CHEMICAL TRANSMITTERSDEFINITION : it is the substance which transmits the nerve impulse

from pre - synaptic to post - synaptic membrane . MECHANISM : Arrival of nerve impulse to Pre-synaptic membrane → causes Ca+ uptake by acetyl choline

vesicles→ causes swelling and rupture of vesicles→ causes release of acetyle choline which can cross the synaptic cleft→ formation of acetylcholin - receptor complex→ Increase Na permeability → Depolarisation Action potential This Causes Propagation of Nerve Impulse

TYPES OF NERVE ENDINGS

ADRENERGIC CHOLINERGIC(nor adrenaline) (ac . choline)

I) Cholinergic neurotransmission :- ( six steps )1- Synthesis of acetyl choline :-( In cytoplasm) choline + acetyl CoA CAT Ach + CoA. ( choline - acetyl - transferase)2- Storage of acetyl choline in vesicles In the synaptic vesicles . 3- Release of Acetyl choline :-Ca++ channels in the presynaptic membrane opens → Ac.ch. releaseby exocytosis4- Binding to receptors .5- Degradation of Ac.ch. choline Ac.ch. choline + acetate esterase

6- Recycling of cholineInto the neurone for resynthesis of Ac .ch.

SITES OF RELEASE OF ACETYL CHOLINE

1- Autonomic ganglia (i.e all preganglionic fibers)

2- All parasympathetic post - ganglionic fibers .

3- Some sympathetic post - gangljpnic as sweet glands and

blood vessels of skeletal muscles.

4- M.E.P = motor end plate (i.e neuro - muscular junction)

5- Adrenal medulla (pre ganglionic )

6- C.N.S .

TYPES OF CHQLINERGIC RECEPTORS:

MUSCARINICNICOTINIC

1-This name from muscarine, a substance which has a same action as ac.choline in these sites:

a) parasympathetic postb) sympathetic (ganglionic

1- Name from nicotine which in small dose has the same action of ac.choline in a) M.E.PB) autonomic gangliac) adrenal medullad) C.N.S

2- Blocked by atropine by comopetitive Inhibition, not blocked by cholinestrase, so they have longer duration of action than ac.choline

2-Blocked by large dose of nicotine (autonomic)or by curare ( in MEP )

A) Muscarinic receptors

Sites : In cardiac muscles, smooth muscle and exocrine glands .

Subtypes : Ml , M2 , M3 and M4 .3-Some sympathetic post-ganglionic as sweet glands and

blood vessels of skeletal muscles.4- M.E.P = motor end plate (i.e neuro - muscular junction)5- Adrenal medulla (pre ganglionic )6- C.N.S . Ml : in autonomic ganglia, CNS and gastric mucosa M2 : in cardiac cells and smooth muscles . M3 : in smooth muscles and secretory glands . M4 and M5 : unknown sites .

Functions of muscarinic receptors:

- It has prolonged reseponse, lasts for seconds, either exitation or inhibition :-

1- Cardiac inhibition ( slow heart rate.)2- Broncho-constriction .3- Salivary secretion4- Increases G.I.T secretion and motility.5- Pupillary constriction .6- Contraction of ciliary muscle.7- Contraction of urinary bladder and rectum .

B) Function of Nicotinic Receptors :-

It has short timed receponse only exitatory :

1- Help ganglion transmission .

2- Secretion of epinephrine and nor-epinephrine from Ad. Medulla.

3- Stimulates N.M.J (MEP) to produce skeletal muscle contraction

FATE (REMOVAL) OF AC CHOLINE .By choline-estrase enzyme

2 types .

True pseudo (false)

- present in nerve –endings - present in plasma.- specific only for Ac - non specific, can act on

- any ester

- highly potent (strong) - less potent.

PARASYMPATHOMIM ETIC DRUGS

Acts By Two Ways :

A) Direct : on tissues as muscarine, nicotine in small dose and carbachol.

B) Indirect : anticholinesterases as DFP and Eserine

(war gas)

Anti cholinesterases : Two types:

a) Reversible :- short acting e.g

Eserine : generalized i.e. ↑ both muscarinic and nicotinic actions. Prostigmine: Nicotinic i.e ↑ skeletal muscles MEP activity = used in treatment of myasthenia gravis .

b) Irreversible :- long acting drugs i.e toxic, called nerve gases, or insecticides as DFP which causes paralysis of motor functions → difficulty in breathing → death

PARASYMPATHOLYTIC DRUGS

Mechanism of action :1) Persistent depolarization2) Competitive inhibition as curare. Types : A) ganglion blockers- Nicotine in large doses - Hexamethonium They cause paralysis of autonomic ganglia by persistant

depolarization .B) post - ganglionic blockers -AtropineC) MEP blockers - Curare - Botulinum - Flexidil - Succinyl cholin

( persistent depolarization)

Curare :- acts by competitive inhibition to Ac.ch . It can be used

together with succinyl choline as muscle relaxants ATROPINE (anti-muscarinic drug ):ACTION :a) ON THE EYES :- Mydriasis and cycloplegia(loss of

ability for near vision)b) ON SALIVARY GLANDS :- Dryness of mouthc) ON G.I.T :- Decrease motility = antispasmodicd) ON RESPIRATION : - Block secretions in respiratory

tract e) ON C.V.S :- Tachycardia = ↑ heart rate .f) ON URINARY TRACT :- ↓ motility of urinary bladder .

Effect of injection of Ac.ch. after Atropine on A.B.P:

Nicotinic receptors in adrenal medulla unblocked rise in A.B.P

CLINICAL USES OF ATROPINE1- Fundus examination → Mydriasis2- Bronchial asthma → Bronchodilatation .3- Treatment of colic →↓ motility of G.I.T .4- pre anaethetic drugs to prevent cardiac arrest.5- Befor surgery → to block respiratory secretions

ADRENERGIC TRANSMISSION

5- STEPS :- Hydroxylase enz. 1- Tyrosine DOPA (In cytoplasm). Dopa dopamine .2- Storage of nor epinephrine in vesicles :- OH

Dopamine Nor. epinephrine ( In synaptic vesicles .) N.B In adrenal medulla only: CH3

Nor - epinephrine epinephrine .

3- Release of nor-epinephrine :- Into the synapse.

4- Binding by receptors : either post-synaptic ( on the effector organ) or pre- synaptic receptors ( on nerve endings.)

5- Removal of nor- epinephrine ( Fate ) .

SITES OF RELEASE OF CATECHOLAMINES:

1- Adrenergic endings :- only nor - adrenaline .2- Adrenal medulla :- causes release of : 80% epinephrine 20% nor-epinephrine

FATE OF CATECHOLAMINES:1- Active reuptake = 80-90% back into ad. vesicles.

(Na-k Atpase sys.)2- Destruction = 7 % by MAO (oxidation) COMT (methylation)3- Excretion as such = 3 %

ADRENERGIC RECEPTORS (ALQUISTE)

211 2

α1 : STIMULATORY a) V.C

b) stimulation of sphincters .

α2 :- INHIBITORY 0 a) relaxation of walls of G.I.T

b) pre - synaptic inhibition of release of nor epinephrine (-ve feedback)

βl :- STIMULATORY (+) a) heart +ve increase H.R & contraction

b) adipose tissue = lipolysisc) renin - angiotensin . system = ↑ ABP.

β2 :-INHIBITORYO (–) relaxation of smooth muscles in :1- bronchi = bronchodilatation .2- blood vessels = V.D in skeletal blood vessels & coronaries.

N.B β1 receptors are stimulated equally by epinephrine and nor-

epinephrine B2 receptors stimulated more by epinephrine than N.E

β2 adrcnoreceptors : tow groups α 1 & α2:αl receptors have high affinity for phenyl-ephrine

present on post.synapticmembrane of effector organ . α2 receptors have high affinity for clonidine.

present on Pre-synaptic nerveendings to control release of nor-epinephrine

(causes its inhibition). N.B β2 pre-synaptic receptors stimulate NE

release, both a 2 and β2receptors are called pre - synoptic receptors.

RECEPTOR STIMULANTS:

α Receptors stimulated by : nor - adrenaline ]- adrenaline} isoproterenol

β Receptors stimulated by : isoproterenol J. adrenalin]- nor - adrenaline N.B nor - adrenaline, has a more pressor effect because it acts mainly on α due to receptor sensitivity.

RECEPTOR BLOCKERS :α Blockers : ergot alkaloids .β Blockers : inderal .(Propranolol.) N.B In G.I.T inhibition of

the wall is by α2 and may be β2 receptors.While stimulation of sphincters only by al receptors (not β1 ). N.B α is stimulatory except on G.I.T, it is inhibitory While β is inhibitory except on heart, it is stimulatory.

COMPARISON BETWEEN a & B RECEPTORS

α – RECEPTORβ - RECEPTOR

1 -papillary dilatation2- vasoconstriction3- intestinal relaxation4- contraction of G.I.T sphincters5- pilomotor contraction6- contraction of spleen capsule7- inhibition of insulin secretion8- contraction of internal uretheral

sphincter9- salivary secretion10- ejaculationstimulated by :N.E , epinephrine and phenyl -

ephrineBlocked by: Ergot alkaloids

1 -far vision (ciliary muscle relaxation)2- vasodilatation3- intestinal relaxation4- gastric wall relaxation5- increase heart rate6- increase heart contractility7- stimulation of insulin secretion8- Broncho-dilatation.9- glycogenolysis .10- Liplysis11- Renin secretion.stimulated by:Isoproterenol, adrenaline , N.adrenalinBlocked by : Propranolol.

MECHANISM OF ACTION OF ADRENERGIC RECEPTORS

αl Increases intra-cellular C-AMP.

α2 Inhibit adenyl cyclase enzyme, so it decreases cyclic AMP so interfering between the combination between the transmitter and its receptor

βl receptors stimulates adenyl cyclase , increases cyclic AMP

β2 receptors → unknown mechanism but may also act by increasing C-AMP

Sympathomimetic drugs (adrenergic Agonists )

Mechanism Of Action:

1- stimulate release of catecholamines e.g Tyramine

↓

(indirect acting agonist )

2- inhibit reuptake e.g Cocaine

3- α stimulants

Direct acting agonist

4- β stimulants

SYMPATHOLYTIC DRUGS

1- Inhibit synthesis and storage e.g reserpine .

2- Inhibit release of catecholamines e.g guanithidine .

3- Recepor blockers a & B receptors4- False transmiters e.g a methyl

dopa( aldomet ).5- Ganglion blockers e.g hexamethonium

and arfonad

DIFFERENCE BETWEEN

EPINEPHRINNOR - EPINEPHRE

1 -sites of release2- receptor sensetivity3- on heart4- pressor effect (peripheral resistance)5- metabolic6- systolic pressure7- diastolic pressure5- G.I.T motility

-adrenal medulla- α and β equal- increase cardiac output and heart rate- decrease-glycogenolysis, lipolysis- increase- decrease- decrease

adrenal medulla & adrenergic nerve ending- mainly a & β slightly- decrease both- increase- no effect- little effect- increase- increase- decrease

PHEOCHROMOCYTOMA

* Tumour of adrenal medulla resulting in attacks of hypertension in emergency states, discharge of sympathetic leading to:

1- increased arterial pressure2- increased blood flow to active muscles3- increased blood glucose level4- increased rate of blood coagulation . 5- increased mental activity6- increased glycogenolysis in liver and muscles .7- increased rate of cellular metabolism.

Control of A.N.S by Higher centers

1- Some autonomic reflexes as micturation, defecation and erection are under inhibitory control of centers in C.N.S .

2- Cardio-vascular, respiratory and digestive activity are under control of medulla within the brain stem.

3- Stimulation of anterior nucleus of hypothalamus is accompanied by parasympathetic effects, while stimulation of posterior nucleus is

accompanied by sympathetic effects.

1- Cardiovascular autonomic reflexes :-High arterial pressure → baro-receptors → pressure fall back

toward normal.2- Gastrointestinal autonomic reflexes :-a) Un-conditioned reflex e.g. presence of food in mouth

causing salivary secretion .b) Defecation reflex.c) Micturation reflex. d) Sexual reflexes : Erection (parasympathetic function,

followed by ejaculation (sympathetic function)N.B biofeedback research demonstrate that the A.N.S is not

autonomic, it can be voluntary.

DISORDERS OF AUTONOMIC FUNCTIONS

SYMPATHETIC QVERACTIVITY:-

1- HYPERTENSION :- sympathetic increases peripheral resistance

2- ANGINA PECTORIS :- sympathetic increases myocardial O2

3- Hyperthyroidism: Thyroid hormone increases sensitivity or number of adrenergic receptors