Introduction to ANS PharmacologyDr. Kaukab Azim + Dr. Hanin Osama

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NS

• Central – Brain – Spinal cord

• Peripheral – Afferent (sensory)– Efferent (motor, autonomic )

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ANS Regulates Involuntary Functions

• Blood pressure• Heart rate• Respiration• Body Temperature• Glandular Secretion• Digestion• Reproduction

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• The ANS facilitates immediated physical reactions associated with a preparation for violent muscular action.

• Acceleration of heart and lung action• Paling or flushing, or alternating between both.• Inhibition of stomach and upper intestinal action (digestion

slows down or stops)• Liberation of nutrients for muscular action• Dilation of blood vessels for muscles • Inhibition of Lacrimal gland and salivation • Dilation of pupil

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Sympathetic System Parasympathetic System

Originates in thoracic and lumbar regions of the spinal cord (T1 – L2)

Originates in brainstem (cranial nerves III, VII, IX, and X) and sacral region of spinal cord

(S2 – S4)

Ganglia located in paravertebral sympathetic ganglion chain

Terminal ganglia located near or embedded within target tissue

Short pre-ganglionic fibersLong postganglionic fibers

Long pre-ganglionic fibersShort postganglionic fibers

Ratio of pre-ganglionic fiber to post- ganglionic fibers is 1 : 20

Ratio of pre-ganglionic fibers to postganglionic fibers is 1 : 3

Activity often involves mass discharge of entire system Activity normally to discrete organs

Primary neurotransmitter of postganglionic neurons is norepinephrine

Primary neurotransmitter of postganglionic neurons is acetylcholine

Predominates during emergency “fight-or-flight” reactions and exercise Predominates during quiet resting conditions

Divergence coordinates activity of neurons at multiple levels of spinal cord Limited divergence

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T1T2T3

T4T5T6T7T8T9T10T11T12L1L2L3L4L5S1S2S3S4

T1T2T3T4T5T6T7T8T9T10T11T12L1L2L3L4L5S1S2S3S4

Sympathetic Parasympathetic

Pre-ganglionicBlue

Post-ganglionicPink

Pre-ganglionicRed

Post-ganglionicGreen

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VII

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X – Vagus

Nervi erigentes

III

VII

IX XVII

Ciliary

Pterygopalatine

Submandibular

Otic

All preganglionic nerves secrete Ach. Ganglionic blocking drugs block transmission. (e.g.Mecamylamine)

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Acetylcholine Norepinephrine Epinephrine

Site of release

All preganglionic neurons of ANS; all postganglionic neurons of parasympathetic system; Some sympathetic postganglionic neurons to sweat glands

Most sympathetic postganglionic neurons; adrenal medulla (20% of secretion)

Adrenal medulla (80 % of secretion)

ReceptorNicotinic (Nn or Nm), Muscarinic (M1, M2, M3, M4, M5) - cholinergic

α1, α2, β1 (adrenergic) α1, α2, β1, β2 (adrenergic)

Termination of activity

Enzymatic degradation by cholinesterase

Reuptake into nerve terminals; diffusion of synaptic cleft, metabolic transformation by monoamine oxidase (within nerve terminal) or cahechol-O-methyl-transferase within liver)

Metabolic transformation by catechol-O-methyl-transferase within liver

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Location of cholinergic transmission

• All autonomic ganglia• Voluntary muscles (neuromuscular junction)• Adrenal medulla (secretion of adrenaline)• Post ganglionic parasympathetic• Post ganglionic sympathetic to sweat glands

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Acetyl Choline (Ach)

Synthesis: • At the nerve terminals• CAT (choline acetyl transferase), From

Choline• 50% of it, is recaptured by nerve terminals

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Potential targets for drugs

Five key features of neurotransmitter function provide potential targets for pharmacologic therapy: • synthesis, • storage, • release, • termination of action of the transmitter, • functions of the receptor.

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Parasympathomimetic

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Effects of Muscarinic agonistsA. Cardiovascular system • Slow heart rate (negative chronotropy)• Decreases conduction velocity and increases

refractory period• Bradycardia and vasodilatation lead to drop in

BP• Vasodilatation of arteries and veins due to

stimulation of M3 receptors in the endothelium, releasing NO

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Continue…

B. RESPIRATORY • Bronchio-spasm • increase secretion

C. GIT• Increase peristalsis • Increase secretions mainly salivary and gastric• Sphincters are relaxed

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Continue…D. GU• Stimulation of detrusor muscle and Relaxation of

the trigone and sphincter of the bladder thus promote micturition.

E. Eye • Causes contraction of the smooth muscle of the

iris causing miosis and of the ciliary muscle (accommodation of near vision)

• It will facilitate the outflow of aqueous humor into the canal of Schlemn which drains the anterior chamber 17

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F. Exocrine gland • Increased their secretion, sweating,

lacrimation and salivation

G. CNS• Ach is widely distributed in the brain • It is a excitatory neurotransmitter in the

basal ganglia • Its effect include; increased locomotor

activity tremor19

Nicotinic agonists

A. Peripheral nervous system

• Activation of nicotinic receptors in the autonomic ganglia result in firing action potential in postganglionic neurons

• The action is same on both sympathetic and parasympathetic ganglia

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B. NMJ

• Application of nicotine agonist in NMJ leads to depolarization of the endplate

• The response vary from fasciculation of independent motor units to a strong contraction of entire motor unit.

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MUSCARINIC ANTAGONIST

• Atropine • Scopolamine • Ipratropium • Pirenzepine

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Pharmacological actionMuscarinic antagonist

1- CNS: • Atropine in therapeutic doses has a minimal stimulant

effect on CNS and a slower-long lasting sedative effect on the brain

• Scopolamine has more marked CNS effects producing drowsiness in recommended doses

• In high doses scopolamine and to a lesser extent atropine causes agitation, excitement, hallucination and coma

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2- eye: • Mydriasis • Cycloplegia leads to loss of accommodation of near

vision (eye can not focus on near objects)• Reduction of lacrimal secretion, dry eyes

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3- CVS: • The initial effect is bradycardia followed by

tachycardia • The initial bradycardia is often with lower doses and is

due to blockade of presynaptic M1 muscarinic receptors on vagal nerve, thus facilitate Ach release

• The tachycardia is due to blockade of M2 receptors in the SAN

• Therapeutic doses of atropine is abolishes peripheral vasodilatation induced by cholinomimetics.

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4- Respiratory system: • Antimuscarinic drugs are added to general

anesthetics to reduce secretion in the trachea

5- GIT• marked reduction in salivary secretion (dry mouth)• Gastric secretion is blocked less effectively.

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6-GU:• Smooth muscle of the uterus is relaxed• Bladder wall is relaxed and voiding is slower

7- sweat glands• Sweat gland secretions are blocked by antimuscarinic

drugs, thermoregulation is suppressed leading to increase in body temperature.

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Nicotinic antagonistsA) neuromuscular blockers :1- depolarizing NMJ blocking drugs; the depolarizing blockers first depolarize the motor end-plate and then prevent further depolarization. E.g. Succinylcholine

2- non-depolarizing NMJ blocking drugs; compete with acetylcholine for receptors at the neuromuscular junction and clinical relaxation begins when 80–85% of the receptors on the motor end-plate are blocked. tubocurarine

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Ganglion blocking drugs

B. Ganglion blocking drugs can occur by several mechanisms:–By interfering with Ach release –By prolonged depolarization due to

large dose of stimulation–By interfering with postsynaptic action

of Ach.

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ADRENERGIC AGONIST & ANTAGONIST

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SYMPATHOMIMETICSClassification:A- According to the source:1. Natural; NE, EP, DA2. Synthetic; isoproternol, ephedrine,

amphetamine B- chemically:3. Catecholamines; NE, EP, DA and isoproternol 4. Non catecholamines; ephedrine, amphetamine,

tyramine31

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• α1 found in the smooth muscle of many organs and they cause contraction of the blood vessels, relaxation of the GIT and glycogenlysis

• α2 found in presynaptic neuron ,CNS, blood vessels , it inhibit transmitter release, in addition they cause platelets aggregation and blood vessel contraction. If found postsynaptically work as α1

• β1 mainly in the heart ,stimulation result in an increase cardiac out put and heart rate

• β2 present in the smooth muscle of many organs and its stimulation lead to bronchodilation, perpherial vasodilation, relaxation of the visceral smooth muscle and skeletal muscle tremor 33

PHARMACOLOGYCAL EFFECTS OF SYMPATHOMIMETIC

1- Cardiovascular system•The overall effects on blood vessels depend on the

relative activities of the sympathomimetics at α or β receptor.

•α1; increase arterial resistance •β2 receptors promote smooth muscle relaxation

• β1: Activity of both normal (SAN) and abnormal (purkinje fibers) is increased (positive chronotropic effects).

• Contractility is increased (positive inotropic effects)34

2. eye: • Activation by α1 agonist causes mydriasis • α1- agonists increases the outflow of aqueous

humor from the eye, while β antagonists decreases the production of the aqueous humor. These effects are beneficial in treatment of glaucoma.

3. Respiratory • Activation of β2 receptors in the bronchial

muscle results in bronchiodilatation.

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4. GU• In human uterus the β2 receptors mediate relaxation

that might be useful during pregnancy. • The bladder base, urethral sphincter and prostate

contain α receptors that mediate contraction and therefore promote urinary continence.

5. effects on endocrine function• Insulin secretion is stimulated by β receptors and

inhibited by α2• Renin secretion is stimulated by β1 and inhibited by

α2

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6- Metabolic effect •Activation of β3 receptors in fat cells leads to

increased lipolysis.•Sympathomimetics enhances glycogenolysis in

the liver that leads to increased glucose release into the circulation (mediated mainly by β2)

•Activation of β2 receptors promotes uptake of potassium into cells, leading to fall in extracellular potassium..

•Carbohydrates metabolism in the muscle and liver is enhanced

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α-blocker

• Selective α1 (prazosin): – Vasodilation – Hypotension

• Selective α2 (yohimbine)– Increase nor adrenaline release and cause

sympathomimetic effect – Can block α2 in blood vessel and cause

vasodilatation

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• Non selective α-blockers– Phenoxybenzamine, phentolamine– Vasodilatation – Reduce blood pressure

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β-blocker

• Non selective: – Propranolol, labetalol

• Selective – Atenolol, metoprolol – Reduce HR (-ve chronotropic) – Reduce force of heart contraction (-ve

ionotropic)

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