PARASYMPATHETIC DRUGS

(Cholinomimetic Drugs)

. .

Objectives
1. Cholinoceptor-Activating Drugs 1.1 Direct-acting cholinergic receptor agonists 1.2 Indirect-acting cholinergic receptor agonists 2. Cholinoceptor-Blocking Drugs 2.1 Muscarinic-blocking drugs 2.2 Nicotinic-blocking drugs
2

1. Cholinoceptor-Activating Drugs

Cholinergic NT & Sites of Drug Action

All muscarinic receptors appear to be the GPCR type

+ PLCPIP2 IP3 & DAG cascade Ca+2 (smooth muscle) - AC cAMP K+ flux across cardiac cell membranes

Ex: Heart
ACh + M2R linked via Gi/o to a K+ channel hyperpolarization. Voltage-dependent opening of pacemaker Na current channels (If) is shifted to more negative potentials, and 5 2+ The phosphorylation of L-type Ca channels (ICa) is reduced.

Nicotinic agonist

Ex: NMJ ACh + NMR Na+ influx + EPSP (excitatory postsynaptic potential) EPSP depolarizes muscle membrane action potential + 6. muscle contraction

 Cholinoceptor Subtypes
Receptor Location Type M1 Nerves M2 Heart, nerves, smooth muscle Glands, smooth muscle, endothelium Neuromuscular junction CNS postganglionic cell body, dendrites

and Characteristics
Postreceptor Mechanism -IP3, -DAG cascade -Inhibition of cAMP production, -Activation of K+ channels -IP3, -DAG cascade Na+, K+ depolarizing ion channel Na+, K+ depolarizing ion channel

Structural Features Seven transmembrane segments, Gq/11 protein-linked Seven transmembrane segments, Gi/o protein-linked Seven transmembrane segments, Gq/11 protein-linked Pentamer Pentamer

M3

NM NN

1. Cholinoceptor-Activating Drugs
1.1 Direct-acting cholinergic receptor agonists
Directly bind to muscarinic and nicotinic receptors Types
1. Choline esters:

- Acetic acid esters: ACh, methacholine - Carbamic acid esters: carbachol, bethanechol 2. Plant alkaloids: pilocarpine, nicotine, lobeline

1.2 Indirect-acting cholinergic receptor agonists

Drugs that inhibit ChE: edrophonium, neostigmine

Drugs that augment effects of ACh: sildenafil (Viagra) 8

1.1 Direct-Acting Cholinergic Receptor Agonists

1.1.1 Chemistry & Pharmacokinetics: 1.1.1.1. Choline esters
Quaternary NH4-cpds poorly absorbed from GI tract & -/-> CNS ACh & carbachol activate both M & N receptors, Bethanechol activates only M receptors Due to non- specificity for M receptor subtypes wide range of effects on many organ systems ACh: choline ester of acetic acid, rapidly hydrolyzed by AChE extremely short duration Bethanechol & carbachol, choline ester of carbamic acid 9 resistant to AChE lasting for several hours

1.1.1.2. Plant Alkaloids: Muscarine,

found in mushrooms, can cause diarrhea, sweating, salivation & lacrimation, no medical use

Nicotine,
derived from Nicotiana plants & contains in cigarettes & tobacco products, use for smoking cessation

Pilocarpine,
is tertiary amine well absorbed, use as second-line drug for chronic glaucoma use for xerostomia (dry mouth), low dose,
oral pilocarpine stimulates salivary secretion (high sensitivity of salivary gland)

10

1.1.2 Drugs acting on muscarinic receptors

ANS Effects on Organs

11

Parasympathetic effects

Sympathetic effects

12

Pharmacologic effects (Most of direct organ system effects of M receptors)

CVS:- CO atrial contraction (negative inotropic effect ) HR (depress SA node, negative chronotropic effect)
(depress AV node, negative dromotropic effect)

- Vasodilation ACh ->+ endothelial cell -> Smooth muscle: - GI (colicky pain), - Bladder & bronchus (contraction) - Male (erection) Exocrine gland:

NO

- Sweating, lacrimation, salivation, and bronchial secretion

Eye: + Ciliary muscle: accommodation the eye for near vision + Iris muscle: adjust pupil size & regulate intraocular pressure 13

Structures of the anterior chamber of the eye

(Show ANS receptors)

Aqueous humor is secreted by the epithelium of the ciliary body ()

flows in front of the iris trabecular meshwork-->canal of Schlemm (arrow). Blockade of the adrenoceptors: - secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control 14 and influence aqueous drainage

Autonomic Effects on the Eye

( )

(M)

(M)

Suspensory ligament

( )

Iris; para+ constrictor muscle pupil size = miosis sym+ dilator muscle pupil size = mydriasis Ciliary muscle constrict relax suspensory ligament eye accommodation for near vision 15 Trabecular meshwork increase aqueous humour drainage

Effects of pilocarpine and atropine on the eye

A. Normal eye: Relationship B. Muscarinic agonist (:pilocarpine)
- iris sprincter contraction ->pupil constrict (miosis) - ciliary contraction -> relax suspensory ligament -> len thickness -> focus on close object.

between iris sprincter & ciliary muscle

C. Muscarinic antagonist (:atropine)

- iris sprincter relax ->pupil dilate (mydriasis) - ciliary muscle relax -> suspensory ligament contraction -> len thickness 16 -> blurred vision (cycloplegia).

Drugs that lower intraocular pressure

Muscarinic agonist Prostaglandins -antagonist & -agonist Carbonic anhydrase inhibitor

Muscarinic agonist(:pilocarpine)
ciliary muscle contraction open trabecular space drainage 17

Drugs that lower intraocular pressure

Drugs Pilocarpine Ecothiopate Timolol Mechanism Muscarinic agonist Anticholinesterase -Adrenoceptor antagonist Carbonic anhydrase inhibitor Notes Widely used as eye drops Widely used as eye drops Can cause muscle spasm & systemic effects Given as eye drops but may still cause systemic side effects: bradycardia, bronchoconstriction. Acetazolamide is given systemically. Side effects include diuresis, loss of appetite, tingling, neutropenia. Dorzolamide is used as eye drops. Side effects include bitter taste and burning sensation. Used as eye drops Can cause ocular pigmentation

Acetazolamide, dorzolamide

Clonidine, apraclonidine Latanoprost

2-Adrenoceptor agonist Prostaglandin analogue

18

 Effects of Direct-Acting Cholinoceptor Stimulants

Eye Heart

Organ

Sphincter muscle of iris Ciliary muscle Sinoatrial node Atria AV node Ventricles Arteries Veins

Blood vessels Lung

Bronchial muscle Bronchial glands GI tract Motility Sphincters Secretion Urinary bladder Detrusor Trigone and sphincter Glands Sweat, salivary, lacrimal, nasopharyngeal

Contraction (miosis) Contraction for near vision Decrease in rate (negative chronotropy) Decrease in contractile strength (negative inotropy). Decrease in refractory period Decrease in conduction velocity (negative dromotropy). Increase in refractory period Small decrease in contractile strength Dilation (via EDRF). Constriction (high-dose direct effect) Dilation (via EDRF). Constriction (high-dose direct effect) Contraction (bronchoconstriction) Stimulation Increase Relaxation Stimulation Contraction Relaxation Secretion 19

Response

Drug

Receptor specificity

Hydrolyzed by ChE Yes

Route of administration Intraocular

Clinical use Miosis during ophthalmic surgery Stimulate GI & bladder motility Glaucoma Miosis during ophthalmic surgery

Choline esters
Acetylcholine M & N

Bethanechol Carbachol

M M&N

No No

Oral, sc Topical ocular, Intraocular

Plant Alkaloids
Muscarine Nicotine Pilocarpine M N M>N No No No None Oral, transdermal Topical ocular, oral Smoking cessation Glaucoma, 20 xerostomia

1.1.3 1.1.3 Drugs Drugs Acting Acting on on Nicotinic Nicotinic Receptor Receptor : :Autonomic Autonomic ganglion ganglion & & NMJ NMJ
1.1.3.1 Drugs acting on autonomic ganglia: nicotine Stimulate both sym & parasym ganglia complex effects - tachycardia and - increase of blood pressure; - variable effects on GI motility and secretions; - increased bronchial, salivary and sweat secretions. Ganglion stimulation may be followed by depolarisation block. Nicotine also has important CNS effects. No therapeutic uses, (Except for nicotine to assist giving up smoking)

21

1.1.3.2 Drugs acting on neuromuscular junction (NMJ)

Acetylcholine (ACh)
ACh + Receptor (alpha site) Open Na ion channel Na+ influx Depolarization Muscle contraction

Succinylcholine (SCh or suxamethomium)

SCh + NMR (postsynaptic site) prolong depolarization unresponse to subsequent impulse neuromuscular block 22 = Depolarizing neuromuscular blocking agents

1.2 Indirect-acting cholinergic receptor agonists

1.2.1 Drugs that inhibit ChE 1.2.2 Drugs that augment effects of ACh 1.2.1 Drugs that Inhibit ChE (Anticholinesterase drugs) Cholinesterase: Two main forms of ChE: 1. Acetylcholinesterase (AChE)
: membrane-bound, specific for ACh
rapid ACh hydrolysis at cholinergic synapses

2. Butyrylcholinesterase
- non-selective

(BuChE or pseudocholinesterase)

- occurs in plasma and many tissues (liver), 23

Hydrolysis of ACh by AChE

(Rapid hydrolysis, 150 sec)

catalytic Anionic site site

1. N+ of ACh attracted to (-) anionic site ester portion of ACh close to catalytic site 2. The ester bond on ACh is cleaved, the enzyme is acetylated, & choline is released

24 3. Hydrolysis of the acetylated enzyme rapidly liberates the acetate free enzyme

Anticholinesterase drugs 1. Reversible binding slow hydrolysis

1.1 Short-acting: Edrophonium - Reversible binding to anionic site of ChE (~10 min) 1.2 Medium-acting: Physostigmine, neostigmine, pyridostigmine - All are ester of carbamic acid - Physostigmine, plant alkaloid with tertiary amine well absorbed & penetrates to CNS - Neostigmine & pyridostigmine, synthetic quaternary amine less absorbed, -/-> CNS

2. Irreversible binding very slow hydrolysis

- Organophosphates (:Echothiophate, isoflurophate, malathion) - Are ester of phosphoric acid, highly lipid soluble 25 well absorbed accidental poisoning

: Carbamates

(:neostigmine) formed carbamoylated enzyme slow hydrolysis

Reversible antiChE

Irreversible antiChE
: Organophosphates (:parathion) formed covalent bond very slow hydrolysis

(2-PAM)

26

Pharmacologic Effects of antiChE Drugs

cholinergic transmission at synapses

Autonomic actions:
-CVS: bradycardia, hypotension -RS: excessive secretions, bronchoconstriction -GI: gastrointestinal hypermotility -Eye: intraocular pressure
-muscle

Neuromuscular action:

CNS effects:

fasciculation and -can produce depolarisation block

- convulsion: physostigmine, organophosphates (antiChEs that cross BBB) - AntiChE poisoning may occur from exposure to insecticides or nerve gases

27

Clinical Uses of Anticholinesterases

1. Anaesthesia: neostigmine + atropine -to reverse action of non-depolarising
neuromuscular-blocking drugs

2. Myasthenia gravis

-to test : edrophonium

-treatment : neostigmine & pyridostigmine

3. Glaucoma
: ecothiopate (eye drops)

4. Alzheimers
:donepezil, galantamine, 28 rivastigmine

Anticholinesterase Drugs
Edrophonium Quaternary alcohol, Reversibly binds to anionic site on ChE, Short duration (~10 min) Diagnosis of muscle weakness in patients suspected of having Myasthenia gravis (MS) ( MS cholinergic crisis) MS, autoimmune disease, destroy nicotinic receptors severe fatigue, especially muscles of the face, throat, neck.

- (ptosis) (diplopia) - -
In excessive dose of ChE inhibitor cholinergic crisis muscle weakness 29

Physostigmine, Neostigmine & Pyridostigmine Ester of carbamic acid slow hydrolysis, duration 0.5-2 h Physostigmine -Tertiary aminewell absorbed & penetrates BBB - Use in the treatment of anticholinergic drug overdose
(atropine, phenothiazine, tricyclic antidepressant)

Neostigmine & Pyridostigmine, - Synthetic quaternary amine cpds absorbed -/-> BBB. - Clinical uses: - treatment of MS,
- antidote of nondepolarizing blocking agent - stimulate bladder & GI tract (SC)

Donepezil, galantamine, rivastigmine

Are centrally acting, reversible ChE inhibitors that readily cross BBB & increase brain ACh conc, treat Alzheimers disease

30

: Sildenafil (Viagra), Used in erectile dysfunction

Erection requires

1.2.2 Drugs that Augment Effects of ACh

relaxation of the nonvascular smooth muscle of the corpora cavernosa In response to the release of NO from NANC associated with parasympathetic discharge. Sildenafil cGMP (- phosphodiesterase isoform 5)

31

2. Cholinoceptor-Blocking Drugs
2.1 Muscarinic-Blocking Drugs
- Compete with ACh for M-receptors parasympatholytic drugs - Obtained from: - Plants (Belladonna alkaloids): atropine, scopolamine, hyoscyamine - Synthesis: ipratropium, dicyclomine, tropicamide, pirenzepine - Have similar effect, differ in pharmacokinetics & clinical uses

2.2 Nicotinic-Blocking Drugs

2.2.1 Ganglionic blocking agents 2.2.2 Neuromuscular blocking agents
- Nondepolarizing Neuromuscular blocking agents: Tubocurarine - Depolarizing Neuromuscular blocking agents: Succinylcholine

32

2.1 Muscarinic-Blocking Drugs Pharmacological effects (: atropine)

Secretion dry mouth HR tachycardia Eye mydriasis, cycloplegia, & intraocular pressure GI: GI motility & gastric acid secretion Relax smooth muscle: bronchial, biliary & urinary tract CNS: atropine + CNS

33

Dose Dependent Effect of Atropine

Low dose of atropine inhibits salivation & sweating, The effects are dose-dependent. Higher doses tachycardia, urinary retention & CNS effects

(Brenner 2006 p 66)

34

Clinical uses of muscarinic antagonists

-CVS : sinus bradycardia -Eye : dilate pupil -CNS : motion sickness (scopolamine), parkinsonism (benztropine, biperiden) -RS : asthma (ipratropium, used in combination with 2

agonists in the management of chronic asthma)

-GI anasethetic premedication (atropine) : antispasmodic peptic ulcer
35

Muscarinic-Blocking Drugs
Compound Atropine Pharmacological properties Non-selective antagonist Well absorbed orally CNS stimulant Clinical uses Adjunct for anaesthesia
(reduced secretions, bronchodilatation)

Notes Belladonna alkaloid Main side effects: urinary

AntiChE poisoning Bradycardia GI hypermotility (antispasmodic) As atropine Motion sickness Mainly for GI hypermotility

retention, dry mouth, blurred vision Dicycloverine, similar & used mainly as antispasmodic agent

Hyoscine (Scopolamine) Atropine methonitrate

Similar to atropine CNS depressant Similar to atropine but

Belladonna alkaloid Causes sedation; other side effects as atropine Quaternary ammonium derivative

poorly absorbed & lacks CNS effects

Significant ganglionblocking activity

lpratropium

Similar to atropine methonitrate Does not inhibit mucociliary clearance from bronchi Similar to atropine May raise intraocular pressure Similar to tropicamide Selective for M1 receptors Inhibits gastric secretion by action on ganglion cells Little effect on smooth muscle or CNS

By inhalation for asthma, bronchitis

Quaternary ammonium compound Tiotropium is similar

Tropicamide

Ophthalmic use to produce mydriasis and cycloplegia (as eye drops) Short acting As tropicamide (long acting) Peptic ulcer Fewer side effects than other muscarinic antagonists Largely superseded by other antiulcer drugs

Cyclopentolate Pirenzepine

36

2.2 2.2 Nicotinic-Blocking Nicotinic-Blocking Drugs Drugs : :Autonomic Autonomic ganglion ganglion & & NMJ NMJ
2.2.1 Ganglion-blocking drugs : Hexamethonium, trimetaphan Block all autonomic ganglia and enteric ganglia. Main effects: - hypotension and loss of cardiovascular reflexes, - inhibition of secretions, gastrointestinal paralysis, - impaired micturition. Clinically obsolete, except for occasional use of trimetaphan control hypotension in anaesthesia.

37

2.2.2 Neuromuscular-blocking drugs

Tubocurarine (nChR antagonist) - NMR at postsynaptic site -/-> depolarization neuromuscular block flaccid paralysis
= Non-depolarizing blocking drug

Succinylcholine (nChR agonist) + NMR (postsynaptic site) prolong depolarization unresponse to subsequent impulse neuromuscular block paralysis 38 = Depolarizing blocking agents

Drug Agonists
Nicotine Lobeline

Nicotinic receptor agonists and antagonists

Main site Type of action

Notes

Autonomic ganglia CNS Autonomic ganglia Sensory nerve terminals Epibatidine Autonomic ganglia, CNS Suxamethonium NMJ Decamethonium NMJ Antagonists Hexamethonium Autonomic ganglia Trimetaphan Autonomic ganglia Tubocurarine NMJ Pancuronium Atracurium NMJ Vecuronium

Stimulation then block No clinical uses Stimulation Stimulation Stimulation Stimulation Isolated from frog skin. Highly potent. No clinical uses Depolarisation block Used clinically as muscle relaxant Depolarisation block No clinical use Transmission block No clinical use Transmission block Blood pressure lowering in surgery (rarely used) Transmission block Now rarely used used as muscle relaxants in Transmission block anesthesia

39

Questions Questions

40