Autonomic nervous system (ANS) pharmacology.pptx

AUTONOMIC NERVOUS SYSTEM
(ANS) PHARMACOLOGY

Introduction to nervous system
Nervous system, or the body’s system of communication, is the most complex of the body
organ systems.
The neuron (nerve cell) is the basic functional unit in this system. There over 100 billion
neurons in the brain alone.
Neurons also transmit information from the brain to the entire body.
The primary parts of this system are the brain and the spinal cord, called the central
nervous system (CNS).
The peripheral nervous system is composed of nerves that branch out from the spinal cord.

There are subdivisions of the peripheral nervous system called the somatic nervous system
and the autonomic nervous system.
 The autonomic nervous system controls the automatic (involuntary)
functions of the body,
e.g., breathing, digestion, heartbeat, etc.
 The somatic nervous system controls the voluntary actions of the body, e.g., skeletal muscle
movements.
 The ANS is further divided on anatomic grounds into two major portions:
 Sympathetic nervous system
 Parasympathetic nervous system

ANS have two neurons from CNS to the effector tissue.
They are called presynaptic and postsynaptic.
The place where the two neurons are connected and communicate with each other is called
synapse. Hence synapse is the junction between two neurons, or between a neuron and an
effecter organ (muscle or gland)

Functions of ANS
ANS system controls the body's internal organs.
 It innervates smooth muscles, cardiac muscle, and glands,
 controlling the circulation of blood, activity of the gastrointestinal tract and body
temperature.
Autonomic nervous system is involuntary, that is, the function of sympathetic and parasympathetic
nerves cannot be influenced by our mind.
Sympathetic and parasympathetic systems have opposing actions in some situations (e.g. control of
heart rate), but not in others (e.g. salivary glands).
 Sympathetic activity increases in stress ('fight or flight ‘), whereas
 PNS activity predominates ‘rest & digest’.
 Both systems exert a continuous physiological control of specific organs under normal condition

ORGAN SYMP. PARASYMP.
Heart  rate and force  rate and force
Blood vessels mostly constriction (dilates
some skeletal muscle arterioles
and some veins)
no effect
Airway smooth muscle dilatation constriction
GI tract  motility  motility
Male sex organs ejaculation erection
Eye (pupil) dilatation constriction
Sailvary glands secretion secretion
Liver glycogenolysis no effect

NEUROTRANSMITTERS AT DIFFERENT PERIPHERAL SITES

Neurotransmitters in autonomic nervous system
Neurotransmitters are chemical substances that are used for the transmission of information
between nerve cells and between nerve cells and their effector cells.
Acetylcholine and Norepinephrine (noradrenaline) are the major autonomic neurotransmitters.
 Neurons that release norepinephrine are known as adrenergic neurons. Norepinephrine binds
to adrenergic receptors.
 Neurons that release acetylcholine are known as cholinergic neurons. Acetylcholine binds to
cholinergic receptors.

Cholinergic receptors
Acetylcholine binds to cholinergic receptors.
Cholinergic receptors are classified into muscarinic and nicotinic cholinergic receptors.
Cholinergic receptors have subtypes, such as nicotinic 1 (N1),
nicotinic 2 (N2), muscarinic 1 (M1), and muscarinic 2 (M2).
The action of ACh is quickly terminated through hydrolysis by the enzyme
acetylcholinesterase.

Adrenergic receptors
Receptors that respond to adrenergic nerve transmitter are termed adrenergic receptors.
These receptors are subdivided into alpha and beta adrenoreceptor types on the basis of
both agonist and antagonist selectivity.
The receptors have subclasses depending on drug selectivity. These are
alpha 1 and 2 and beta 1, and 2.
 The binding of norepinephrine to alpha receptors in the smooth muscle of blood vessels
has a stimulating effect on the muscle that causes the muscle to constrict.
 The binding of norepinephrine to beta receptors in the smooth muscle of a different blood
vessel produces opposite effects.
The binding of norepinephrine to beta receptors in cardiac muscle has a stimulating effect
that results in a faster and stronger heartbeat.

Cholinergic agonists
Cholinergic agonists can be divided into directly and indirectly acting drugs.
 Direct-acting (agonist)
o Bind to cholinergic receptors, causing stimulation
 Indirect-acting
o Inhibit the enzyme “cholinesterase” and prolong the effect of endogenous acetylcholine

Directly acting cholinergic agonists
Cholinergic agonists mimic the effects of ACh by binding directly to muscarinic or nicotinic.
 These agents may be broadly classified into two groups:
1. choline esters which include Ach and synthetic esters of choline, such as carbachol and
bethanechol, and
2. naturally occurring alkaloids, such as nicotine and pilocarpine

Pilocarpine
 is a directly acting muscarinic agonist and used for the treatment of glaucoma (a disease
with enhanced pressure of fluid in the eyeball).
 Pilocarpine constricts the ciliary muscle in the eye, which promotes the outflow of intraocular
fluid through the canal of Schlemn
Bethanecol
has mainly muscarinic actions
Relaxes sphincters in bladder and GI tract, allowing them to empty
Helpful for postsurgical atony of the bladder and GI tract
Dose:10-40 mg oral, 2.5-5.0 mg SC

Carbachol
is a direct agonist of both muscarinic and nicotinic receptors
It is useful only as an eye drop to treatment of glaucoma as second line drug next to
pilocarpine.
Adverse effects
Adverse effects of cholinergic agonists are practically muscarinic types:
 bronchoconstriction,
bradycardia,
increased gastric acid secretion,
sweating,
difficulty in visual accommodation, increased salivation.

Indirectly acting cholinergic agonists
Indirectly acting drugs, logically, do not directly act on the receptor.
They inhibit the acetylcholine esterase enzyme (AchE) and thus, these drugs do not mimic but
increase both the level and duration of the neurotransmitter.
According to the mode of action, AChE inhibitors can be divided into two groups: irreversible
and reversible.
Reversible inhibitors
Edrophonium
It is used for diagnosis of Myasthenia gravis

Neostigmine: is a reversible AchE inhibitor and used for the treatment of:
 Myasthenia gravis treatment (nicotinic action).
 Paralytic ileus (like bethanechol which is direct drug)
 Urinary retention
 Competitive (non-depolarizing) neuromuscular blockers intoxication
Physostigmine
is lipid soluble (non-polar) reversible AchE inhibitor used for the treatment of Glaucoma and
Atropine toxicity (anti-muscarinic drug).
Donepezil, Rivastigmine, and Galantamine:
used in treatment of Dementia of Alzheimer’s disease

Irreversible inhibitors
The result is a long-lasting increase in ACh at all sites where it is released
Many of these drugs are extremely toxic and were developed by the military as nerve
agents.
Related compounds, such as parathion and Malathion, are used as insecticides.
Ecothiopate: are topical eyedrops only for the treatment of severe glaucoma.
Adverse effects: (same for both direct and indirect cholinomimetics)
Mnemonics (reminders) helpful to remember the muscarinic (mostly parasympathetic)
peripheral effects of cholinesterase inhibitors are DUMBBELLS:
Diarrhea (Diaphoresis), Urination, Miosis, Bronchospasm (secretion) Bradycardia, excite
skeletal muscle and CNS (Emesis), Lacrimation, Lethargy, and Salivate

Organophosphate
 Signs of toxicity
Due to excessive activation of muscarinic receptors
 Bronchial constriction Diahhroea
 Salivation vomiting
 Hypotension(bradycardia) Defecation
 Urination contraction of detrusor muscle
→
Nicotinic excess (Ach excess at the ganglion + NMJ)
Fasculation (muscle twitch), tremor, paralysis, convulsion
Respiratory muscle paralysis (diaphragm) results in death
→

Contraindications: (same for both direct and indirect cholinomimetics)
Both direct and indirect cholinomimetic drug should not be given for those patients with the
following clinical problem:
 Bronchial asthma
 Peptic ulcer
 Angina pectoris
 urine incontinence
 Intestinal obstruction

Cholinergic antagonists
Cholinergic antagonist is a general term for agents that bind to cholinoceptors (muscarinic or
nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists.
Nicotinic receptor blockers are ganglionic blocking drugs or neuromuscular blockers (skeletal
muscle relaxants) depending on the location of the nicotinic type acetylcholine receptors.
Antimuscarinic agents
Antimuscarinic are drugs which block ACh at the muscarinic receptors
in the PSNS
Drugs include: Atropine, Scopolamine (Hyoscine), Ipratropium bromide, Benztropine,
Trihexyphenidyl

Therapeutic uses
 Parkinson’s disease: Benztropine, Biperiden, Procyclidine & Trihexyphenidyl used as
adjunctive therapy
 Motion sickness: Scopolamine (oral or transdermal prophylactically 4 hrs. before journey)
 As Anti-secretory and Preanesthetic medication: Atropine used for this purpose
 Urinary incontinence: Tolterodine is M3 selective drugs used to relieve urinary frequency,
and urgency and Enuresis in children
Asthma: Ipratropium bromide is used as inhalational drug in asthma
 Chronic obstructive pulmonary disease (COPD) patients – Chronic smokers, older
patients:
Tiotropium bromide a long acting quaternary anti-muscarinic drug and can be given once
daily

Bradycardia and partial heart block: Atropine is useful if these cases are occurred
Abdominal cramp and intestinal colic: Dicyclomine is good drug for this purpose
Non- infectious, traveler and drug induced diarrhea: atropine (usually used in combination
with diphenoxylate)
 To reverse the toxicity of organophosphate (irreversible cholinesterase
inhibitors)poisoning:
IV atropine sulfate every 5-15 min until signs of toxicity reversed.
Adverse effects
 Dry mouth, mydriasis, blurred vision tachycardia, dry eyes, hot & flushed skin, body
temperature increases, constipation, hallucinations, agitation, delirium which may progress to
depression, collapse of circulatory and respiratory system, coma and death.
 Simply the adverse effects of muscarinic blocker are anti- DUMBBELLS.

Contraindication of Antimuscarinic drugs
 Avoid the use of anti-muscarinic drug in
glaucoma patients especially angle closure, and
with a history of prostatic hyperplasia and use in elderly men with caution.

Adrenergic agonists
 Drugs that stimulate the sympathetic nervous system (SNS)
 Also known as adrenergic agonists or sympathomimetics
Mimic the effects of the SNS neurotransmitters: norepinephrine (NE) and epinephrine (EPI)

The sympathomimetic classified by mode of action into three groups
Direct acting
 Act directly interact with and activate one or more of the adrenergic receptors
e.g., norepinephrine and epinephrine
Indirect acting
Increase the availability of norepinephrine or epinephrine to stimulate adrenergic receptors by
causing displacement of stored catecholamines from adrenergic nerve endings
(e.g., Amphetamine and tyramine) or
inhibition of reuptake of already released catecholamines from the synapse
(e.g., Cocaine and tricyclic antidepressants (TCADs))
Blocking the metabolizing enzymes: e.g. Monoamine oxidase (MAO) is inhibited
by pargyline while catechol-O-methyltransferase (COMT) is inhibited by entacapone

Mixed acting sympathomimetics
 Refers drugs that indirectly release norepinephrine and also directly activate
adrenoreceptors. e.g., ephedrine, dopamine

Epinephrine (adrenaline)
Epinephrine interacts with both and receptors.
α β
At low doses, effects (vasodilation) on the vascular system predominate, whereas at high
β
doses, effect (vasoconstriction) is the strongest.
α
Therapeutic uses of epinephrine
Bronchospasm: in treatment of acute asthma and anaphylactic shock, epinephrine is the
drug of choice and can be lifesaving in this setting. Within a few minutes after subcutaneous
administration, respiratory function greatly improves.
Anaphylactic shock: Epinephrine is the drug of choice for the treatment of types I
hypersensitivity reactions (including anaphylaxis) in response to allergens

Cardiac arrest: Epinephrine may be used to restore cardiac rhythm in patients with cardiac
arrest.
Anesthetics: Local anesthetic solutions may contain low concentrations Epinephrine greatly
increases the duration of local anesthesia by producing vasoconstriction at the site of
injection.
This allows the local anesthetic to persist at the injection site before being absorbed into the
systemic circulation.
Epinephrine Side Effects
Nervousness, tremor, insomnia Paradoxical bronchospasm, Angina, arrhythmias, Hypertension,
Tachycardia Nausea/Vomiting and Hyperglycemia

Dopamine
At low rates of infusion
D1-mediated vasodilation in renal, coronary vessels with little effect on other blood vessels
or on the heart.
At higher rates of infusion
It causes β1-mediated increased force of heart contraction and œ1-mediated generalized
vasoconstriction
Indications
Treatment of severe congestive failure
Treatment of cardiogenic and septic shock

Selective alpha 1 agonists
E.g. Phenylephrine
Phenylephrine causes marked arterial vasoconstriction during intravenous infusion.
Phenylephrine is used as a nasal decongestant and as a mydriasis in various nasal and
ophthalmic formulations.
Alpha 2 selective agonists: methyldopa and clonidine
Methyldopa
Centrally acting antihypertensive agent (it is the preferred agent during pregnancy)
Causes activation of central alpha2 receptors
Inhibits SNS activity and leads to a fall in Blood pressure
Adverse effects: sedation, dry mouth, bradycardia, hepatotoxicity, hemolytic anemia

Beta 1-selective agonists E.g. Dobutamine
Dobutamine injection is used for treatment of heart failure, shock and atrioventricular heart
block
Adverse Effects of Beta1 Activation: tachycardia (excessive heart rate), dysrhythmias
(irregular heartbeat) and Angina Pectoris.

Beta 2 selective agonists
Used for treatment of asthma
Classified into two based on the duration of action
i. Short acting: Albuterol and terbutaline are short-acting 2 agonists.
β
Albuterol is the short acting 2 agonist of choice for the management of
β
acute asthma symptoms.
ii. Long acting: Salmeterol and formoterol are long acting agonists (LABAs) that are 2
β β
selective.
Salmeterol and formoterol are the agents of choice for treating nocturnal asthma in
symptomatic patients taking other asthma medications.

Adverse Effects
 Tremor is a relatively common adverse effect
 Can be minimized by starting oral therapy with a low dose of drug and progressively
increasing the dose as tolerance to the tremor develops.
 Feelings of restlessness, apprehension, and anxiety
 Tachycardia is a common adverse effect with systemic administration

Adrenergic antagonist
The adrenergic antagonists (also called adrenergic blockers or Sympatholytic) bind to
adrenoceptors but do not trigger the usual receptor-mediated intracellular effects.
These drugs act by either reversibly or irreversibly attaching to the adrenoceptors, thus
preventing activation by endogenous catecholamines

Alpha-adrenergic blocking agents
The adrenergic antagonists (also called adrenergic blockers or sympatholytic) bind to
adrenoceptors but do not trigger the usual receptor-mediated intracellular effects.
As indicated in the flow chart above adrenergic blockers are classified into selective and
non-selective based on their affinity toward either beta1 or beta 2 receptors.
Non-Selective Alpha -Adrenergic Receptor Antagonists:
Non-selective Alpha-receptor antagonists may be reversible (Phentolamine) or irreversible
(Phenoxybenzamine) in their interaction with these receptors.

Therapeutic Uses: both drugs are used in the following condition
Treatment of pheochromocytoma
Treat patients in preparation for surgery
 Prolonged treatment in patients with inoperable or malignant pheochromocytoma
 Erectile dysfunction
Toxicity and adverse effects
Postural hypotension accompanied by reflex tachycardia, reversible inhibition of
ejaculation.

1
α -Adrenergic Receptor Selective Antagonists
Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin are selective competitive blockers
of the 1
α receptor
Inhibits vasoconstriction induced by endogenous catecholamines; vasodilation may occur in both
arteriolar resistance vessels and veins,
Resulting in a fall in blood pressure due to decreased peripheral resistance.
Therapeutic use:
Treatment of hypertension (prazosin, terazosin, doxazosin)
Congestive heart failure
Benign prostatic hyperplasia (especially Tamsulosine)

Adverse effects
Most common side effect is postural hypotension and syncope when administered for the first
time (“first- dose phenomenon”).
This disappears with continued therapy, tolerance develops and
cardiovascular reflexes are not impaired appreciably by chronic
therapy.
Other side effects: - headache, drowsiness, dry mouth, blurred vision, stress incontinence

Beta-adrenergic blocking agents
Block stimulation of beta receptors in the SNS
Two types
Non-selective beta blockers: Propranolol, timolol, nadolol, pindolol
Cardioselective (Beta1) blockers: atenolol, esmolol, metoprolol
Therapeutic use:
Angina and Certain tachyarrhythmia
Myocardial infarction
Heart failure
Hypertension
Glaucoma (topical use): reduce production of aqueous humor
Eg. timolol
Hyperthyroidism, migraine headache, anxiety: propranolol

Adverse effects
Bronchoconstriction: non-selective beta blockers like propranolol
Bradycardia
Hypoglycemia
Contraindication
 Asthma is an absolute contraindication
 Insulin-dependent diabetes
Masking of hypoglycemia in insulin-dependent diabetes because of
blunting of sympathetic nervous activation.

Autonomic nervous system (ANS) pharmacology.pptx

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