oxymetazoline) are used as nasal
decongestants.
• Orally active α1 agonist, midodrine is used for the treatment of Chronic orthostatic
hypotension* due to inadequate sympathetic tone.
• Alpha agonists are often mixed with local anesthetics to reduce the loss of anesthetic from
the area of injection into the circulation.

* Orthostatic hypotension: Hypotension that is most marked in the upright position; caused by venous pooling (typical of α blockade) or
inadequate blood volume (caused by blood loss or excessive diuresis)
6. Genitourinary Tract:
• Beta2 agonists (ritodrine, terbutaline) are sometimes used to suppress
premature labor (Nonsteroidal anti-inflammatory drugs, calcium channel
blockers, and magnesium are also used for this indication).
• Long-acting oral sympathomimetics such as ephedrine are sometimes used to
improve urinary continence in the elderly and in children with enuresis
(mediated by α receptors in the trigone of the bladder and, in men, the
smooth muscle of the prostate).
Adrenoceptor Blockers
 ALPHA-BLOCKING DRUGS
• Nonselective α blockers
• Irreversible, long-acting—Phenoxybenzamine long-acting α blocker.
• Reversible, shorter-acting—Phentolamine is a competitive, reversible blocking
agent.
• Alpha1-selective blockers—(Prazosin, Doxazosin, terazosin) are highly
selective, reversible pharmacologic α1 blocker.
• Alpha2-selective blockers—Yohimbine.
• Phenoxybenzamine has a short elimination half-life but a long
duration of action—about 48 h—because it binds covalently to its
receptor.
• These agents cause a reduction in vascular tone with a reduction of
both arterial and venous pressures. This leads to baroreceptor reflex-
mediated tachycardia.
 Clinical uses of α blockers
• Nonselective α blockers: Nonselective α blockers have limited clinical
applications.
• The best-documented application is in the presurgical management of
pheochromocytoma*. Such patients may have severe hypertension and
reduced blood volume, which should be corrected before surgery.
• Overdose with drugs of abuse such as amphetamine and cocaine may lead to
severe hypertension because of their indirect sympathomimetic actions. This
hypertension usually responds well to α blockers.
• Selective α1 blockers—Prazosin, doxazosin, and terazosin
• are used in hypertension.
• These α1 blockers, as well as tamsulosin and silodosin are also used to reduce
urinary retention in men with benign prostatic hyperplasia.

* Pheochromocytoma: a tumor consisting of cells that release varying amounts of norepinephrine and
epinephrine into the circulation
 Toxicity of α blockers
• orthostatic hypotension
• reflex tachycardia
• Oral administration of some of these drugs can cause nausea and
vomiting.
 BETA-BLOCKING DRUGS
Drugs in this group are usually classified into subgroups on the basis of β1 selectivity, partial agonist
activity, local anesthetic action, and lipid-solubility
• Receptor selectivity
• Beta1-receptor selectivity (β1 block > β2 block) is a property of acebutolol, atenolol,
esmolol, metoprolol. This property may be an advantage when treating patients with
asthma because functioning β2 receptors are important in preventing bronchospasm
in such patients.
• Labetalol and carvedilol have combined α- and β-blocking actions.
• Partial agonist activity
• may be an advantage in treating patients with asthma (eg, pindolol, acebutolol).
• Local anesthetic activity
• is a disadvantage when β blockers are used topically in the eye because it decreases
protective reflexes and increases the risk of corneal ulceration.
• Local anesthetic effects are absent from timolol and several other β blockers that are
useful in glaucoma.
• Most of the systemic agents have been developed for chronic oral use.
Esmolol is a short-acting ester β blocker that is used only parenterally.
 Effects and Clinical Uses of Beta Blockers
• The treatment of open angle glaucoma by decreasing the secretion of aqueous humor from the
ciliary epithelium.
• The cardiovascular applications of β blockers:
• Hypertension
• Angina
• Arrhythmias
• chronic (not acute) heart failure
• Pheochromocytoma is sometimes treated with combined α- and β-blocking agents (eg, labetalol)

Toxicity of beta blockers

• bradycardia, atrioventricular blockade, and heart failure.
• Patients with airway disease may suffer severe asthma attacks.
• CNS adverse effects include sedation, fatigue, and sleep alterations.
• Sexual dysfunction.