Munir Gharaibeh, MD, PhD, MHPEmgharaib@ju.edu.jo

Sites of OriginsLength of Preganglionic and

Postganglionic neurons.Ratio of preganglionic:

postganglionic

FunctionFunctionSympatheticSympatheticParasympatheticParasympatheticHeart rateHeart rateIncreasedIncreasedSlowedSlowedBlood vesselsBlood vesselsConstrictedConstrictedDilatedDilatedStomach and Stomach and intestineintestine

Decreased Decreased activity and activity and secretionssecretions

Increased Increased activity and activity and secretionssecretions

Salivary and Salivary and bronchial bronchial glandsglands

Decreased Decreased secretionsecretion

Increased Increased secretionsecretion

Urinary bladderUrinary bladderBody relaxed, Body relaxed, sphincter sphincter constrictedconstricted

Body Body contracted, contracted, sphincter sphincter relaxedrelaxed

Bronchial Bronchial musclemuscle

RelaxedRelaxedContractedContracted

Blood sugarBlood sugarRaisedRaisedEyeEyePupils dilatedPupils dilatedPupils Pupils

constricted, constricted, accommodation accommodation for near visionfor near vision

Munir Gharaibeh 15

Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (ChT). This transporter can be inhibited by hemicholinium drugs.

In the cytoplasm, acetylcholine is synthesized from choline and acetyl Co-A (AcCoA) by the enzyme choline acetyltransferase (ChAT).

Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol.

Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle.

Munir Gharaibeh 17

Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft. This step can be blocked by botulinum toxin.

Acetylcholine's action is terminated by metabolism by the enzyme acetylcholinesterase.

Receptors on the presynaptic nerve ending modulate transmitter release.

Munir Gharaibeh 18

Munir Gharaibeh 19

ACh released from the motor nerve terminal interacts with subunits of the pentameric nicotinic receptor to open it, allowing Na+ influx to produce an excitatory postsynaptic potential (EPSP).

The EPSP depolarizes the muscle membrane, generating an action potential, and triggering contraction. Acetylcholinesterase (AChE) in the extracellular matrix hydrolyzes ACh.

The ENS receives input from both the sympathetic and the parasympathetic systems and sends afferent impulses to sympathetic ganglia and to the central nervous system.

Many transmitter or neuromodulator substances have been identified in the ENS.

AC: absorptive cellCM: circular muscle layerEC: enterochromaffin cellEN: excitatory neuronEPAN: extrinsic primary afferent neuronIN: inhibitory neuron IPAN: intrinsic primary afferent neuronLM: longitudinal muscle layer MP: myenteric plexusNP: neuropeptides SC: secretory cell SMP: submucosal plexus

Definition: Drugs which produce effects similar to

those observed during the stimulation of postganglionic parasympathetic nerve fibers or have actions similar to acetylcholine.

Choline Esters.Alkaloids.Cholinesterase Inhibitors or

Anticholinesterases.

Munir Gharaibeh 26

Choline Esters: Acetylcholine:

▪ Naturally released ACh from the cholinergic nerve endings.

▪ Very short acting because of rapid hydrolysis by AChase enzyme.

▪ Used only in experimentation.

Munir Gharaibeh 27

Methacholine: Used in in the diagnosis of bronchial asthma

”Methacholine Challenge” Carbachol: not used clinically because of

nicotinic activity Bethanechol:

Works mainly on M3( smooth muscles and glands), but weak at M2, so minimal cardiac effects.

▪ Synthetic, long acting, used orally or s.c..▪ Used in gastric and bladder atony, when there is

no obstruction.▪ Causes flushing, sweating, colic.

Choline Esters.Alkaloids: produce similar actions to ACH but

inconsistent Muscarine: present in some species of

mushroom (Amanita muscaria), can cause poisoning.

Pilocarpine: ▪ not hydrolyzed by cholinesterase▪ works mainly on M3 receptors.▪ used topically in glaucoma.

NicotineMunir Gharaibeh 30

▪ Uses: Non medical use( smoking and as an insecticide) and medical use in smoking cessation

▪ Kinetics: ▪ Rapidly absorbed through skin, lungs, and gut▪ For smoking cessation, used orally as a gum or topically as a patch.

▪ Works on the ganglia, parasympathetic, sympathetic, motor end plate, CNS).▪ Dependence: due to activation of nicotinic receptors on neurons in the brain’s

dopaminergic reward pathway(venrtal tegument area). ▪ Nm stimulation can lead to fasiculations, spasms, and depolarizing blockade.▪ Nn stimulation can lead to:

▪ High heart rate▪ Vsoconstriction▪ High gastric motility and secretions.▪ Increased respiratory rate, due to chemoreceptor activation.▪ Medullary emetic chemoreceptor stimulation, so nausea and vomiting.

▪

Partial nicotinic agonist.Highly effective in supporting

smoking cessation.May be associated with

psychiatric symptoms, including suicidal ideation.

Choline Esters.Alkaloids.Cholinesterase Inhibitors or

Anticholinesterases: Reversible

▪ Alcohols: e.g. Edrophonium▪ Carbamic acid esters: e.g. Neostigmine,

Carbaryl. Irreversible( Organophosphates): e.g.

Echothiophtae, Soman, MalathionMunir Gharaibeh 34

Mechanism of Action: Inhibit cholinesterase enzyme

leading to accumulation of acetylcholine at neuromuscular junctions and synapses

Munir Gharaibeh 38

Very potent agricultural insecticides and lethal war weapons.

Very easily absorbed through all parts of the skin.

Inhibit the enzyme and cause accumulation of ACh at all sites.

Munir Gharaibeh 39

Tissue or Tissue or SystemSystem

EffectsEffects

SkinSkinSweatingSweatingVisualVisualLacrimation, miosis, blurring, spasmLacrimation, miosis, blurring, spasmDigestiveDigestiveSalivation, increased secretions, tone, Salivation, increased secretions, tone,

and motility (cramps, vomiting, diarrhea, and motility (cramps, vomiting, diarrhea, and defecation)and defecation)

UrinaryUrinaryFrequency and incontinenceFrequency and incontinenceRespiratoryRespiratoryIncreased secretions, Increased secretions,

bronchoconstriction, weakness of bronchoconstriction, weakness of musclesmuscles

Skeletal muscleSkeletal muscleFasiculation, weakness, paralysisFasiculation, weakness, paralysisCardivascularCardivascularBradycardia, decreased cardiac output, Bradycardia, decreased cardiac output,

hypotension.hypotension.CNSCNSTremor, anxiety, restlessness, confusion, Tremor, anxiety, restlessness, confusion,

convulsions, comaconvulsions, coma

Munir Gharaibeh 40

Stop the exposure, wash extensively, very lipid soluble.

Atropine, a parasympatholytic drug, in very large doses, until the appearance of Atropine Poisoning.

Pralidoxime, when given very early after the poisoning, can regenerate the enzyme.