مادة االدوية املرحلة الثالثة أ.م.د. حسام الدين سامل 2017-2016 FUNCTIONS OF THE PARASYMPATHETIC NERVOUS SYSTEM • Protects the retina from excess light • Decreases heart rate • Promotes glandular secretions • Promotes the emptying of hollow organs • Promotes the conservation of energy • Promotes rest and repair • Physiologically antagonizes the sympathetic nervous system

DUAL INNERVATION AT MOST SITES CONCEPT OF DOMINANCE IN THE AUTONOMIC NERVOUS SYSTEM • The sympathetic nervous system dominates at some sites • The parasympathetic nervous system dominates at other sites

PARASYMPATHETIC INNERVATION FROM THE BRAIN PARASYMPATHETIC INNERVATION FROM THE SACRAL CORD FIBER • There is always sufficient in the blood so it is never a problem. Acetyl choline A is a daughter molecule that is transported to vesicles in the nerve membrane. When travels down the fiber, there is an uptake of calcium and the vesicles fuse with the membrane and is released. As a result, acetylcholine is able to act on muscarinic or nicotinic receptors. rapidly metabolizes acetylcholine into choline and acetic acid and choline is taken up. Hardly any of it gets a chance to diffuse away from the active site and get into the bloodstream.

AGENTS AFFECTING CHOLINERGIC TRANSMISSION

• Hemicholinium • • Botulinus • Calcium • • Atropine • d-Tubocurarine • Hemicholinium – blocks choline uptake, thereby blocking synthesis of Ach. These compounds are poisonous and not used for any therapeutic purpose • Latrotoxin is a toxin from the black widow that produces an explosive release of Ach, causing muscular spasm. • Botulinus toxin is a toxin that is able to bind to the neuron and interferes with the trafficking as they come together to promote the fusing of the vesicles to the membrane. • Calcium is involved in the vesicular release. Its uptake is important in the fusion of vesicles to membrane of neuron. • Physostigmine is an example of a drug that affects cholinergic transmission by increase Ach in the plasma at the synaptic cleft, inhibiting acetylcholinesterase and Ach concentrations in the synaptic cleft will increase and rebind to muscarinic and nicotinic receptors. This drug is considered an inhibitor of acetylcholinesterase and these type drugs are only effective where you have cholinergic innervation. • Atropine is a drug that blocks muscarinic actions of Ach. • D-Tubocurarine blocks the nicotinic actions, which are primarily at the endplate of the . Higher doses of this do tend to block nicotinic receptors at the autonomic ganglion.

WHAT ACETYLCHOLINE DOES

• Promotes transmission in postganglionic autonomic fibers • Promotes release of epinephrine and norepinephrine from the adrenal medulla • Promotes transmission in skeletal muscle fibers • Promotes the functions of the parasympathetic nervous system at cardiac muscle, smooth muscles and glands

NEURONAL INNERVATION TO ORGANS NICOTINIC RECEPTORS • Nicotinic receptors areTwo subtypes

– NN subtype is present on cell body of postganglionic autonomic neuron – NM subtype is present at the endplate of the neuromuscular junction MUSCARINIC RECEPTORS

Several subtypes: M1 M2 M3…….. M1 in autonomic ganglia , gastric tissue. M2 in cardiac fibers M3 smooth muscles , glands

PARASYMPATHETIC FUNCTION AT ORGANS SITES • Gastrointestinal tract  increases tone and motility – Longitudinal muscles  contraction – Circular muscles  contraction – Sphincter muscles  relaxed to allow emptying of hollow organs • Bile duct  increased tone and motility • Gall bladder  increased tone and motility • Urinary tract  increased tone and motility – Ureters – Detrusor muscle of the bladder – Trigone  RELAXED – Sphincter muscle of the bladder  RELAXED • Bronchial smooth muscles  respond to presence of Ach by constriction • Lacrimal glands  tearing • Pharyngeal glands  secretion • Salivary glands  copious secretion of saliva • Mucus glands – Respiratory tract  secretion – Esophagus  secretion of glands • Intestinal glands • Gastric glands • Pancreas  foodstuff also causes secretion of hormones (cause secretion of trypsin and chymotrypsin  aiding in digestion) as PNS causes secretion of fluids

PARASYMPATHETIC CONTROL OF THE CARDIOVASCULAR SYSTEM • SA Node  reduction in rate of diastolic depolarization • Atrial muscle  decreased refractory period, decreased force of contraction • AV node  increased refractory period, decreased impulse flow • Purkinje fibers  reduced impulse flow • Ventricles  decrease in force of contraction • Blood vessels  vasodilation, causing fall in peripheral vascular resistance

• M2 is found in the cardiac muscles. • SA node  pacemaker of the heart so if it is slowed down, heart rate will decrease • Ach has negative chronotropic effect (decreases rate of heart) and negative ionotropic effect (decreases force of contraction). A decrease in force of contraction is primarily at atrial muscle. • M3 is found in blood vessels. ACETYLCHOLINESTERASE • Sites of location – Cholinergic neurons – Cholinergic synapses – Neuromuscular junction Substrates Acetylcholine is the best substrate ORGANOPHOSPHATE INHIBITORS OF AChE

• Their action promoting accumulation of ACh at the NN nicotinic receptor is the basis for their , but actions at muscarinic receptors contribute to their toxic actions as well • Inhibition of AChE by these agents is irreversible – New synthesis is required for recovery of enzyme function Hydrolysis of the AChE-phosphorylated is extremely slow, in the order of days. The phosphorylated enzyme is considered to be irreversibly inhibited, and recovery of function is in the order of days.

THERAPEUTIC USES OF INHIBITORS OF ACETYL CHOLINESTERASE

• Glaucoma (wide angle) • Atony of the bladder • Atony of the gastrointestinal tract • Intoxication by antimuscarinic agents • Intoxication by tricyclic antidepressants (TCA’s) or phenothiazines (use physostigmine) • Myasthenia gravis e.g: • Physostigmine  atropine intoxication •  Myasthenia gravis •  Myasthenia gravis

• Recovery of neuromuscular function after

competitive blockade of NN receptor of skeletal muscle fibers as neostigmine • Alzheimer’s disease as : •

SOME ORGANOPHOSPHATE INHIBITORS OF ACETYLCHOLINESTERASE • Tetraethylpyrophosphate • (N+) • Diisopropylflurophosphate (DFP) •  nerve gas •  nerve gas •  nerve gas • , only one still used, even in homes •  insecticide •  insecticide •  insecticide used in the home? • Many others

ORGANOPHOSPHATES AS NERVE GAS AGENTS IN CHEMICAL WARFARE

• Extremely volatile agents such as sarin, tabun, soman, and agent VX may be used as nerve agents in chemical warfare. • Accumulation of ACh at cholinergic receptors produces effects reflecting stimulation of cardiac muscle, smooth muscles and glands. Suchs effects would be identical to those cause by muscarine . • Bradycardia and hypotension occurs. However, in some cases, tachycardia may be observed, due to intense sympathetic discharge in response severe hypoxemia. • Irreversible inhibition of acetylcholinesterase by these agents produces accumulation of ACh at the end plate of skeletal muscle fibers. This in turn leads to depolarizing blockade of the NM nicotinic receptor. Skeletal muscle paralysis occurs. Movement is impossible. The diaphragm is also paralyzed. The individual eventually dies due to respiratory paralysis. • , atropine, and removal of the person from the source of exposure are all to be employed in cases of posioning MUSCARINIC RECEPTOR BLOCKING AGENTS • ACETYLCHOLINE IS AN AGONIST AT BOTH MUSCARINIC AND NICOTINIC RECEPTORS • THE NICOTINIC ACTIONS OF ACETYLCHOLINE REMAIN WHEN MUSCARINIC RECEPTORS ARE BLOCKED

MUSCARINIC RECEPTOR BLOCKADE DOES NOT AFFECT GANGLIONIC TRANSMISSION Autonomic ganglia: -Nicotinic sites -Muscarinic sites Muscarinic receptor blockade prevents generation of the IPSP and the sEPSP but not the fEPSP

Muscarinic receptor blockade does not interfere with transmission at autonomic ganglionic sites, the adrenal medulla, or skeletal muscle fibers. Sympathetic adrenergic functions are not affected. In dual innervated organs, muscarinic receptor blockade allows sympathetic dominance • PHARMACOLOGY OF MUSCARINIC RECEPTOR BLOCKADE/ATROPINE