by

Prof. Sara Hashem Nassar

Clinical Pharmacology Department Faculty Of Medicine-Alexandria University

Cholinergic receptors
(1)Nicotinic Recptors (Na Channels) Sites of NN :
1. Autonomic ganglia 2. Suprarenal medulla 3. CNS

Sites of NM :
Motor end plate

(1) Muscarinic Receptors

A.Ch

M2:

(K out &cAMP) Heart, .

cAMP, Ca++

M3:

M1:

(cAMP) Parietal cells,

(Ca++) Sm .m Endothelium, .

Drugs Acting On Cholinergic Receptors

1) Peripheral (Muscarinic)
a)Parasympathomimetics b)Parasympatholytics

2) Central (nicotinic)

a) Autonomic ganglia(NN)
Stimulants
b) Depressants

b)Neuromuscular junction (NM)

Stimulants b) Depressants

a)Direct Muscarinic Stimulants

b)Indirect muscarinic stimulants (Anticholinestrases)

Reversible 1. Physostigmine 2. Neostigmine 3. ..

i) Choline esters: 1. Acetyl choline 2. Methacholine 3. Carbachol 4. Bethanechol

ii) Cholinomimetic alkaloids Pilocarpine

Irreversible Organophosphorous poisoning

Choline Esters Acetylcholine

Sites of its release

Release of Neurotransmitter

Excitatory Post Synaptic Potential

diffuses across synaptic cleft 1. AP arrivesTransmitter at presynaptic membrane. and Ca++ bindschannels to receptors located on the 2. Voltage gated open. postsynaptic which in turn, 3. Increase of intracellular membrane, Ca++ opens of ligand-gated ion-channels. causes exocytosis transmitter into the synaptic cleft.

Inhibitory Post Synaptic Potential

Selective in permeability to K+ and Cl- leads to hyperpolarization of the membrane i.e. IPSP.

Absorption and Fate

Enzymatic destruction

Absorption:

Fate: True cholinestrase Pseudocholinestrase

Pharmacological actions
(1) Muscarinic actions

1) CVS:

2) GIT:

1. Heart 2.Blood vessels 3.Blood pressure

3) Urinary tract: 4) Bronchi

5) Exocrine glands

(2) Nicotinic actions

1) On autonomic ganglia

A.Ch Reversal

0.5 g/kg A.Ch

0.5 g/kg 50 g/kg Atropine A.Ch A.Ch

2) On skeletal muscle

Synthetic Choline Esters

Advantages
A longer duration of action. Effective orally and parenterally. More selective in their action

Carbachol Bethanechol

Contra-indications
1. Bronchial asthma

2. Hyperthyroidism
3. Peptic ulcer 4. Coronary insufficiency

Main differences among Choline Esters

Acetylcholine Absorption GIT from Nil Very short true & pseudo ChE *** +++ Carbachol Complete Longer Bethanechol Complete Longer

Duration of action Hydrolysis by cholinesterase Nicotinic actions Muscarinic actions Specificity of muscarinic actions Administration

Not by the true or PseudoChE. *** +++ +++

Eye G.I.T. Urinary bladder Oral or SC

IV

II. Cholinomimetic alkaloids Pilocarpine

1. Eye

1. Absorption & fate

2. Mechanism of action

3. Pharmacological actions

Aqueous formation and drainage

Cornea Iris

Anterior chamber angle

Trabecular meshwork Schlemms canal

(out)

Pupil

Posterior chamber Ciliary body

Lens Vitreous

(in)

Effect of pilocarpine on the eye

1. Miosis 2. Spasm of ciliary muscle 3.

IOP

Therapeutic uses
1. Glaucoma
2. To counteract mydriatics 3. To break mild recent adhesions 4. To stimulate salivation

5. To promote the growth of hair

6. To treat atropine overdosage

Anticholinestrases
Inhibit A.Ch. Degradation Potentiate A.Ch. Action

1. Reversible: physostigmine,

neostigmine & its substitutes

2. Irreversible: organophosphorous
poisons

Reversible Anticholinesterase
Physostigmine (Eserine) Source Natural alkaloid from plant Physostigma venonosum (Calabar beans). Tertiary amine. Neostigmine (Prostigmine) Synthetic.

Chemistry

Quaternary ammonium compound Poor and irregular. Cannot pass blood brain barrier.

Absorption from G.I.T. Penetration of lipoid barriers.

Complete. Can reach the CNS to produce stimulation.

Physostigmine (Eserine)
Pharm. actions Accumulation of acetyl choline at different sites producing: a- Muscarinic action. b- Nicotinic action. c- CNS stimulation. Locally on the eye : Miosis Contraction of ciliary muscle & accom for near objects. IOP Lachrymation. Twitches of the eye lids (nicotinic action).

Neostigmine (Prostigmine)
AntiChE activity direct st. action on skeletal muscle. Muscarinic effects are more on G.I.T. & urinary bladder. Stimulation of skeletal muscle: Through inhibition of cholinesterase MEP. Direct stimulant action.

Special effects

Physostigmine (Eserine)
Therapeutic uses Locally on the eye: Glaucoma.

Neostigmine (Prostigmine)

Diagnosis and
treatment of myasthenia gravis.

Alternately with
mydriatics to break adhesions between the iris and lens.

Antidote to curare. Paralytic ileus . Postoperative urinary

retention

To counteract the
mydriatic effect of homatropine and euactropine.

Neostigmine Substitutes
[1] Edrophonium [2] Pyridostigmine Uses of edrophonium:

Diagnosis of myasthenia gravis.

Differentiation between "myasthenic

crisis" and cholinergic crisis"

As an antidote to curare.

Myasthenia Gravis
A.Ch. NM receptors Weak power of Sk. m

Diagnosis of

Myasthenia Gravis

[1] Neostigmine
1.5 mg IM preceeded by 0.6 mg atropine

[2] Edrophonium: 2 mg I.V.

Muscle power improve

Treatment of Myasthenia Gravis

Neostigmine Or Neostigmine substitutes as pyridostigmine tablets orally + Atropine. Ephedrine Immunosuppressive therapy. Thymectomy in selected cases.

ALZHEIMERS DISEASE
It is a brain disorder in which nerve cells in the brain degenerate, making it difficult for signals to be transmitted properly.

A person with Alzheimer's disease has problems with memory, judgment, and thinking, which makes it hard for the

person to work or take part in day life.

Loss of brain volume Atrophy of various lobes

Alzheimer

Normal

Alzheimers MRI

Normal MRI

NEUROPATHOLOGY OF AD
Deposits of protein fragments called beta amyloid fill up spaces between brain cells Tangles of protein inside the cells Neurotransmitter losses (Acetylcholine ) Inflammatory responses

Normal versus degenerating neuron

Therapy of Alzheimers Disease

The use of cholinesterase inhibitors would to some extent compensate for the loss of the cholinergic neurons . These drugs are palliative only and do not cure or prevent neurodegeneration. Available drugs are tacrine , donepezil, Adverse effects include nausea, diarrhea, vomiting, and insomnia. These symptoms are most frequent and severe with tacrine. Hepatotoxicity is associated with tacrine therapy. Because of these significant side effects, tacrine is not widely used.

Therapeutic uses of Anticholinestrases

Alzheimers Disease Paralytic ileus Glaucoma Myathenia gravis Insectisides Nerve gases

Irreversible Anticholinesterases Organic Phosphate Poisoning

1. Causes

Eating Dusting accidental

2. Symptoms

1. Muscarinic effects:

2. Nicotinic effects:
3. CNS effects:
Death is usually due to respiratory failure.

R of organic phosphate
poisoning

Atropine IV or IM till Oximes (if patient is seen within 6-8hs) Mechanism of action: 1. Set the enzyme free 2. Bind circulating poison before reaching the enzyme. Anticonvulsants Care of respiration Gastric lavage/ wash skin

Atropine

Mechanism of action

By competing with acetylcholine for M receptors

Pharmacological actions
(1) Antimuscarinic actions
Miosis secretions Bronchodilatation & secretions 1) Heart: If IV, initial bradycardia followed by tachycardia Mydriasis 2) BV and BP:. 1) Passive mydriasis Tone, motility 2) Cycloplegia and secretion 3) IOP (antispasmodic) 4) Loss of light reflex 5) lacrymation Antispasmodic, urine retention

(2) CNS actions

Stimulant actions Therapeutic dose: 1. CIC bradycardia 2. RC Large dose: Cereberal cortex Depressant actions 1. tremors & rigidity RC 2. central excitation of eserine & . 3. Brain electric activity.

Therapeutic uses of Atropine

Preanaesthetic medication (Why?) Colic Heart block Hyperactive carotid sinus. Eye: . Organic phosphate poisoning.

Side effects of atropine

Dryness of mouth, blurred vision and tachycardia.
Retention of urine may occur in patients with enlarged prostate. Acute glaucoma may be precipitated. In children, cutaneous vasodilatation with flushing of the skin and elevation of body temperature.

Contra-indications to atropine
Old persons, or in those susceptible to glaucoma .
Patients with enlarged prostate .
Fever.

Cardiac patient
Thyrotoxicosis

Acute Atropine Poisoning

1. Symptoms

2. Treatment 1. Gastric lavage, if atropine taken orally. 2. Artificial respiration with oxygen, if 3. Ice bags to reduce fever. 4. Parasympathomimetics e.g. pilocarpine or eserine 5. Sedatives if..

2- Hyoscine (Scopolamine)
Atropine Duration Acting more on CNS actions Long GIT, Heart Both stimulant and depressant actions, but mainly stimulant Short Eye, exocrine glands Mainly depressant: -Sedation & hypnosis. -Amnesia to recent events. -Antimotion sickness action. -Antiparkinsonian action.
Stimulant actions: RC In presence of pain

Hyoscine

Therapeutic Uses of Hyoscine

Preferred over atropine in pre-anaesthetic medication. (Why?)

Colic Motion sickness

Parkinsonism

Synthetic Atropine Substitutes

Available groups as:
1. Mydriatics. 2. Antisecretory-antispasmodic 3. Antiparkinsonian. 4. urinary bladder activity. 5. Bronchial asthma.

Mydriatic Atropine Substitutes

Atropine
Duration action Concentration of

Homatropine 24 hrs.

Eucatropine 3-4 hrs.

Tropicamide 4 hrs

Cyclopentolate

7-10 days 1% + Not complete

12 hrs

2% + Complete

2-5% Complete

0.5%

0.5%

Cycloplegia Antagonism by eserine

+
Complete

+
Complete

Uses

Iritis

Fundus examination

Fundus examination

Fundus examination

Fundus examination

Antisecretory Antispasmodic Substitutes

1. Atropine methyl nitrate

2. Oxyphenonium
3. Hyoscine butyl bromide 4. Pirenzepine

Pirenzepine

Selective M1 blocker
No effect on the eye

No effect on the heart

No effect on bladder No effect on CNS No effect on GIT motility

Pirenzepine
Therapeutic Uses: Ulcer dyspepsia. non-ulcer dyspepsia such as: Hyperacid irritable stomach. Gastritis. Gastric complaints caused by drugs as (NSAIDs).

Pirenzepine
Therapeutic Uses: Ulcer dyspepsia. non-ulcer dyspepsia such as: Hyperacid irritable stomach. Gastritis. Gastric complaints caused by drugs as (NSAIDs).

Antiparkinsonain Atropine substitutes

Trihexy phenidyl Benztropine

Decreasing Urinary Bladder Activity

Emepronium
For urine incontinence

Decreasing Urinary Bladder Activity

Emepronium
For urine incontinence

Atropine subtitutes for Bronchial asthma

Ipratropium bromide

Drugs Acting on autonomic ganglia

Site

Predominant tone

Effect of ganglion blockers

Arterioles

Sympathetic (adrenergic)

- Vasodilatation. - Increased blood flow to extremities. - Hypotension.

Veins

Sympathetic

- Dilatation: decreased venous return.

Heart

Parasympathetic

- Decreased cardiac output. - Tachycardia.

Genital system (Erection).

Parasympathetic

- Impotence.

Site

Predominant tone

Effect of ganglion blockers

GIT

Parasympathetic

- Reduced tone and motility. - Constipation. - Decreased gastric secretion. - Urinary retention. - Mydriasis and cycloplegia. - Decreased (anhidrosis). - Dry mouth (Xerostomia). sweating

Urinary bladder Eye Sweat glands Salivary glands

Parasympathetic Parasympathetic Sympathetic (cholinergic) Parasympathetic

Trimetaphan

Very short competitive ganglion blocker Vasodilator by: Ganglion blocking action Histamine Direct VD. Used in

1. 2. 3.

1. Neuromuscular Blocking Agents. 2. Antispasticity Agents.

Learning objectives

Revise neuromuscular transmission. Classify NMBAs Describe the pharmacological characterisics of competitive NMBAs. List some drug interactions with NMBs. Describe the lines of treating toxicity with NMBAs.

Outline the main differences among dTUBOCURAINE, PANCURONIUM and ATRACURIUM

Neuromuscular Blockers (NMBs)

Drugs

that interfere with transmission

of the nerve impulse at the neuromuscular junction

Classification Of NMBs
Competitive (non-depolarizing) NMBs
Compete with acetylcholine (ACh) at the NMJ and prevent depolarization of muscle cells

1) d-Tubocurarine 3) Pancuronium 5) Atracurium

2) Gallamine 4) Vecuronium

Depolarizing NMBs
Initially act as an ACh receptor agonist at NMJ, causing stimulation of the muscle cell but unlike Ach, this action is Succinylcholine sustained and prevents NMJ from repolarization

Competitive NMBs

Depolarizing NMBs

Initial depolarization

Sustained depolarization

Common features Dont enter into the CNS so dont affect consciousness.

Always administered intravenously

Competitive (non-depolarizing) NMBs

Curare Alkaloids

Pharmacological actions 1. Competitive NMB blocking action:

2. Weak ganglion blocking action

3. Histamine release

4. Central nervous system: NO CNS action

NB. Rapid I.V. of a large dose may cause hypotension due to: a- Peripheral VD due to histamine release. b- Sympathetic ganglionic blockade. c- Diminished VR due to loss of skeletal m. tone.

Drug Interactions:
1. Synergists
1. Many inhalational anaesthetics 2. Some antibiotics 3. Chlorpromazine 4. Local anaesthetics 5. Calcium channel blockrs 6. Diseases (e.g. myathenia gravis) and ageing

2. Antagonistic

Neostigmine and edrophonium

Overdose Toxicity

Failure of respiration (Why?)

Hypotension.

Histamine release leading

to bronchospasm,

Treatment Of Toxicity
(1) Artificial respiration with oxygen under positive pressure.

(2) Antidotes:
1. Neostigmine (I.V.) preceded by atropine but not given I.V. simultaneously (Why?)

2. Edrophonium (10 mg IV)

(3) H1 and H2-blockers

Gallamine
1. 2. 3. 4. 5. 1/5 the activity of d-tubocurarine Shorter duration of action (20-30 min). Much weaker ganglionic blocking activity. Much weaker histamine releasing action. Selective M2-blocker (atropine-like) leading to tachycardia. So not used in thyrotoxicosis. 6. No effect on blood pressure. 7. Drug interactions are similar to curare. 8. Excreted by the kidney (95-100%) and hence must not be given to patients suffering from renal failure.

PANCURONIUM
1. Synthetic and 5 times as potent as d-tubocurarine. 2. Longer duration of action (30-45 minutes).

3. NO ganglionic blocking activity, no histamine release, (= no hypotension or bronchoconstriction).

4. Some increase in heart rate (M2 block).

5. Cause some rise in BP

6. Drug interations similar to curare. 7. Mainly excreted by the kidney (80%)

8. It is a popular long acting relaxant and is the drug of choice in patients susceptible to hyperthermia.

VECURONIUM

An analogue of pancuronium that is metabolized by the liver

ATRACURIUM
1. It is as potent as tubocurarine but shorter duration of action
2. Undergoes Hofmann's degradation so noncumulative & could be used in pts. with liver and/or kidney disease. The relaxant of choice in patients with liver and renal impairment. 3. Weak histamine releaser 4. Drug interactions (the same as d-tubocurarine)

Tubocurarine Potency Duration of action Elimination Histamine release Long liver

Pancuronium 5 times as tubocurarine Longer kidney

Atracurium Same as tubocurarine Shorter Hoffman Weak releaser

Good releaser NO

CVS

Some rise in HR and No effect BP Drug Synergistic: inhalation and local anaesthetics, some interactions antibiotics, diseases & aging Antagonistic: Neostigmine & edrphonium

Hypotension

Learning objectives

Describe the mechanism of action succinylcholine.

Identify the main differences between competitive and depolarizing NMBs .

Recognize the main side effects of succinylcholine.

List the therapeutic uses of NMBs.

II. Depolarizing NMBs

SUCCINYLCHOLINE (SUXAMETHONIUM)

Absorption & fate

Poorly soluble in lipid Inactive orally Always given I.V Can t enter the CNS. Short duration of action due to its rapid hydrolysis by pseudocholinesterase.

Pharmacological actions A- Phase I block (depolarization block):

Therapeutic dose

B - Phase II block (desensitization block):

Overdose/ prolonged infusion

Succinyl choline
Side effects:
1. Succinylcholine apnoea 2. Bradycardia 3. Hyperkalaemia 4. Increased intraocular pressure 5. Increased intragastric pressure 6. Post-operative muscle pain 7. Malignant hyperthermia

Administration:
1. Single slow IV dose to produce muscle

relaxation of short duration (5 minutes) e.g. for intubation.

2. IV infusion: to produce muscle relaxation as

long as required.

Therapeutic Uses of NMBs

1. Adjuvant in general anaesthesia.

2. Facilitation of intubation, laryngoscopy, bronchososcopy,.

3. To prevent coughing and laryngospasm during operations.

4. Prevention of trauma in electroshock therapy.

5 . Symptomatic treatment of convulsions .

6. Facilitation of mechanical ventilation

Learning objectives

Describe mechanisms of inhibition of NM

transmission in contrast to antispasticity

agents.

Discuss the mechanism of action and therapeutic uses of antispasticity agents.

Antispasticity agents (spasmolytics, myotonolytics)

They decrease spasticity in neurological, muscular or joint lesions, which give rise to painful muscle spasms.

Central muscle relaxants: Act at level of spinal cord and subcortical areas of the brain, inhibiting polysynaptic pathways e.g benzodiazepines, baclofen and mephenesin.

Direct muscle relaxants: They act directly on skeletal muscles e.g. dantrolene.

[1] Central Muscle Relaxants

1) Diazepam
Enhance binding of GABA to GABAA receptors which mediate postsynaptic inhibition
( Cl- ion influx).

Mechanism of action

Diazepam
Therapeutic Uses:
1- Anxiety states (given orally). 2- Anticonvulsant in status epilepticus (given I.V.). 3- Antispasticity agent (given orally).

2) Baclofen
Mechanism of action
A) It is a GABAB agonist, mediating presynaptic inhibition by reducing calcium ion influx, and the release of excitatory neurotransmitters in the brain and spinal cord. B) Inhibits release of substance P in the spinal cord.
Therapeutic Uses: 1) Antispasticity agent. (Oral) 2) Some cases of trigeminal neuralgia.

Myotonlyti cs

Dantrole ne

Antispasticity agents They increase inhibition Inhibitory neuron

Benzodiazepi nes enhance GABA effect

Convulsa nts

GABA
Agonist Baclofe n

Glycine
Strychnine Receptor Antagonist

GABAA receptor GABAB receptor

Glycine receptor

3) Mephenesin
Mechanism of action
It is a glycine receptor agonist thus increasing the activity of spinal inhibitory interneurones where glycine is the transmitter

Therapeutic Uses:
1) Antispasticity agent (Oral) 2) Specific antidote for strychnine (IV).

[2] Direct Skeletal Muscle relaxants

Dantrolene
Mechanism of action Relaxes sk. M. by a direct action on the excitation-contraction coupling, Dantrolene hindering calcium release from the sarcoplasmic reticulum.

Dantrolene
Therapeutic Uses
1. Relieves sk. M. spasm in neurological diseases (Antispasticity action)

2. Malignant hyperthermia (IV)

Match:

Questions

1. d-tubocurarine 2. Succinyl choline 3. Neostigmine A. ..is a depolarizing NMB. B. may be used to reverse competitive blockade of NMJ. C. is a competitive NMB.

True and False:

1. Dantrolene is a Competitive antagonist at NMJ.

2. Pancuronium is a long acting competitive NMB. 3. Tubocurarine is a histamine release 4. Neostigmine reverses succinyl choline induced NMB.

Choose the right answer:

Succinyl Choline
1. Hinders calcium release from the sarcoplasmic reticulum 2. Is useful in skeletal muscle spasm ass. neurological disorders. 3. Is a long acting NMB

4. in sensitive individuals, it may cause malignant hyperthermia

Hoffman degradation occurs with

a) Pancuronium b) Succinyl choline. c) d-tubcurarine d) Atracurium

All of the following are side effects of SuccinylCholine except:

a) Fasciculations b) hyperkalemia c) muscle pain d) Tachycardia