CHEMICAL TRANSMITTERS

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CHEMICAL TRANSMITTERS

• DEFINITION 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

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TYPES OF NERVE ENDINGSADRENERGIC
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. release
• by exocytosis
• 4- Binding to receptors .
• 5- Degradation of Ac.ch.
• choline
• Ac.ch. choline acetate
• esterase
• 6- Recycling of choline
• Into the neurone for resynthesis of Ac .ch.

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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 .

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TYPES OF CHQLINERGIC RECEPTORS
MUSCARINIC NICOTINIC
1-This name from muscarine, a substance which has a same action as ac.choline in these sites a) parasympathetic post b) sympathetic (ganglionic 1- Name from nicotine which in small dose has the same action of ac.choline in a) M.E.P B) autonomic ganglia c) adrenal medulla d) 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 )
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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 .

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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 secretion
• 4- Increases G.I.T secretion and motility.
• 5- Pupillary constriction .
• 6- Contraction of ciliary muscle.
• 7- Contraction of urinary bladder and rectum .

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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

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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.

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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)

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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

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PARASYMPATHOLYTIC DRUGS

• Mechanism of action
• 1) Persistent depolarization
• 2) 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 -Atropine
• C) MEP blockers
• - Curare - Botulinum
• - Flexidil - Succinyl cholin
• ( persistent depolarization)

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• 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 mouth
• c) ON G.I.T - Decrease motility antispasmodic
• d) ON RESPIRATION - Block secretions in
  respiratory tract
• e) ON C.V.S - Tachycardia ? heart rate .
• f) ON URINARY TRACT - ? motility of urinary
  bladder .

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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 ATROPINE
• 1- Fundus examination ? Mydriasis
• 2- 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

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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 ) .

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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

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ADRENERGIC RECEPTORS (ALQUISTE)

• a1 STIMULATORY
• a) V.C
• b) stimulation of sphincters .
• a2 - INHIBITORY 0
• a) relaxation of walls of G.I.T
• b) pre - synaptic inhibition of release of nor
• epinephrine (-ve feedback)
• ßl - STIMULATORY ()
• a) heart ve increase H.R contraction
• b) adipose tissue lipolysis
• c) renin - angiotensin . system ? ABP.
• ß2 -INHIBITORYO () relaxation of
  smooth muscles in
• 1- bronchi bronchodilatation .
• 2- blood vessels V.D in skeletal blood vessels
  
• coronaries.

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• N.B ß1 receptors are stimulated equally by
  epinephrine and nor-
• epinephrine B2 receptors stimulated more by
  epinephrine than N.E
• ß2 adrcnoreceptors tow groups a 1 a2
• al receptors have high affinity for
  phenyl-ephrine present on post.synaptic
• membrane of effector organ .
• a2 receptors have high affinity for clonidine.
  present on Pre-synaptic nerve
• endings to control release of nor-epinephrine
  (causes its inhibition).
• N.B ß2 pre-synaptic receptors stimulate NE
  release, both a 2 and ß2
• receptors are called pre - synoptic receptors.

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RECEPTOR STIMULANTS

• a Receptors stimulated by nor - adrenaline -
  adrenaline isoproterenol
• ß Receptors stimulated by isoproterenol J.
  adrenalin- nor - adrenaline N.B nor -
  adrenaline, has a more pressor effect because it
  acts mainly on a due to receptor sensitivity.
• RECEPTOR BLOCKERS
• a Blockers ergot alkaloids .
• ß Blockers inderal .(Propranolol.) N.B In
  G.I.T inhibition of the
• wall is by a2 and may be ß2 receptors.
• While stimulation of sphincters only by al
  receptors (not ß1 ).
• N.B a is stimulatory except on G.I.T, it is
  inhibitory
• While ß is inhibitory except on heart, it is
  stimulatory.

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COMPARISON BETWEEN a B RECEPTORS
a RECEPTOR ß - RECEPTOR
1- papillary dilatation 2- vasoconstriction 3- intestinal relaxation 4- contraction of G.I.T sphincters 5- pilomotor contraction 6- contraction of spleen capsule 7- inhibition of insulin secretion 8- contraction of internal uretheral sphincter 9- salivary secretion 10- ejaculation stimulated by N.E , epinephrine and phenyl -ephrine Blocked by Ergot alkaloids 1- far vision (ciliary muscle relaxation) 2- vasodilatation 3- intestinal relaxation 4- gastric wall relaxation 5- increase heart rate 6- increase heart contractility 7- stimulation of insulin secretion 8- Broncho-dilatation. 9- glycogenolysis . 10- Liplysis 11- Renin secretion. stimulated by Isoproterenol, adrenaline , N.adrenalin Blocked by Propranolol.
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MECHANISM OF ACTION OF ADRENERGIC RECEPTORS

• al Increases intra-cellular C-AMP.
• a2 Inhibit adenyl cyclase enzyme, so it
  decreases cyclic AMP so interfering between the
  combination between the transmitter and its
  receptor
• ßl receptors stimulates adenyl cyclase ,
  increases cyclic AMP
• ß2 receptors ? unknown mechanism but may also
  act by increasing C-AMP

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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- a stimulants
• Direct acting agonist
• 4- ß stimulants

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SYMPATHOLYTIC DRUGS

• 1- Inhibit synthesis and storage e.g reserpine .
• 2- Inhibit release of catecholamines e.g
  guanithidine .
• 3- Recepor blockers a B receptors
• 4- False transmiters e.g a methyl dopa( aldomet
  ).
• 5- Ganglion blockers e.g hexamethonium and
  arfonad

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DIFFERENCE BETWEEN
EPINEPHRIN NOR - EPINEPHRE
1- sites of release 2- receptor sensetivity 3- on heart 4- pressor effect (peripheral resistance) 5- metabolic 6- systolic pressure 7- diastolic pressure 5- G.I.T motility - adrenal medulla - a and ß equal - increase cardiac output and heart rate - decrease -glycogenolysis, lipolysis - increase - decrease - decrease adrenal medulla adrenergic nerve ending - mainly a ß slightly - decrease both - increase - no effect - little effect - increase - increase - decrease
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PHEOCHROMOCYTOMA

• Tumour of adrenal medulla resulting in attacks
  of hypertension in emergency states, discharge of
  sympathetic leading to
• 1- increased arterial pressure
• 2- increased blood flow to active muscles
• 3- increased blood glucose level
• 4- increased rate of blood coagulation .
• 5- increased mental activity
• 6- increased glycogenolysis in liver and muscles
  .
• 7- increased rate of cellular metabolism.

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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.

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• 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.

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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