naglaa f. el- orabi , ph d, m sc, b sc department of pharmacology & toxicology,

PHL 315Pharmacology

IPart IINaglaa F. El-Orabi, Ph D, M Sc, B SC

Department of Pharmacology & Toxicology,College of Pharmacy,King Saud University, Riyadh, KSA

Cholinergic Transmission

References

“ Rang & Dale’s Pharmacology”6th ed.,

Rang HP, Dale MM, Ritter JM, Moore PK, eds. Elsevier Science, 2007. Chapter 10, page 144

Cholinergic transmission • An important traditional classification of

autonomic nerves is based on the primary neurotransmitter molecules released from their terminals into adrenergic and cholinergic.

• A large number of peripheral ANS fibers synthesize and release Ach; they are cholinergic fibers.

• These include all preganglionic efferent autonomic fibers (both sympathetic and parasympathetic).

• In addition, most parasympathetic and some sympathetic (to sweat glands) postganglionic fibers are cholinergic.

• Somatic (non-autonomic) motor fibers (NMJs) to skeletal muscle (motor end plates).

• Ach is also very important central NT.

Parasympathetic nervous syste (PSNS)

Anatomy• PSNS originates from cranio-sacral

parts of spinal cord.• Cranial outflow originate from cranial

nerve nuclei in the brain stem. Preganglionic fibers run via:

a)Oculomotor nerve (III)b)Facial nerve (VII)c)Glossopharyngeal nerve (IX)d)Vagus nerve (X)

• These nerve fibers innervate organs of the head & neck (eye, nasal mucosa, salivary glands,…), thorax & upper abdomen ( heart, respiratory system, esophagus, stomach, pancreas, liver, small intestine and upper half of the large intestine).

PSNS anatomy (cont.)• Sacral outflow originate from visceral motor region of

spinal cord (S2-S4). Preganglionic fibers run via pelvic nerves.

• These nerve fibers innervate organs of the pelvis and lower abdomen (lower half of large intestine, the rectum, urinary and reproductive systems)

• PSNS does not innervate most of blood vessels, sweat glands, adrenal medulla and arrector pili muscles.

• Parasympathetic pathway• Brain areas (hypothalamus & brain stem)• Cranial or sacral outflow• Relatively long pre-ganglionic neurons to terminal or

intramural ganglia (in walls of viscera, close to effector organs)

• Short post-ganglionic neurons.

PSNS anatomy (cont.)

• All Parasympathetic nerve fiber (both preganglionic postganglionic) are cholinergic, that is, they work by releasing ACh neurotransmitter.

• Acetylcholine is synthesized in the cytoplasm of neuronal cells from acetyl-CoA and choline through the catalytic action of the enzyme choline acetyltransferase (ChAT).

• Acetylcholine is then transported into the storage vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of Ca2+. The resulting increase in intracellular Ca2+ causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine into the junctional cleft and interact with postsynaptic receptors.

PSNSNeurotransmitters

• Acetylcholine's action is terminated by metabolic degradation by the enzyme acetylcholinesterase (AChE). AChE splits ACh into choline and acetate, neither of which has significant transmitter effect, and thereby terminates the action of the transmitter . Most cholinergic synapses are richly supplied with AChEs; the half-life of ACh in the synapse is very short (1-2 milliseconds).

• AChE is also found in other tissues, eg, RBCs. Another cholinesterase with a lower specificity for ACh, butyrylcholinesterase (pseudocholinesterase) , is found in blood plasma, liver, glia, and many other tissues. Little or no acetylcholine escapes into the circulation. Any acetylcholine that reaches the circulation is immediately inactivated by plasma esterases.

PSNS neurotransmitters (cont.)

Na+- CHT

ACETYLCHOLINE

ChAT

VAT

•Cholinergic receptors have two major families; nicotinic (nAChR) and muscarinic (mAChR) receptors. •Ach acts as specific agonist for both receptor subclass•In contrast, because of their unique configurations,Nicotine and Muscarine are selective for the cholinergic receptor subtypes whose structure complements their own.

Cholinergic receptors

http://en.wikipedia.org/wiki/File:Muscarine.svg

http://en.wikipedia.org/wiki/File:Nicotine.svg

(a) Muscarinic receptors • mAChRs are G-protein-coupled

receptors causing: • activation of PLC (hence ↑IP3,

DAG as 2nd messengers) • inhibition of adenylyl cyclase

(↓cAMP)• activation or inhibition of ion (K+

& Ca2+ ) channels . • mAChRs mediate ACh effects at

postganglionic parasympathetic synapses (mainly heart, smooth muscle, glands), and contribute to ganglionic excitation. They occur in many parts of the CNS.

• Five main types of mAChR occur (M1-5).

• All mAChRs are activated by acetylcholine and blocked by atropine. There are also subtype-selective agonists and antagonists.

Muscarinic receptors (cont.)

Receptortype

Location MOA Functional response

M1(neuronal)

Autonomic ganglia, Glands , CNS (cerebral cortex)

Stimulatory (↑IP3, DAG, ↑intracellualr Ca2+)

CNS excitation (?memory) Gastric secretion

M2(cardiac)

Myocardium, smooth muscles, some in CNS

Inhibitory (↓cAMP, ↓K+ & Ca2+

conductance)Cardiac inhibitionNeural inhibitionCentral muscarinic effects (e.g. tremor, hypothermia)

M3(glandular , smooth muscles)

Exocrine glands , Smooth muscle (GIT, eye, airways, bladder)Vessels endothelium,

Stimulatory (↑IP3, ↑intracellualr Ca2+)

Gastric, salivary secretion GI smooth muscle contraction Ocular accommodation Vasodilatation

M4 CNS Inhibitory (↓cAMP) Enhanced locomotion

M5 CNS: very localised in substantia nigra,Salivary glands, Eye(Iris/ciliary muscle)

Stimulatory (↑IP3 Excitation) Not known

(b) Nicotinic receptors • nAChRs are directly coupled

to cation channels (like Na+/K+ channels), and mediate fast excitatory synaptic transmission at the neuromuscular junction (Skeletal muscles), autonomic ganglia, and various sites in CNS.)

• Muscle (Nm) and neuronal (Nn) nAChRs differ in their molecular structure and pharmacology.

• mAChRs and nAChRs occur presynaptically as well as postsynaptically, and function to regulate transmitter release.

Receptortype

Location MOA Functional response

Nn Post ganglionic neurons, adrenal medulla

Opening of Na+, K+ channels, depolarization

Excitation of autonomic gangliaStimulate Epi, NE from adrenal gland

Nm Skeletal muscle neuromuscular endplates

Opening of Na+, K+

channels, depolarization

Skeletal muscle contraction

Nicotinic receptors (cont.)

(α1)2β1δγ

http://en.wikipedia.org/wiki/File:Acethylcholine_receptor_blocked_by_cobra_venom.png

Physiological actions of muscarinic stimulation

Organ Receptor Action

Eye

Circular muscle of the iris

M3 Contracts(miosis)

Ciliary muscle

M3 Contracts

Heart

SA node M2 SlowsMyocardium (Atrium & ventricles)

M2 Negative inotropic (Reduced contractility) action (more in atria) and negative chronotropic action

AV node M2 Reduced conduction velocity

Blood vessels Endothelium

M3 Vasodilatation

GIT

Smooth muscle walls

M3 Contraction ( motility)

Sphincters M3 RelaxGlands M3 SecretionGallbladder

M3 Contraction

Organ Receptor Action

BronchiSmooth muscles

M3 Contraction

Glands M3 Secretion

Urinary bladder

Wall (detrusor)

M3 Contracts

Trigone sphincter

M3 Relax

Pregnant uterus M3 ContractsPenis and clitoris M3 Erection Glands (Salivary,

Lacrimal, Nasopharyngeal , vaginal lubrication& Sweat ; symp. Cholinergic)

M3 Secretion

Physiological actions of muscarinic stimulation (cont.)

Modifying Autonomic Nervous System Function

Parasympathomimetics = Cholinoceptor stimulants: bind to acetylcholine receptors (Muscarinic & Nicotinic) and stimulates them or enhance cholinergic transmission by other mechanism:

Muscarinic agonists (stimulants) Anticholinesterases and other drugs that enhance

cholinergic transmission. Ganglion-stimulating drugs Parasympatholytics (cholinergic antagonists –

anticholinergic drugs): bind to acetylcholine receptors and reduce the effects of parasympathetic stimulation by preventing endogenous acetylcholine from binding to them:

Muscarinic antagonists ganglion-blocking drugs Neuromuscular-blocking drugs

Na+- CHT

ACETYLCHOLINE

ChAT

VAT

Muscarinic antagonists

Na+- CHT

ACETYLCHOLINE

ChAT

VAT

Parasympathomimetics (Muscarinic receptor stimulants)

Cholinoceptorstimulants

Direct

Choline Esters

Cholinomimetic alkaloids

Indirect

Cholinesterase inhibitors

Direct cholinoceptor stimulants

Choline esterse.g. Acetylcholine, Methacholine, Carbachol and Bethanechol

Colinomimetic alkaloidse.g., Muscarine, Oxotremorine and Pilocarpine• Many of these muscarinic agonists are

used as experemintal tools.• Use of muscarinic receptor agonists, is

contraindicated in patients with asthma, coronary insufficiency and peptic ulcers

Direct cholinoceptor stimulants (cont.)1- Bethanechol (Urecholine®)

• Selectively stimulates muscarinic receptors (with further selectivity for M3 receptors)

• Unlike acetylcholine, bethanechol is not hydrolyzed by cholinesterase and will therefore have a long duration of action

• Clinical uses:1. To assist bladder emptying in non-obstructive urinary retention resulting from general anesthetic or diabetic neuropathy of the bladder

2. To treat gastroparesis (delayed gastric emptying), because it stimulates GI motility and secretion

3. To stimulate salivary gland secretion in patients with xerostomia (dry mouth, nasal passages, and throat)

Bethanechol (cont.)

Side Effects associated with bethanechol therapy:

1.Abdominal cramps or discomfort2.Nausea and diarrhea3.Excessive salivation4.Hypotension and bradycardia5.Urinary urgency6.Bronchial constriction and asthmatic attacks

Direct cholinoceptor stimulants (cont.)1- Pilocarpine (Salagen®)

Indications: It is more commonly used than bethanechol to induce salivation, and also for various purposes in ophthalmology. 1.Treatment of primary or acute

glaucoma and also to lower IOP prior to surgery for acute glaucoma by local instillation in the form of eye drops.

2. Treatment of symptoms of dry mouth from salivary gland hypofunction caused by radiotherapy for cancer of the head and neck (xerostomia )

Pilocarpine(cont.)

Side Effects associated with pilocarpine therapy: Most of them are related to its non-selective action as a muscarinic receptor agonist

1.Excessive sweating2.Excessive salivation3.Bronchospasm and increased bronchial mucus

secretion4.Bradycardia, hypotension5.Nausea and diarrhea6.It may result in miosis when used chronically as

an eye drop

Muscarinic effects on the eye

Normal:Ciliary Muscle Relaxed

Suspensory Ligaments Under TensionLens is Flattened

Focus on Distant Objects

Accommodation:Ciliary Muscle Contracts

Reduced Tension on Suspensory LigamentsLens becomes Round

Focus on Near Objects

• The smooth muscles of the iris:

• The sphincter muscle is innervated by M3 receptors. Its contraction under the influence of muscarinic agonist (e.g. pilocarpine) results in miosis, and its blockade by muscarinic antagonist (e.g. atropine) results in mydriasis.

• On the other hand, the radial muscle is innervated by α-1 receptor. Its contraction by an agonist results in mydriasis and its blockade results in miosis.

Sphincter muscle

Radialmuscle

Muscarinic effects on the eye (cont.)

Glaucoma • Glaucoma is an eye disorder in which the

optic nerve suffers damage, permanently impacting vision in the affected eye(s) and progressing to complete blindness if untreated.

• It is often associated with increased pressure of the aqueous humour in the eye (Intraocular pressure “IOP”).

• The aqueous humour is a thick watery substance filling the space between the lens and the cornea. It is rich in amino acid, glucose, antioxidants , and immunoglobulins. Its main role to maintains IOP and keep the eyes slightly distended. In addition to providing nutrition and protection for the occular tissues

• Aqueous humour is secreted into the posterior chamber by the ciliary body epithelium, it flows in through the pupil to the anterior chamber, and then to drain out of the eye via Schlemm's canal into the veins of the orbit.

http://en.wikipedia.org/wiki/File:Schematic_diagram_of_the_human_eye_en.svg

Drug Mechanism NotesEcothiopate,Pilocarpine,Physostigmine

Cholinomimetics

work by contraction of the iris sphinctr muscle (miosis) and ciliary muscl that tightening the trabecular meshwork and allowing increased outflow of the aqueous humour. Widely used as eye drops. Can cause muscle spasm and systemic effects.

Timolol, carteolol

β-Adrenoceptor antagonist

decrease aqueous humor production by the ciliary body epithelium. Given locally as eye drops but may still cause systemic side effects: bradycardia, bronchoconstriction.

Acetazolamidedorzolamide

Carbonic anhydrase inhibitor

lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body epitheliumAcetazolamide 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.

BrimonidineClonidine, apraclonidine

α2-Adrenoceptor agonist

work by a dual mechanism, decreasing aqueous humor production and increasing trabecular outflow. Used locally as eye drops

Pratanoprost, Travoprost

Prostaglandin analogue

Increase aqueous humor outflow. Given locally as eye drops. Can cause ocular pigmentation

Glaucoma (cont.)

Parasympathomimetics (Muscarinic receptor stimulants)

Cholinoceptorstimulants

Direct

Choline Esters

Cholinomimetic alkaloids

Indirect


Indirect cholinoceptor stimulants• Drugs that enhance cholinergic

transmission act either by inhibiting cholinesterase or by increasing ACh release.

• Example of drugs that enhance cholinergic transmission via increase of Ach release:

- Aminopyridines, which block K+ channels and thus prolong the action potential in the presynaptic nerve terminal.

- This drug are not selective for cholinergic nerves but increase the evoked release of many different transmitters, so have too many unwanted effects to be useful in treating neuromuscular disorders.


• Indirect-acting agents produce their primary effects by inhibiting acetylcholinesterase, which hydrolyzes acetylcholine to choline and acetic acid by forming a complex with acetylcholinesterase enzyme .By inhibiting acetylcholinesterase, the indirect-acting drugs increase the endogenous ACh concentration in synaptic clefts and neuroeffector junctions. The excess ACh, in turn, stimulates cholinergic receptors to evoke increased responses. These drugs act primarily where ACh is physiologically released and are thus amplifiers of endogenous ACh.

• Some cholinesterase inhibitors also inhibit butyrylcholinesterase (pseudocholinesterase).

• The inhibitory effect of anticholinesterases may be:

• Reversible: as that produced by edrophonium, pyridostigmine, physostigmine (eserin) or neostigmine

• Irreversible: such as echothiophate and malathion (orgonophosphorus compounds).

Cholinesterase inhibitors (Cont’d)

Alcohols Carbamic acid esters Organophosphates1- Edrophonium 1- Neostigmine

2-Pyridostigmine2- Physostigmine (eserine)

1- Echothiophate2-Isoflurophate, 3-Soman, 4-Parathion,5- Malathion 6- Dyflos

The action of the drug is very brief. It is used mainly for diagnostic purposes (myasthenia gravis )

Neostigmine is not absorbed and does not enter CNSPhysostigmine is absorbed from all sites including conjunctiva and enters CNS

All organophosphorous compounds are well absorbed from all sites of administration and enter the CNS except echothiophateMost of these compounds developed as war gases and pesticides as well as for clinical use.

Reversible inhibition after 2-10 min (short-acting anticholinesterases)

Reversible inhibition after 30 min to 6 hours (intermediate-acting anticholinesterases)

Irreversible inhibition (can be reversed by pralidoxime)


Pharmacological effects:CNS Tertiary compounds, such as physostigmine, and the non-polar

organophosphates penetrate BBB and affect the brainLow concentrations cause alertness. High concentrations cause initial stimulation and convulsions followed by depression coma.

Autonomic cholinergic synapses:(Eye, GIT, Bronchioles, and urinary bladderCardiovascular system, glands…etc)

Increased secretions from salivary, lacrimal, bronchial and gastrointestinal glands; increased peristaltic activity; bronchoconstriction; bradycardia and hypotension; pupillary constriction; fixation of accommodation for near vision; fall in intraocular pressure.Acute anticholinesterase poisoning causes severe bradycardia, hypotension and difficulty in breathingNeostigmine and pyridostigmine tend to affect neuromuscular transmission more than the autonomic system, whereas physostigmine and organophosphates show the reverse pattern.

Neuromuscular junction

Therapeutic doses increases strengh of contractionIn large doses, such as can occur in poisoning, anticholinesterases initially cause muscle twitching and fibrilation. Later, paralysis may occur due to depolarisation block, which is associated with the build-up of ACh in the plasma and tissue fluids.


Therapeutic uses:Disease Mechanism of action Drug

1- Glaucoma Contraction of the ciliary muscle and circular sphinctor muscle of the iris that increasing the outflow of the aqueous humor

Physostigmine echothiophate(as eye drops)

2- Postoperative To reverse the action of non-depolarising neuromuscular-blocking drugs. neostigmine

3- Urinary retention Non-obstructive urine retention neostigmine4- Myasthenia gravis a-treatment

neostigmine, pyridostigmine

b-test for myasthenia gravis

and to distinguish weakness caused by anticholinesterase overdosage ('cholinergic crisis') from the weakness of myasthenia itself ('myasthenic crisis'):

edrophonium

5- Dementia like Alzheimer's dieases

cholinesterase inhibitors may act to reduce neurotoxicity by inhibiting formation of Aβ, and therefore the progression of AD as well as producing symptomatic benefit

donepezil, tacrinerivastigmine and galantamine


Toxicity:Acute toxicity (cholinergic crisis): Treated by atropine and pralidoximeA- miosis, nausea, vomiting, diarrhea, salivation,

sweating, lacrimation cutaneous vasodilation, and bronchial constriction and excessive urination

B- These manifestations are followed by:central stimulation, which cause convulsions and

may progress to coma and respiratory arrest; skeletal muscle paralysishypertension and cardiac arrhythmias.


Ganglion Stimulants

• Autonomic ganglia (both sympathetic and parasympathetic) and neuromuscular junctions contain nAChRs (Nn and Nm respictively). Most nAChR agonists affect both ganglionic and neuromuscular junction receptors.

• Nicotine (at low conc), lobeline, Tetramethylammonium (TMA) and dimethylphenylpiperazinium (DMPP) affect ganglionic receptors preferentially.

• Nicotine and lobeline are tertiary amines found in the leaves of tobacco and lobelia plants

• Nicotine is the most commonly encountered nicotinic agonist

• It has Biphasic action on ganglionic nAChR• Stimulates at low doses• Stimulates then blocks at high doses

• Nicotine works in both PNS and CNS .

• One of the most toxic effects is the dependence-producing psychoactive compounds overall

Ganglion Stimulants (cont.)

Pharmacological actions of nicotine:Nicotine has a complex effect in autonomic

gangliaA- At low dosages it stimulates ganglionic

nAChRs ( causing marked activation and initiation of action potentials in postganglionic neurons) thus enhancing both sympathetic and parasympathetic neurotransmission

The initial response therefore often resembles simultaneous discharge of both the parasympathetic and the sympathetic nervous systems

- Regarding CVS, the effects of nicotine are chiefly sympathomimetics (increased HR, force of contraction and vasoconstriction)


- In the GI, glands and urinary tracts, the effects are largely parasympathomimetic (Increased tone, motility and secretions of the GIT, increased bronchial, salivary and sweat secretions, and also urinary outflow).

B- As nicotine dosages increase, nicotine possesses some antagonist effect at nicotinic receptors.Prolonged exposure results in depolarizing blockade of the ganglia (initial increase then decrease in HR, vasodilation )


• Nicotine have the ability to cross the BBB and affects CNS (especially brainstem and cortex)

• It cause initial stimulation followed by depression upon increasing the dose.

• Nicotine may induce tremor, vomting, and stimulation of the respiratory center. At still higher levels, nicotine causes convulsions, which may terminate in fatal coma

• Nicotine is one of the most dependence-producing drugs.


• Most of ganglion stimulants are not used clinically, but only as experimental tools.

• Only nicotine is used clinically in the form of transdermal patches, gums, SL tablets which is used as an aid to smoking cessation.


Anticholinergic drugs

Muscarinic blockers

Nicotinic blockers

Selective

Non-selective

Neuromuscular blockers

Ganglionic blockers

1- Muscarinic blockers Parasympatholytics

• Muscarinic receptor antagonists• Muscarinic receptor antagonists are competitive

antagonists whose chemical structures usually contain ester and basic groups in the same relationship as ACh.

• Two main subgroups of muscarinic antagonists ar erecognized:

• 1- Naturally occurring (non-selective) compounds: most of these compounds are alkaloids found in solanaceous plants like Atropa belladonna and Datura stramonium, e.g. atropine, hyoscine (scopolamine).

• 2- Synthetic (more selective) derivatives of atropine: like Ipratropium (broncheal muscles), Cyclopentolate (eye), Oxybutynin (urinary bladder) , and Pirenzepine (M1-selective).

1-Atropine• Atropine is an alkaloid derived from the plant

• Atropa belladonna.• It is act as non selective competitive

inhibitor of Ach on muscarinic receptors both peripherally and centrally.

Pharmacokinetics:• It is a tertiary ammonium, lipid-soluble

compound that is readily absorbed from the GIT or conjunctival sac and cross BBB.

• Metabolized in the liver, excreted in urine. • It Has short duration of action on most

organs except eye

Pharmacological effects:Effects on CNS

• Atropine produces mainly excitatory effects on the CNS.

• At low doses, this causes mild restlessness.• higher doses cause agitation and disorientation.• In atropine poisoning, marked excitement , irritability,

hyperactivity and a hyperthermia. These central effects are the result of blocking mAChRs in the brain, and they are opposed by anticholinesterase drugs such as physostigmine, which is an effective antidote to atropine poisoning.

Atropine (cont.)

Atropine pharmacological effects (cont.)

• Atropine also affect the extrapyramidal system, reducing the involuntary movement and rigidity of patients with Parkinson's disease and counteracting the extrapyramidal side effects of many antipsychotic drugs.

Effects on cardiovascular system A- Heart:- Initial bradycardia (central) followed by tachycardia ( peripheral M2 blockade ).- ↑ AV conduction ( + ve chronotropic effect ). B- Blood vessels:- Most of resistance vessels have no cholinergic

innervation (arterial blood pressure is unaffected). - ↓ Vasodilatation induced by cholinomimetics. At relatively high dose, atropine produces cutaneous

vasodilatation (atropine flush).


Effects on gastrointestinal tract

- Relaxation of smooth muscles (constipation).

- ↓ GIT tone and motility → Antispasmodic effect. This requires larger doses of atropine.

- ↑ Sphincter contractions.-↓ Gastric secretion


Effects on secretions– ↓ Salivary secretion → ( Dry mouth ).– ↓ Sweating → Dry skin → Fever in

infants– and children.– ↓Bronchial secretion → ↑ Viscosity.

Mucociliary clearance in the bronchi is inhibited, so that residual secretions tend to accumulate in the lungs

– ↓ Lacrimal secretion → Sandy eye.


Effects on the eye‐ The pupil is dilated (Passive mydriasis) ,due to

paralysis of circular muscle ‐ Cycloplegia (loss of accommodation for near

vision) , due to paralysis of ciliary muscle. ‐ Loss of light reflex (eye pupil becomes

unresponsive to light). ‐ It increase IOP, this is unimportant in normal

individuals, it can be dangerous in patients suffering from closed-angle glaucoma. .


Effects on other smooth muscle• Bronchial smooth muscles are relaxed by atropine

(broncheodilation) and bronchial secretions are decreased.

• Reflex bronchoconstriction (e.g. during anaesthesia) is prevented by atropine (preanaestetic medication).

• Biliary smooth muscles are relaxed by atropine (management of bilary colic)

• Urinary tract smooth muscles are relaxed by atropine

- Relaxation of the ureter and bladder smooth muscles

- Contraction of sphincter (urinary retention)


Atropine (cont.)Clinical uses:1. preanesthetic medication to : -↓ salivary & bronchial secretion and inhibit reflex

bronchoconstriction - Protect the heart from excessive vagal tone. 2. Antispasmodic in renal , bilary, and intestinal

colics.3. It is also useful in the treatment of peptic ulcer

(decrease gastric secretions).4. antidote in cholinomimetic or organophosphorous

poisoning. 5. Treatment of sinus bradycardia after myocardial

infarction(to prevent vagal discharge).6. Ophthalmic administration is used for producing

mydriasis. This helps in fundus examination

Atropine (cont.)

Adverse effects• Blurred vision • Tachycardia and rapid pulse• Urinary retention (especially in eldry)-

Constipation.• Dryness of mouth , Sandy eye• Hyperthermia ,especially in children, and

Atropine flush.• Hallucination, excitationan, restlessness,

confusion and disorientation (Toxic dose). Physostigmine is the antidote in case of atropine poisoning.

2- Hyoscine (Scoplamine)Pharmacological effects:• Scoplamine Like atropine, possesses strong

antimuscarinic actions.• It is more potent than atropine in producing

mydriasis , cycloplegia, and a decrease in bronchial, salivary, and sweat gland secretions.

• It is less potent than atropine in its cardiac, bronchial muscles, and intestinal effects.

• Atropine has a longer duration of action, than scopolamine.

• In therapeutic doses , it causes marked CNS depression and sedation, but has similar effects to atropine in high toxic doses.

• It also has a useful antiemetic effect (CTZ) and is used in treating motion sickness.

Therapeutic uses:• Preanesthetic medication • Antiemetic action (Motion sickness) by oral

orTD patchs.• To facilitate endoscopy and GIT radiology by

relaxing GIT smooth muscle (spasmolytic) Side effects:• Similar to those of atropine.

2- Hyoscine (Scoplamine)

3- Synthetic atropine dreivatives

These drug are more selective than atropine and mostly have minimal effects on CNS. They are classified according to tissue selectivity and clinical uses.

M1 Muscarinic Receptor Antagonists: e.g. Pirenzepine and Telenzepine. They are

useful for treatment of peptic ulcerM3 muscarinic Receptor Antagonists: e.g. Oxybutynin, tolterodine and

darifenacin . They are new drugs that act on the bladder to inhibit micturition, and are used for treating urinary incontinence and urinary colics.

Antimuscarinic drugs for ophthalmic applications:

e.g. Cyclopentolate and Tropicamide. They mostly used to dilate the eye pupil for funduscopic examination of the eye. They shorter duration of action than atropine (12hrs, 6 hrs and 5-7 days).

Antimuscarinic drugs for antispasmodic effects:

e.g. Dicyclomine, Oxyphencyclimine, Propantheline,

Glycopyrrolate , and Hyoscine-butylbromide (Buscopan) . They are useful for spasms of the GIT, bilary duct, ureters, especially in those severe conditions as an irritable bowel syndrome, billary or uretheral stones


Antimuscarinic drugs for treatment of neurological disorders :

e.g. Benzhexol, Benztropine. They are mostly used in management of movement disorders associated with Parkinson’s disease and extrapyramidal side effects of antipsychotic drugs.

Antimuscarinic drugs for treatment of respiratory disorders :

e.g. Ipratropium and Tiotropium. They are mostly used in treatment of asthma and COPD. Taken by inhalation as aerosol to produce bronchodilation and decrease bronchial secretions.


• Compounds like• - Quaternary ammonium compounds

e.g. Hexamethonium, tetraethylammonium, tubocurarine

• - Amines (secondary/tertiary)• e.g. Mecamylamine, Pempidine• - Monosulfonium compound• e.g. Trimethaphan

• - and nicotine (at high concentration) have the ability to block the autonomic ganglia.

• Ganglionic blockers reduce transmission in all autonomic ganglia, both sympathetic and parasympathetic

2- Nicotinic blockers

A- Ganglion blockers

Pharmacological effects:• In some sites, sympathetic activation seems to

predominate over parasympathetic, while in other sites, the opposite is true

• Ganglionic blockade thus "covers" the predominant system

Ganglion blockers (cont.)

Effects of Ganglionic Blockade on Organ SystemsORGAN DOMINANT TONE Effect of ganglionic blockade

HEART Para-sympathetic Tachycardia (palpitation)BLOOD VESSELS Sympathetic Dilatation, abolition of

reflexes, syncope, hypotensionIRIS Para-sympathetic Mydriasis (photophobia)

CILIARY MUSCLES Para-sympathetic Cycloplegia (blurring of near vision)

INTESTINES Para-sympathetic Hypomotility (constipation)

BLADDER Para-sympathetic ↓ tone (difficulty in micturition)

MALE SEXUAL FUNCTION Para-sympathetic Inhibition of erectionAnd ejaculation (Impotence)

SALIVARY GLANDS Para-sympathetic Inhibition of watery salivation (dry mouth or xerostormia)

SWEAT GLANDS Sympathetic (cholinergic) Inhibition of sweating (anhydrosis)

• In practice, the CVS effects are the most important ones:

- A marked fall in arterial blood pressure results mainly from arteriolar vasodilatation.

- Most cardiovascular reflexes are blocked. In particular, the venoconstriction, which occurs normally when a subject stands up, and which is necessary to prevent the central venous pressure from falling sharply, is reduced. Standing thus causes a sudden fall in cardiac output and arterial pressure (postural hypotension) that can cause fainting or even shocking.

- Similarly, the vasodilatation of skeletal muscle during exercise is normally accompanied by vasoconstriction elsewhere (e.g. splanchnic area) produced by sympathetic activity. If this adjustment is prevented, the overall peripheral resistance falls and the blood pressure also falls (postexercise hypotension).


Therapeutic Uses:

Use of the ganglion blockers is infrequent due to many severe side effects accompanied with.

Mecamylamine is being studied for possible use in reducing nicotine craving in patients attempting to quit smoking.



Trimethaphan is a very short- acting drug that can be administered as an IV infusion in certain anaesthetic procedure to control blood pressure during anaesthesia.

Also, used to minimize bleeding during certain kinds of surgery.

Trimetaphan can also be used in the treatment of hypertensive emergencies and during electroconvulsive therapy.

Side effects

•Orthostatic hypotension

•Blurred vision

•Urinary retention, constipation

•Sexual impotence


B- Neuromuscular blockers• Neuromuscular junction (NMJ) is the junction of the nerve terminal of a motor neuron with the motor end plate (skeletal muscle fiber).

• Skeletal muscle relaxants: are groups of drugs which affects skeletal muscle function and decreases the muscular tone. It includes two categories of drugs, spasmolytics and neuromuscular blockers.

Neuromuscular blockers

(Peripherally-acting sk. Muscle

relaxants)

Skeletal muscle

relaxants

Spasmolytics(Centerally-acting sk.

Muscle relaxants)

Neuromuscular blockers (cont.)• Spasmolytics are a group of drugs was traditionally know as “centrally-acting skeletal muscle relaxants”. However, at least one of these agents (dantrolene) has no significant central effects.

• Spasmolytic drugs are used in the treatment of muscle spasm and immobility associated with strains, sprains, and injuries of the extremities, back and neck. In addition to their usage to alleviate painful muscular spasm associated with many neuropathological disorders.

• They have a diverse mechanisms of action, but they are not directly affect transmission within motor end plates.

• Guaifenesin , Chlordiazepoxide ,Baclofen , Chlorphenesin, and Dantrolene are examples of spasmolytics

Neuromuscular blockers (cont.)• Neuromuscular blockers are group of drugs act peripherally post-synaptically on motor end plate to interfere with transmission at muscular nicotinic receptors (NmAChRs). They lack any CNS effects and may share some charecterestics with autonomic ganglionic blockers.

• They are used mainly to produce a certain level of muscle paralysis for patients requiring ventilatory assistance during surgical procedures and in intensive care units.

• Two different kinds of functional blockade may occur at the neuromuscular endplate, and hence clinically used drugs fall into two categories

Competitive neuromuscular blockers

These group of drugs act as competitive antagonists with Ach at the site of NmAChRs.

No depolarization of postjunctional membrane.

Cholinesterase inhibitors (like neostigmine) can reverse this blockade.

Examples: d-tubocurarine, Gallamine, Atracurium, Pancuronium, Vecuronium, and Mivacurium

Nicotinic receptorNMJ

TAch

Ion channel

Competitive neuromuscular blockers (cont.)

Pharmacokinetic aspects :• Competitive neuromuscular-blocking agents are

used mainly in anaesthesia to produce muscle relaxation. They are given intravenously (inactive when used orally)

• Most of the non-depolarising blocking agents are metabolised by the liver or excreted unchanged in the urine. With exceptions being atracurium, and mivacurium, which are hydrolysed by plasma pseudocholinesterase.

• Their duration of action varies between about 15 minutes and >2 hours , by which time the patient regains enough strength to cough and breathe properly, although residual weakness may persist for much longer.

Pharmacological actions:• Skeletal muscle relaxation is the main

pharmacological effect. This effect is mainly due to motor paralysis. The first group of muscles to be affected are the extrinsic eye muscles (causing double vision) and the small muscles of the face, limbs and pharynx area (causing difficulty in swallowing).

• Respiratory muscles are the last to be affected and the first to recover.


Unwanted side effects:1- Hypotension is the main side effect many competitive

NMBs (d-tubocurarine, atracurium and mivacurium), this happened mainly due to ganglion block effect (d-tubocurarine).

2- Also, stimulation of histamine release from mast cells which can help in reduction of arterial BP and also give rise to bronchospasm in sensitive individuals. Gallamine and pancuronium lack these side effects.

3- Gallamine, and pancuronium, block mAChRs, particularly in the heart, which results in tachycardia.

Anticholinesterase drugs (e.g. neostigmine) are very effective in overcoming the blocking action of competitive agents.



d-Tubocurarine (curare): It is a plant alkaloid that has slow onset of action (> 5 min) and longer duration(1-2 h). It also affect autonomic aganglia.

The main side effects is Bronchoconstriction and hypotension. In addition to other side effects related to its ganglion blocking activity ( blurred vision , urine retention , conistipation and male impotence)

D-tubocurarine

Gallamine (Flaxedil): It is synthetic compound has less

potent NM blocking activity than curare ( 1/5 potency)

It has shorter onset (2-3 min) and longer duration ( > 2h) than d-tubocurarine.

It is execreted unchanged mainly by kidney. It is contraindicated in renal failure

Main side effect is “tachycardia” due to an atropine-like action and stimulation of NA release from adrenergic nerve endings.


Gallamine

Atracurium: It has similar potentency as curare (1-1.5 times) with

intermediate onset (2-3 m) and intermediate duration (< 30 min)

It has unusual mechanism of elimination (spontaneous non-enzymaic hydrolysis in plasma at body pH); degradation slowed by acidosis.

It is widely used especially in liver failure & kidney failure

The main side effects is the transient hypotension (due to histamine release), but has no effect on muscarinic receptor nor ganglia.


Mivacurium: It is new drug that is chemically-related to

atracurium. It has Fast onset (∼2 min) and short duration (∼15 min).

It is metabolized by plasma pseudocholinesterases (Longer duration in patient with liver disease or genetic cholinesterase deficiency).

Transient hypotension is the main side effect.


Competitive neuromuscular blockers (cont.) Pancuronium: It is the first steroid-based

compound that is more potent than curare ( 6 times ). It has Intermediate onset (2-3 min) and slight long duration (>2h)

Excreted mainly by the kidney ( 80 % ).

Tachycardia is the main side effect (due to an atropine-like action and stimulation of NA release from adrenergic nerve endings).

Pancuronium

Competitive neuromuscular blockers (cont.) Vecuronium: It is more potent NMBs than curare (6times) with

Intermediate onset (2-3 min) and Intermediate duration (30-40 min)

It is metabolized mainly by liver. Its metabolites have some activity. It has few side effects (no histamine release, no ganglion block and no antimuscarinic action). Occasionally causes prolonged paralysis, probably owing to active metabolite

It is widely used.

Depolarizing neuromuscular blockers This group of NMBs have the ability to combine with NmAChRs and stimulate motor end plates by initiation of membrane depolarization This initial depolarization is accompanied by transient twitching of the skeletal muscle (fasciculation) Phase I (phase of initial depolarization).

Phase I block is augmented not reversed by anticholinestrases.

• Continuous exposure to depolarizing NMBs (not liable to be hydroilized with cholinesterase) and persistent depolarization, the skeletal muscle tone cannot be maintained, decreases and the membrane become gradually repolarized (as the sodium channel closes), and the membrane cannot be depolarized by Ach as long as the NMB is present , therefore, this continuous a functional muscle fatigue occurs and paralysis (flaccid paralysis; muscles are weak and have little or no tone) leads to depolarization Phase II ( Phase of desensitization block of the membrane) .

This phase reversed by anticholinesterase. Succinylcholine and decamethonium are examples of this

class of drugs.

Depolarizing neuromuscular blockers (cont.)

Phase I (Depolarization)

Phase II (Desensitization block)

Succinylcholine (suxamethonium):• It has a short onset of action ( 1 min. ) and

short duration of action (5-10 min.). It must be given by continuous IV infusion if prolonged paralysis is required. It is destroyed by pseudocholinesterase.

• Mostly used for brief procedures (e.g. tracheal intubation, electroconvulsive shock therapy).

Depolarizing neuromuscular blockers (cont.)

Succinylcholine

Succinylcholine (cont.)Side effects:• Bradycardia ( due to muscarinic agonist effect) .this

could be prevented by atropine.• Cardiac dysrhythmias or even cardiac arrest (increase

K+ permeability of the motor endplates causes a net loss of K+ from muscle and increased plasma K+

concentration “hyperkalemia”). It should be avoided in patients with burns or severe trauma .

• Raised intraocular pressure (nicotinic agonist effect on extraocular muscles).

• Prolonged paralysis or succinylcholine apnea in patients with liver insuffeciency or genetic deficiency of plasma cholinesterase

• Increase the intragastric pressure and may leads to regurgitation of gastric content to esophagus.

•

Malignant hyperthermia: • Malignant hyperthermia (MH) is a rare inherited condition,

due to a mutation of the Ca2+ release channel of the sarcoplasmic reticulum (the ryanodine receptor “RYR1”), which results in intense muscle spasm and a dramatic rise in body temperature with an increased heart rate and respiratory rate.

• This is a disorder that can be considered a gene-environment interaction. In most persons with Malignant hyperthermia susceptibility, they have few or no symptoms unless they are exposed to a triggering agent. The most common triggering agents are volatile anesthetic gases (such as Halothane,and Isoflurane) , the depolarizing muscle relaxants (Suxamethonium and Decamethonium) catecholamines (such as EP,NE and DA), phenothiazines (such as Chlorpromazine, and Promethazine), and MAO inhibitors (such as Phenelzine, Moclobemide, and Selegiline).

•

Succinylcholine (cont.)

Succinylcholine (cont.)• Some other factors could trigger symptoms of MH in suceptable individuals like physical exercise and hot environment.

• The condition carries a very high mortality (about 65%) and is treated by IV administration of Dantrolene, a drug that inhibits muscle contraction by preventing Ca2+ release from the sarcoplasmic reticulumin addition to discontinuation of triggering agents, and supportive therapy to control hyperthermia, and acodosis.

naglaa f. el- orabi , ph d, m sc, b sc department of pharmacology & toxicology,

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