•Red : important •Black : in male / female slides •Pink : in female’s slides only •Blue : in male’s slides only •Green : Dr’s notes •Grey: Extra information, explanation Editing File

LECTURE 3: DIRECT ACTING CHOLINERGIC DRUGS OBJECTIVES:

By the end of this lecture students should be able to: ✓ Mention different types, locations, and actions of cholinergic receptors

✓ Identify the mechanism of action of direct acting cholinomimetics

✓ Describe the pharmacokinetics of cholinergic drugs

✓ Identify pharmacological actions and uses of cholinomimetics

this slide is just for good understanding Nervous System:

Central Nervous System peripheral Nervous System

● Brain ● Afferent (Sensory) ● Efferent (Motor): ● Spinal cord Somatic; skeletal muscles Autonomic; Smooth muscles: Sympathetic Parasympathetic Enteric

Autonomic peripheral Nervous System

Parasympathetic Sympathetic Enteric (Cholinergic) (Adrenergic) (For GIT) “The drugs of this lecture”

Preganglionic neurons: Postganglionic neurons: -Long Synapses with -Short Synapses on the postganglionic at or organ. near organ. -Acetylcholine is -Acetylcholine is neurotransmitter. neurotransmitter. -Muscarinic receptor on -Nicotinic receptor on the organ. postganglionic neuron *Cholinergic Fibers: or adrenal medulla. Fibers release Ach in ANS or Somatic Nervous System * ANS: Autonomic Nervous System

Found in Male’s slides only

Botox is Botulinum toxin that’s produced by clostridium botulinum. Cholinomimetics Drugs that produce actions similar to stimulation of M.O.A parasympathetic system or similar to Acetylcholine.

Class Direct Cholinomimetics Indirect Cholinomimetics

Cause direct stimulation of cholinergic Acts indirectly by inhibiting receptors. Each receptor will give different Acetyl cholinesterase thus preventing effect depending on the receptor and the the hydrolysis of Ach. Action drug/neurotransmitter. They are called Cholinesterase inhibitors or anticholinesterases Cholinergic drugs act upon two types of receptors: Site of ● Nicotinic receptors Action ● Muscarinic receptors

Cholinergic or Parasympathetic receptors Nicotinic receptors (N) Muscarinic receptors (M) “Central Receptors” “Peripheral Receptors”

Type I receptors: *when stimulation happens, Type II receptors: channels open. G-protein linked receptors Ion channel linked receptors (Ligand gated ion channels) Located at: Located in: ● Skeletal muscles (Neuromuscular junction) (Nm) ● All target organs that are innervated ● Autonomic ganglia (Sympathetic and by parasympathetic fibers (Heart, parasympathetic ganglia) (Nn) CVS, Eye, Bladder, etc).Internal organs ● Adrenal Medulla (Nn) ● CNS (Nn) except ventricles Subclasses: Subclasses: ● Nm: A class of nicotinic receptors found in skeletal muscles. ● M1,M3,M5 are excitatory or اﻻﻋداد اﻟﻔردﯾﺔ .Nn: A class of nicotinic receptors found in stimulatory in function ● اﻻﻋداد .autonomic ganglia (sympathetic and ● M2,M4 are inhibitory in function اﻟزوﺟﯾﺔ .parasympathetic) , CNS, and adrenal medulla Nn —> nerve to nerve Nm—> Nerve to muscle

Nicotinic Receptors VS Muscarinic Nicotinic receptors Muscarinic receptors “Central cholinoceptors” “Peripheral cholinoceptors” Almost excitatory Excitatory or inhibitory

Autonomic ganglia Nn On all peripheral organs innervated by sympathetic & parasympathetic postganglionic parasympathetic fibers stimulation

Adrenal medulla Nn Heart (bradycardia, M2) release of catecholamines exocrine glands (secretion,M3) (adrenaline & noradrenaline) Skeletal muscles Nm contraction Smooth muscles (contraction, M3) (GIT, urinary tract, bronchial muscles, uterus) Direct Acting cholinergic drugs:

Actions that are similar to the effects of parasympathetic system activation. And are classified according to the type of receptor acting on into gical Action Pharmacolo Nicotinic Action Muscarinic Action

*Contraction of circular muscle of iris (also called iris sphincter muscle or constrictor pupillae)(miosis) . Low concentration (Therapeutic *Contraction of ciliary muscles for near vision dose) of Nicotine : When these 2 contractions happen , a Muscle Contraction decrease in intraocular pressure happens. . High concentration (Toxic dose) Eye (M3) (IOP) So we use drugs that have muscarinic of Nicotine: actions to treat glaucoma. Persistent depolarization and -Bradycardia (decrease in heart rate) M2 relaxation (Blocking of depolarization). Constant -Release of Nitric oxide(NO) (EDRF) um contraction of muscle means there Heart which causes Vasodilation M3 endotheli

is no repolarization which is essential for muscle relaxation Skeletal muscle leading to muscle paralysis. Constriction of bronchial smooth Succinylcholine has similar effect. muscles and increase bronchial secretion. Contraindication: Asthma Lung (M3)

-Increase in motility(peristalsis) over

stimulation leads to diarrhea. -Gastric acid secretion M1

GIT -Relaxation of sphincter causing By stimulating it. defecation M3 This happens by both

sympathetic and Urinary bladder: parasympathetic stimulation. Contraction of muscles Secretion of Relaxation of sphincter leading Neurotransmitters to urination.

Smooth Smooth muscle: Autonomic ganglia Contraction. Uterus is not sensitive muscles (M3) to muscarinic agonists

Increase in exocrine glands release of Catecholamine secretions (exocrine glands are glands (Adrenaline and that secretes through ducts) Noradrenaline). Over

(M3) which are: Adrenal medulla stimulation leads Adrenergic Sweat, Saliva, Lacrimal, crisis Bronchial, intestinal secretion. Exocrine glands

___ -CNS excitation M1

-Memory, arousal, attention and ____ analgesia M4+M5 CNS Parasympathetic Actions on Eye ● It innervates the constrictor pupillae (circular muscle of iris) which is important for adjusting the pupil in response to change in light intensity and regulating the intraocular pressure. ● Aqueous humor secreted by ciliary body is removed continuously by drainage into the canal of schlemm. ● Normal intraocular pressure: 10-15 mmHg above atmospheric pressure. Abnormal raised pressure (glaucoma) leads to retinal detachment. if the ciliary body is contracted the canal of schlemm will ● Cholinergic drugs leads to Miosis which decreases the open allowing the drainage of intraocular pressure in glaucoma by increasing the filtration fluid Ciliary muscle is contracted angle. Suspensory ligament is ● When the ciliary muscle contracts, the lens bulges more. relaxed. This parasympathetic reflex is essential to accommodate (Opposite action) for near vision. Direct Acting Cholinergic Drugs

Drug Type Natural Alkaloids Synthetic Choline Esters

● Are lipid soluble nitrogen ● Polar (contains N ion) nonpolar compound found in quaternary ammonium nature compounds Features ● Tertiary amines ● muscarinic quaternary amine less ● Common suffix (-ine) which completely absorbed from the GIT means natural and basic but still toxic when ingested in mushroom. Nicotine & lobeline has ● Pilocarpine ● Acetylcholine an alerting action on ● Carbachol Mnemonic: ● Nicotine the CNS Always Care Examples ● Bethanechol. ● Lobeline and high levels of Before Calling nicotine leads to ● Cevimeline convulsions and coma ● Methacholine 3X more resistant to hydrolysis

● Non-polar, lipid soluble ● Poor distribution ● Well absorbed by the skin. ● Cannot cross BBB so no CNS effects ● Pharmaco Not metabolized by kinetics cholinesterase EXCEPT Ach ● all of them have longer duration of action than Ach ● Never given I.V. or I.M. BUT S.C.

● Bronchial asthma (because asthmatics are already hyperresponsive to cholinergic agonist, giving cholinergic drugs may cause unwanted bronchoconstriction which leads to increased narrowing of airways). ● Peptic ulcer (M1 muscarinic agonists can stimulate gastric acid secretion from gastric parietal cells, thus intensifying the acidity and ulceration) ● Angina pectoris (Chest pain, mostly related to a coronary artery disease, muscarinic receptors are Contra- found on the SA node of the heart and slows heart rate when activated which can decrease the heart flow indications further than it already is) ● Urinary incontinence (inability to hold in urine, spontaneous urination) ● Intestinal obstruction (the treatment for intestinal obstruction is providing rest for its activities, muscarinic agonist increase its GIT motility and irritate the GIT even more in this case) Natural Alkaloids

Drug Pilocarpine

● Direct muscarinic agonist M.O.A ● Acts mainly on eye and secretion

● Non-polar (lipophilic) tertiary amine ● Well absorbed, good distribution ● Cross BBB, so has CNS effects P.K ● Cross placenta ● Not metabolized by cholinesterase because basic drugs ● Long duration of action are best excreted in ● Excretion is enhanced by acidification of urine acidic medium

● Xerostomia (dry mouth) Uses ● Drug of choice in emergency glaucoma (applied as eye drops)

● Profuse sweating ● Salivation Side ● Bronchoconstriction Effects ● Diarrhea ● CNS effects

Synthetic Choline Esters

Drug Acetylcholine Carbachol Bethanechol Cevimeline (Carbamoylcholine) (Carbamoyl-β-methylcholine)

Muscarinic and -Muscarinic action - Prominent muscarinic Direct acting nicotinic agonist on the eyes, GIT, actions on GI, UT. muscarinic agonist M.O.A UT. - No nicotinic actions (M3) due to the presence of a methyl -Has nicotinic group which reduces its potency actions (side effects) at nicotinic junctions.

-Resistant to -Resistant to hydrolysis - hydrolysis by by acetylcholinesterase - P.K acetylcholinestera -Longer duration than se Acetylcholine -Longer duration than Ach Not used clinically. Drug of choice in: treatment of the (Why?) -Paralytic ileus it’s a dry mouth -not as selective as post-operative side effect of the symptom anesthesia associated with it acts on both -Treatment of -Urinary retention in Sjogren’s muscarinic and glaucoma as eye case of postoperative syndrome Uses nicotinic receptors. drops only atony and neurogenic -Has short duration bladder. Sjogren’s syndrome: of action. Why? Due autoimmune disease to rapid metabolism characterized by formation of antibodies by leading to dryness of mouth (xerostomia) and acetylcholinesterase eye. Side Nicotinic side effects - effects - - Found in Male’s slides only

TOXICITY

muscarinic Nicotinic stimulants stimulants

CNS: Skeletal muscle CVS: -convulsions endplate Hypertension -Nausea -coma depolarization: and -vomiting -respiratory arrest depolarization block Cardiac -diarrhea respiratory paralysis arrhythmias -salivation -cutaneous vasodilation -bronchial constriction

TREATMENT:

● Muscarinic excess → atropine ● CNS stimulation → central anticonvulsants e.g. Diazepam ● Neuromuscular block → mechanical respiration

Chronic Nicotine toxicity:

● 30% of deaths due to cancer and coronary heart disease are due to smoking.

● Nicotine contributes to risk of vascular diseases, sudden coronary death and ulcers. Summary

Drug Acetylcholine Carbachol Bethanechol Pilocarpine (Carbamoylcholine) (Carbamoyl-β-methylcholine) quaternary quaternary quaternary tertiary Polar Polar Polar non Polar chemistry

NOT better absorbed than Ach complete absorption

metabolised by Not metabolised by cholinesterase cholinesterase metabolism

very short longer (++) duration

I.V eye drops oral, eye drops oral, S.C oral, eye drops administrati S.C on

direct Cholinomimetic

Drug Acetylcholine Carbachol Bethanechol Pilocarpine Cevimeline

muscarinic muscarinic muscarinic muscarinic muscarinic recepto nicotinic nicotinic rs

+++ muscari nic

NOT eyes, GIT, GIT, more on exocrine selectiv urinary urinary eyes, glands ity bladder bladder exocrine glands nicotini +++ NO c

NO Glaucoma paralytic ileus, Glaucoma sjogren’s uses urinary xerostomia syndrome retention QUIZ QUIZ

1. Nicotinic receptor - Muscarinic receptors

2.Increase in motility(peristalsis)-Increase in secretion Postsurgical -Relaxation of sphincter causes defecation.

3.Because they are not metabolized by Cholinesterase

4.Pilocarpine

5.eye drops

6. Is not selective as it acts on both nicotinic and muscarinic

receptors-Has short duration of actin.

7. 2 acetylcholine molecules

8.For dry mouth symptom associated with Sjogren’s syndrome

9.Bethanechol

10.No, it has quaternary structure that makes it polar. Thus can't cross the BBB.

11.Diarrhea,Bradycardia,Sweating & Salivation,Broncho-constriction GOOD LUCK

Team Leaders: Nouf Alshammari Zyad Aldosari

Team Members: Deana Awartani Reema Alserhani Najla Alkilani Njoud Almutairi Noura Almazrou Shahad alsahil Reema Almutawa Sources: Team 435 Shahad Althaqeb Team 437