ans - doc rasha

It regulates the involuntary functions which are not consciously controlled including:

Cardiac output, blood pressure and blood flow to various organs.

Respiration. Peristalsis of the GIT.

Tone of smooth muscles (gall and urinary bladders , ureter and uterus.

Glandular secretions (sweat ,saliva and GI secretions,…….)

It regulates other important functions such as cellular metabolism.

FUNCTIONS OF AUTONOMIC NERVOUS SYSTEM

SYMPATHETIC DIVISION (thoraco lumber outflow): a) Origin: the preganglionic nerves originate in

lateral horn cells of all thoracic and upper 3 lumber segments of the spinal cord .

b) The pre ganglionic nerve fiber is short and the post is long.

c) The synapse between the pre- and post- is located in the sympathetic chain.

PARASYMPATHTIC DIVISION (Cranio sacral outflow):

a) Origin : originates from cranial nuclei III, VII, IX and X.

› b) Sacral outflow originates from the 2nd, 3rd and 4th sacral segments of the spinal cord.

› c) The pre ganglionic is long ,while the post is short,

› d) The ganglia being close or even embedded in the effector organ.

›

Anatomy of the autonomic nervous system

Physiological Characteristics of ANS

1 -Both are physiologically antagonists.2 -Activation of one gives the same effect as inactivation of the

other.

3 -Each involuntary organ receives a dual nerve supply ( except

body of the uterus “sympathetic.”4 -The level of activity is the algebraic sum of the two

components.5 -Parasympathetic “trophotropic” leads to growth and concerned

with restoration and conservation of energy.

6 -Sympathetic “ergotrophic” prepares the individual for fight and

flight and leads to energy expenditure.

Sympathetic and parasympathetic actions are elicited by different stimuli

CHEMICAL TRANSMITTERS IN ANS Based on the chemical mediators released ,the ANS can be

divided into: A) Cholinergic division:

Acetylcholine is the neurotransmitter and the cholinergic neurons are:

1 -All of the preganglionic neurons. 2 -The parasympathetic postganglionic neurons.

3 -The sympathetic postganglionic neurons that innervate sweat glands.

4 -The parasympathetic neurons to the skeletal blood vessels. 5-The sympathetic neurons innervating the adrenal medulla .

Norepinephrine is the neurotransmitter , and the adrenergic neurons are:

The remaining postganglionic sympathetic neurons are noradrenergic and secret norepinephrine.

The adrenal medulla is a sympathetic ganglion that secrets norepinephrine (20%), epinephrine (80%) and some dopamine directly into the blood stream .

B) Adrenergic division:

Sites of actions of adrenergic agonists

Chemical transmitters in sympathetic nervous system:

A) Norepinephrine. B) Epinephrine . C) Dopamine.

Steps of adrenergic neurotransmission: 1)Synthesis.

2 )Storage. 3 )Release.

4 )Binding with receptors. 5 )Uptake and metabolism.

Adrenergic Receptors and Drugs Affectingthe Sympathetic Nervous System

1- Synthesis: a) L-tyrosine ------>L-DOPA by tyrosine hydroxylase b) L-DOPA --- dopamine by alanine decarboxylase

c) Dopamine is actively transported into synaptic vesicles.

d) Dopamine--- norepinephrine by dopamine beta hydroxylase.

e) Norepinephrine--epinephrine by N- methyltransferase .

Synthesis ,Storage ,and Release of Norepinephrine:

Norepinephrine is also synthesized in and released from the adrenal medulla.

Chromaffine cells of the adrenal medulla are innervated by sympathetic preganglionic cholinergic neurons and release catecholamines

into blood stream .

2 -Storage: NE is bound to ATP and stored within the vesicles until

released.

3 -Release: I – When the action potential arrives Ca++ channels open allowing Ca++ to enter into the neuron.

II- NE –containing vesicles fuse with the neuronal membrane and expel their contents to the synapses to

allow NE binding with receptors .

.

4- Metabolism: After binding to the receptors NE is

removed by one or more of the following

a) High Affinity uptake system (uptake I ):the major mechanism of removal

NE is transported back into the neuron Where it is stored in the synaptic vesicles (uptake III) for further re-release.

Uptake III is blocked by reserpine

Neuronal uptake I is inhibited by cocaine , guanethedine, phenylpropanolamine and TCA )imipramine).

b) Oxidative deamination by MAO: MAO is located in the cytoplasm of the neuron . It metabolizes un stored NE and the metabolite is excreted in urine.

c) Non neuronal uptake )uptake II system) Occurs in the post junctional cells . NE is O-

methylated by COMT. Uptake II is blocked by phenoxybenzamine.

ADRENERGIC RECEPTORS A) α-Adrenergic receptors:

i- α1 ii- α2 B) β adrenergic receptors:

i- β1. ii- β2 iii-β3 A) α1- Receptors :Present on the postsynaptic membrane of the effector organ.Mechanism:

Receptor stimulation----G protein activates phospholipase-C

--- IP3 + DAG from phosphatidyl inositol--- release of intracellular Ca++ from endoplasmic reticulum.

ACTIONS of α1- RECEPTORS1 -Active mydriasis .

2-Generalized vasoconstrictionperipheral

resistanceBlP

3 -Spasm of GIT and Urinary bladder sphincters.

4 -Uterus: contracts pregnant and relaxes non-pregnant.

5 -Ejaculation .

6 -Contraction of pilomotor muscle--hair erection.

Selective Agonists :Phenylephrine and Methoxamine

Selective Antagonists : Prazosin and Tolazoline. .

Second messengers mediate  the effects of α receptors .

B) α2- Receptors:

Located in the pre synaptic membrane of the ad. nerve terminals and in CNS,Also In the β-cells of pancreas .

They are inhibitory in function cause feedback inhibition of ongoing release of NE.

MECHANISM: ↓ adenylyl cyclase ----- cAMP ---- of further release of NE.

.

1- sympathetic outflow from CNS. 2- release of NE & Ach from nerve

terminal. 3- of insulin release. 4- lipolysis in fat cells Selective agonists: α methyl

noradrenaline ,clonidine , and guanabenz.

Selective antagonists: Yohimbine, tolazoline and phentolamine

ACTIONS of α2:

C) β-Receptors:

β1 receptors are found mainly in the heart.

β2 receptors are located mainly on bronchial and vascular smooth muscle.

β2 receptors are located presynaptic to increase NE release.

β3 located in the adipose tissue to increase free fatty acids.

MECHANISMadenylyl cyclase --- cAMP --- intracellular Ca ++

Actions of β1-ReceptorsCardiac stimulation : tachycardia and increase in myocardial contractility.

Selective agonists: dobutamine and prenalterol.Selective antagonists: atenolol ,acebutolol , and metoprolol.

.

Actions of β2-Receptors 1- Vasodilation in skeletal blood vessels. 2- Bronchodilation. 3- muscle and liver glycogenolysis. 4- Relaxation of GIT and urinary bladder

walls. 5- Relaxation of uterine muscle. Selective Agonists : Salbutamol and

albuterol. Selective Antagonists : Butoxamine

SYMPATHOMIMETICS )ADRENERGIC AGONISTS)

Chatecholamines present in A-cells of adrenal medulla

According to mechanism of action classified into

1- Direct acting agonists e.g.Ep , NE, isoproterenol

and phenylephrine.

2- Indirectly acting : e.g.

amphetamine ,methamphetamine and tyramine.

3- Mixed action agonists :ephedrine & metaraminol.

Direct Acting Agonists1-EPINEPHRINE )ADRENALINE )

Not administered orally due to

Poor absorption from the GIT.

Rapid destruction by the intestinal juice.

Rapid metabolism by liver enzymes.

All CAs. Do not pass bbb.

Administration : S.C. ,I.C ,inhalation , eye drops.Metabolites excreted in urine.Acts on α1, α2 , β1, β2 ,β3 - receptors

General Features:

PHARMACOLOGICAL ACTIONS of EPINEPHRINE

1 -Cardiovascular System:

a)↑ heart rate )+ve chronotropic action), b)↑ force of

contraction )+ve inotropic)[β1].

c)↑ Arterial blood pressure )mainly inc. systolic with slight

dec. in diastolic).

d) ↓ in renal blood flow.

2 -Respiratory System:

a) Bronchodilatation and ↑ in tidal volume )β2).

b) Relieves dyspnea and acute symptoms of asthma.

3- GIT: A)↓ Tone and motility. B)↓

secretions. c) Constriction of the sphincters.

4-Urinary Bladder: Urine retention due to constriction of

trigone muscle and internal sphincter.

PHARMACOLOGICAL ACTIONS of epinephrIne

5 -Eye:a) Topically vasoconstriction of conjunctiva blood vessels (so used as decongestant).

b) Vasoconstriction of ciliary body blood vessels , so reduces the production of aqueous humor (used in open angle glaucoma).

c) Systemic EN causes decongestion and active mydriasis.

a) Inhibition of insulin secretion (α2 receptors ) and stimulation of glucagon secretion (β2-receptors).

b) Increased circulating concentration of :

GLUCOSE , LACTIC ACID hyperglycemia , brief K+ K+

c) Increased lipolysis (β effect ).

6-Metabolic Effects :

EFEECT on LYPOLYSIS

Stimulation of β3-receptors of adipose tissue Adenylyl cyclase- cAMP lipase enzyme hydrolysis of TGs to FFas + glycerol.

7 -Anti-Allergic Effect: The release of histamine ) physiological antagonist ).

8 -Effect on Hormones :

of hypothalamus---> of ant. Pituitary- ACTH-- adr. Cortex - cortisone.

4- Cardiac resuscitation in cardiac arrest. 5- Acute bronchial asthma. 6- Acute insulin hypoglycemia 7- Allergy, urticaria , angioedema and anaphylactic shock.

THERPEUTIC USES: 1- S.C. inj. With local anesthetics, vasoconstriction absorption-> duration and toxicity ,and decreases bleeding. 2- Nasal pack in epostaxis.

3 -Eye drops in open angle glaucoma.

CONTRA-INDICATIONS1- Coronary diseases. 2- Hyperthyroidism.

3- Hypertension. 4- Gangrene.

5- Hemorrhagic shock. 6- Arrhythmia.

7- Pulmonary embolism.

A- Alpha effects: a) Gangrene if injected around the finger or toe.

b) Hypertension ,may lead to cerebral hemorrhage.

B- β1-Effect: a) Tachycardia ,palpitation and angina.

b) Arrhythmia specially in pts, receiving digitalis or halothane.

C- β2- Effects: Skeletal muscle tremors. D- Eye troubles after local application. E- CNS: Anxiety and headache.

Adverse Effects:

DRUG INTERACTION:

1- Digitalis.

2 -General anesthetics: halothane and cyclopropane.

3 -Adrenergic neuron blockers e.g. guanethidine and reserpine.

4 -Ganglion blockers.

5- MAO inhibitors.

It is nonselective α1 ,α2 ,β1 ,β3 agonist.

PHARMACOLOGICAL EFFECTS 1- CVS: a) Blood vessels : Generalized

vasoconstriction (except coronaries) peripheral resistance

blood pressure. b) both systolic and diastolic bl.p.

c) Heart rate :reflex bradycardia due to reflex vagal /baroreceptor stimulation (antagonized by atropine).

If atropine then NE tachycardia. d) Positive inotropic effect due to inc

contractility (β1 effect ) The cardiac output is not affected.

2-NOREPINEPHRINE (NORADRINALINE )

2 -GIT: Relaxes walls and contracts sphincters.3 -Metabolism : Hyperglycemia and hyperlipidaemia.

4 -Uterus; contracts pregnant uterus.5 (CNS : mild stimulation.

THERAPEUTIC USES:1- Acute hypotension ;2- Treats shock due to decreased bl p. but dopamine is better.

CONTRAINDICATIONS: similar to EN

Direct acting synthetic NONSELECTIVELY STIMULATES β1,β2-receptos.Pharmacological Actions:

3-ISOPROTERENOL ( Isoprenaline)

1- CVS:a) Force of contraction ,HR ,Cardiac output and A-V conduction so used in cardiac arrest.

b) excitability and automaticity. c) Generalized arteriolar vasodilatation specially in sk. Bl vessels in per. resistance. d) Systolic pressure slightly increase ( due to intense cardiac stimulation) with reduced mean and diastolic pressure . 2- PULMONARY : Rapid and profound bronchodilation.

3-Smooth Muscles : GIT ,Urinary bladder relaxation.4 -CNS : mild stimulation.

5 -Uterine: relaxation.6 -Metabolism : hyperglycemia and increased lipolysis.

THERAPEUTIC USES:1 -Heart Block (sublingual )

2 -Rarely used in acute bronchial asthma.

ADVERSE EFFECTS and CONTRAINDICATIONS: Similar to EN

Natural sympathetic CA ,Chemical transmitter in CNS, ganglia, and periphery.It acts on α , β1, D1, D2- receptors.D2 are found presynaptic in adrenergic

nerve terminals where it Interferes with NE release and responsible for most of the central actions.

Not absorbed orally.Not pass bbb.

Given by i.v. infusion .

4 -DOPAMINE ( INOTROPINE )

a) Peripheral Actions:1 -Low dose:

D1 renal vasodilatation renal bl. Flow urine outflow.This effect is blocked by haloperidol.It dilates the mesenteric ,coronary and cerebral bl. vs. per.resis

2 -Moderate Dose:β1and D1-receptors selective +ve inotropic +minimal tachycardia

3 -Large Dose: α1-receptors vasoconstriction periph. Resis.

Pharmacological Actions of Dopamine

Dopamine precursor L-DOPA can pass bbb and and converts to dopamine by dopadecarboxylase enzyme.

1 -In limbic system dopamine causes euphoria and psychosis.

2 -In basal ganglia ( negro-striatal) DA has anti-Parkinsonism.

3 -In hypothalamus : hyperpyrexia ,decreased appetite and PL.

4 -DA CTZ nausea and vomiting.THERAPEUTIC USES:

1 -Shock : Cardiogenic, haemorrhagic and endo toxic as it inc. urine output, improves microcirculation of vital organs and causes +ve inotropic effect and inc. Systolic bl.P .

b) Central Actions:

ADVERSE EFFCTS: 1-Tachycardia and arrhythmia. 2- Nausea and vomiting. 3- DA is contra-indicated in Pts on

MAOI’s

Synthetic sympathomimtic CA Selective β1- agonist some α activity.Selective +ve inotropic effect with minimal effect on heart rate.THERAPEUTIC USES :

Cardiogenic shock , resistant heart failure and heart block.

6 -PHENYLEPHRINESynthetic ,selective α1- adrenoceptor agonist.Not CA so not substrate to COMT Both systolic and diastolic bl.P reflex bradycardia.USES : topically as nasal decongestant and as mydriatic.

5 -DOBUTAMINE

Selective α2 adrenergic agonist.Used to lower bl.p. due to its central actions (suppresses sympathetic vasomotor center).

8- Metaproterenol, Albuterol & Terbutaline

Selective β2 agonists , not substrate to COMTGiven mainly by inhalation to control acute asthma.Salmeterol is long acting β2 agonist.

7 -CLONIDINE

1 -Amphetamine:B- INDIRECT-ACTING AGONISTS

It is synthetic sympathomimtic Non CA. Given orally and parenterally. Pass bbb and has central effects.

bl.p.)α1 effect ) , HR )β1 effect ) reflex bradycardia abolished by atropine.

Has CNS effects : so used in the treatment of depression, narcolepsy and Hyperactivity in children)ADHD).

Found in aged cheese and red wine. Normal by-product of tyrosine

metabolism. Normally oxidized by MAO but if the

pt. uses MAOI it causes hypertensive crises.

2 -TYRAMINE

1 -EPHEDRINE MIXED – ACTION AGONISTS

Sympathomimtic non CA not metabolized by COMT or MAO,

Can pass bbb, absorbed orally , and parentrally.It acts by both releasing CA’s and by direct stimulation of α and β- receptors.

It is a potent CNS stimulant but weaker than amphetamine.

PHARMACOLOGICAL ACTIONSSimilar to those of epinephrine .

IT facilitates neuromuscular transmission.

1 -As analeptic in toxicity with CNS depressants.2 -Mydriatic eye drops.3 -Nasal decongestant.

4 -Prophylactic in bronchial asthma (due to slow onset )

5 -Hypotension may be used before spinal anesthesia.

6 -Myasthenia gravis.

ADVERS E EFFECS 1 -CNS : insomnia, anxiety , tremors ,

convulsions. 2-CVS: hypertension ,tachycardia, palpitation ,

and arrhythmia. 3-Urinary retention in old pts. 4- Tolerance

and tachyphylaxis , no addiction.

THERAPEUIC USES OF EPHEDRINE

An acute (sudden) decrease in the response to a drug after its administration. It can occur after an initial dose or after a series of small doses.

Increasing the dose of the drug may be able to restore the original response. This can sometimes be caused by 1-depletion or marked reduction of the amount of neurotransmitter responsible for creating the drug's effect,

or 2-by the depletion of receptors available to which the drug or neurotransmitter can bind.

This depletion is caused by the cells reducing the number of receptors in response to their saturation.

Tachyphylaxis

According to their site of action A) Adrenergic Receptor Blockers

B) Adrenergic Neuron Blockers

C) Drugs that Reduce Central Sympathetic Outflow

SYMPATHOLYTICS (ADRENERGIC ANTAGONISTS)

Have a profound effect on blood pressure (due to reduced vascular resistance). ↓ bl.P. reflex tachycardia.

According to their interaction to the receptors they are classified into:

i- Irreversible Alpha- Blockers : They bind covalently to α –receptors e.g. phenoxybenzamine.

1- PHENOXYBENZAMINEIt produces irreversible noncompetitive block of α1 and α2 adrenergic receptors .

Its effect lasts for 24 hrs. the time required to synthesize new rec.

I- Alpha Adrenergic Antagonists(α-blockers)

It is inactive and biotransformed to active form so has slow onset.

Pharmacological Actions: 1- Reduces bl.p. ( α1 receptors ) BUT it

does not block the vasodilator effect of EN on skeletal bl vessels.

Phenoxybenzamine before EN- blp. i.e. EN reversal.

2- It increases cardiac output due to inhibition of α2rec.(EN )

I- Alpha Adrenergic Antagonists(α-blockers

1 -Treatment of pheochromocytoma chronically or prior to surgery.

2- Phentolamine or phenoxybenzamine is used to control symptoms of Raynaud’s disease (peripheral vasoconstriction in the extremities especially in response to cold).

Therapeutic Uses

Block α1,α2-rec . They cause vasodilatation by blocking

sympathetic tone to bl vessels. This results in orthostatic hypotension.

A reflex tachycardia may result. This may be also due to blocking α2 rec. which increases the release of NE. Which stimulates cardiac β1-rec.

They are contra-indicated in peptic ulcer pts.

2 -Phentolamine and Tolazoline

Selective competitive α1-rec. antagonists Cause less tachycardia than nonselective

blockers .Decrease peripheral vascular resistance and lower arterial blp.Therapeutic Uses:

1 -Control acute hypertensive episodes. 2 -In the treatment of Raynaud’s disease .

3- Treating urine retention in pts. with benign prostate hypertrophy (block of α-rec. dec tone in smooth muscles of bladder neck and improve

renal flow).(TAMSULOSIN)

3 -Prazocine ,Terazocin and Doxazocine

1 -Postural hypotension .

2 -Reflex tachycardia .

3 -Nasal congestion.

4-Additive antihypertensive effects when prazocine + β- blockers or

diuretics .

5 -Mild sexual dysfunction in males.

Adverse Effects:

They are classified into

Non selective β-blockers Selective β1-blockers α & βPropranolol Metoprolol

Labetalol Nadolol AtenololTimolol EsmololPindolol Acebutolol

II- Beta Adrenergic Antagonists ( β –Blockers )

Non selective β-Blockers1- Propranolol:

Pharmacological Actions:1-Dec. H.R. and cardiac contractility red. Cardiac

output and A-V conduction.2-Broncho-constriction due to block of β2 rec.

3-Peripheral vasoconstriction due to block of β2 –mediated vasodilatation.

Reduction of bl.p. due toa- Red. of cardiac output. No postural hypotension.b- Reduced renin release.c- Decreased sympathetic outflow from the CNS .

Therapeutic Uses of propranolol:

1-Treatment of hypertension.

2- Prophylactic in angina pectoris and infarction )it reduces cardiac work and oxygen consumption).

3 -Prophylactic in cardiac arrhythmia specially in hyperthyroidism.

4 -Migraine : it blocks CA –induced

vasodilation in brain .

1- Heart failure sp in pts with disturbed myocardial function.

2- It must be used with caution in asthmatic pts.

3- It must be used with caution in diabetic pts (it masks the warning sign of hypoglycemic coma).

4- Decreases glycogenolysis and decreases glucagon secretion.

5-Cold extremities due to block of β2 rec. and the effect of α- rec. is unopposed.

6- Sexual impairment in male.

Adverse Effects:

2-LABITALOL It is reversible antagonist of α1 ,β1,β2 adrenergic rec.

Its effect is similar to combination of propranolol and prazocine.

It is effective in the treatment of pheochromocytoma and hypertensive Pts with increased peripheral resistance.Other non-selective β-blockers:

Timolol , Nadolol and PindololNadolol has long duration of action.

Timolol the production of aqueous humor so used in chronic open angle glaucoma.

SELECTIVE β1-BLOCKERS(CARDIO-SELECTIVE)Atenolol , Metoprolol , Esmolol , and Acebutolol

Used in the treatment of cardiac disorders & hypertension in pts. with bronchial asthma.

Used in diabetic hypertensive pts.

Pindolol & Acebutolol are antagonist with partial agonist activity so weakly stim. bothβ1 ,β2-rec. i.e.

have intrinsic sympathomimetic activity ISA . Minimize bradycardia and disturbance in lipid and carbohydrate metabolism.

B- Adrenergic neuron blockers

Drugs affecting neurotransmitter release and uptake:

1 -Guanethidine:It inhibits the release of neurotransmitter from peripheral adr. neurons.

It is taken up by the neuron to replace NE .Thus depleting the neuron.

Chronic administration of guanethidine reduce sympathetic tone to all organs.

Therapeutic Use Potent ,long acting antihypertensive.

But rarely used due to side effects. Adverse effects 1- Postural hypotension and nasal

stiffness. 2-GIT disorders

It produces CA depletion.It inhibits the uptake of NE into vesicles , thus allowing its breakdown by MAO.Therapeutic uses:Rarely used in the treatment of hypertension.Adverse effects:Sedation ,peptic ulcer , psychic depression, and diarrhea.

2-Reserpine:

It blocks the Na+-K+- activated ATP-ase required for cellular uptake Of NE .

So NE accumulates in the synaptic space sympathetic activity.

It is CNS stimulant. Considered as a drug of abuse.

3 -Cocaine:

1 -Clonidine:It can penetrate the BBB .

IT activates α2- rec. in the hypothalamus and medullaof Sympathetic outflow of impulses to the peripheral sympathetic neurons.

It causes no postural hypotension..

C- Drugs that Reduce Central Sympathetic Outflow

IT is transported to adr. Neurons where it is converted to

-α-methyl NE that partially displaces NE in synaptic vesicles,Upon stim. it will be released as a false neurotransmitter of no sympathetic activity.It also activates α2-rec. It blp. ,little effect on HR & CO.No postural hypotension.

2 -α-methyl DOPA

Types of cholinergic recptors:

A- Muscarinic Receptors (M):

Stimulated by acetyl choline and muscarine

There are M1 ,M2,M3 ,M4 ,&M5 receptors subtype.

Activity M1 Rec. M2 Rec. M3 Rec

1-location Gastric parietal Myocardium, Smooth muscles,

cells and CNS &smooth muscles Exocrine glands

2-Agonists Ach , Methacholine & and Carbachol

3-Antagonists Atropine Atropine Atropine &

& Pirenzepine & Gallamine Hexahydro-

siladifenidol

CHOLINERGIC RECEPTORS AND DRUGS ACTING ON THE PARASYMPATHETIC NERVOUS SYSTEM

When M1 or M3 are activated conformational changesinteracts with G-proteine↑ phospholipase –C hydrolysis of

phosphatidylinositol DAG+ IP3↑ iCa++iCa++ can stimulate or inhibit enzymes or

cause hyperpolarization , secretion or contraction.

Activation of M2-rec. on the cardiac muscle ↑ G-proteine↓ adenylyl cyclase↑ K+Conductance, ↓ HR & force of contraction.

Mechanism of signal transduction

They are found in the CNS , autonomic ganglia (Ng), adrenal medulla (Ng) and in the skeletal muscles (Nm) ( neuromuscular junction NMJ )Stimulated by Ach. & very low concentration of nicotine.Nicotine initially stimulates then blocks the receptors.Ng are selectively blocked by

hexamethonium ,tetraethylamonium &pentamethonium & high concentration of nicotine.

Nm are blocked by D-tubocurarine

B- Nicotinic receptors (N):

They stimulate muscarinic receptors ( peripheral cholinergic) & mimic the action of acetylcholine.A) Direct Parasympathomimtic:

1 -Synthetic Choline Esters: Methacholine, carbachol,& bethanechol.

2 -Cholinomimetic Alkaloids: Pilocarpine ,muscarine & arecholine.B) Indirect Parasympathomimtic ( anticholinesterases):

Cholinesterase (true & pseudo- )enzyme hydrolyzes Ach.

These drugs cause accumulation of endogenous Ach--↑ of both M &N rec they are miotic & used to reduce the IOP in case of glaucoma .

I- Parasympathomimetics (cholinomimetics,Muscarinic agonists , Cholinoceptive agonists)

Direct and indirect-acting Parasympathomimetic (cholinergic drugs)

a) Quaternary Alcohol : Edrophonium.

b) Carbamate Derivatives (substrate for the enzyme) : Physostigmine, Neostigmine , Pyridostigmine.

2- Irreversible Anticholinesterases (Organophsphorus compounds

They produce noncompetitive irreversible inhibition of CE.

e.g. a) Echothiofate. b) Insecticides.;parathione and

malathion. c) War gases : sarin , tabun &

soman. d) Metrifonate: antibelharzial.

1 -Reversible anticholinesterases

1- Acetylcholine:Natural direct parasympathomimtic.Synthesis , Storage, Release and Fate of Ach:.

1 -Active uptake 0f choline by cholinergic neuron(rate limiting step).Himicholinium inhibits neuronal uptake of choline.

2-In the mitochondria of cholinergic nerve terminal:

Acetate + CoA+ ATP Acetyl CoA + ADP3 -In the cytoplasm of cholinergic nerve ending:

Choline + Acetyl Co A Acetylcholine + Co A

I- Direct parasympathomimeticsA-Choline Esters:

4- Storage in vesicles.5- Release by exocytosis.N.B. Ach release is blocked by Mg+

+, botulinum toxin and procaine.6- FATE : hydrolyzed by

choliesterase enzymes:a)Acetylcholinesterase enzyme

(true): inactivates endogenous Ach.

b) Butryl cholinesterase (pseudo-) : of unknown role.

Types of cholinesterase enzymes (CE)

Acetylcholine esterase (true CE)

Butrylcholinesterase( pseudo CE}

Present in all ch sites, RBC’s &CNS

It takes 3-6 months to

regenerate .It acts on endogenous Ach., methacholine.

Present in liver & plasma

It takes 2-3 weeks to regenerate .

.It acts on exogenous Ach. ,butyryl choline ,succinyl choline & procaine

1 -Muscarinic Actions:I Cardiovascular System:Heart: -ve chronotropic effect through inhibition of SA –node ↓HR (bradycardia)

- ve inotropic effect(↓ force of contraction )

- Ve dromotropic ( ↓ A-V conduction ) ↓ cardiac output.

Pharmacological actions of acetylcholine:

Blood Vessels(M3rec.): they are not innervated by parasympathetic supply.

,but Ach. Injection causes ↑ the release of endothelium derived relaxing factor(EDRF ,nitric oxide) ↑ cGMP vasodilation of peripheral and systemic bl vs

↓ of arterial bl.p. ↓ of periph.vas. resis. ↓ of bl. Flow to some organs e.g. kidney & liver.

Pharmacological actions of acetylcholine

Decrease in blood pressure: Injection of ACh causes vasodilation and lowering of blood pressure by an indirect mechanism of action.

ACh activates M3 receptors found on endothelial cells lining the smooth muscles of blood vessels.

This results in the production of nitric oxide from arginine as endothelium derived relaxing factor NO then diffuses to vascular smooth muscle cells to stimulate protein kinase G production, leading to hyperpolarization and smooth muscle relaxation .

In the absence of administered cholinergic agents, the vascular receptors have no known function, because ACh is never released into the blood in any significant quantities.

Atropine blocks these muscarinic receptors and prevents ACh from producing vasodilation.

2- GIT: a) ↑ motility b)↑ secretions. c) Relaxation of sphincters.3-Urinary Bladder: a) Contraction of detrusor muscle

urination. b) Relaxation of sphincter urination. 4- Eye: a) Circular m. contraction miosis.

b) Ciliary m contraction to see near objects.

5- Glands: Stimulation and increase secretion of sweat , salivary and lachrymal glands.

6-Lung:a) Bronchoconstriction. b) Stimulation of bronchial gland

secretion.

Organ Receptor Action

EyeCircular muscle of the iris

M3 Contracts

Ciliary muscle M3 Contracts

HeartSino-atrial node M2 SlowsMyocardium M2 Negative inotropic action (more in

atria) and negative chronotropic action

Blood vessels Endothelium M3 VasodilatationBronchioles M3 Contraction

GIT

Smooth muscle walls

M3 Contraction

Sphincters M3 RelaxGlands M3 Secretion

Urinary bladderWall M3 ContractsSphincter M3 Relax

Pregnant uterus M3 ContractsGlands M3 Secretion 9

Action of acetylcholine at cholinergic receptors

II- Nicotinic Actions:1- Stimulation of autonomic ganglia &

adrenal medulla:Ach ↑ autonomic ganglia the release of NE

from sympathetic nerve endings, this effect is blocked by ganglion blocker e.g. hexamethonium.

Ach at low conc. After atropine hypertension (Ach reversal action) because:

a) Ach ↑ the parasympathetic ganglia release of postsynaptic Ach ↑ M rec. ↓ bl.p. , this effect is blocked by atropine.

b) Ach ↑ sympathetic ganglia ↑ postganglionic endogenous NE hypertension.

c) Ach ↑ adrenal medulla ↑ the release of adrenaline hypertension.

This hypertension may be: -Abolished by ganglion blockers - Reversed by α – blockers.

2 -Neuromuscular Junction:Ach causes muscle twitching. This effect is

blocked by decamethonium or flaxedil

2- Synthetic Cholinomimetic Esters

General Properties:1 -All are quaternary ammonium compounds.

2-More specific in action & effective orally (compared to Ach).

3-Less metabolized by CE , so longer duration.4-Not given parenterally due to high incidence of toxicity

(can be controlled by atropine).5-Contraindicated in : a) Bronchial asthma.

b) Peptic ulcer. c) Angina pectoris d) Thyrotoxicosis since they cause arrhythmia (atrial fibrillation)

Activity Ach Metacholine Carbachol Bethanechol

1-Oral abs. NO Irregular Complete Complete

2-Metab. True & pseudo true only Not Not

3-M Effects+++ +++ +++ +++

4 -N Effects +++ + +++ NO

5—Selectivity NO CVS EYE ,GIT & UB NO

6-Adminis. IV oral& S.C. Oral ,SC &eye drops oral ,SC

Comparison between Ach & other sympathomimetics

A) MethacholineIt has longer duration of action than Ach.Therapeutic Uses:1- Used in the treatment of peripheral vascular

diseases.2-To relief the attacks of paroxysmal atrial

tachycardia.B) Carbachol: It has longer duration of action than Ach.Therapeutic uses:1- In the treatment of glaucoma. 2- In case

of urine retention.

Synthetic cholinomimetic esters:

C) Bethanechol (Urecholine):

Similar to carbachol but does not have nicotinic action.

Therapeutic uses:

1 -Postoperative urine retention .

2 -Glaucoma.

3 -Following bilateral vagotomy for peptic ulcer to relieve gastric retention.

Pilocarpine: Natural alkaloid of plant origin.Direct , tertiary amine , stable to CE. far

less potent than Ach.Pharmacological Actions:1- Direct M-rec. agonist with very weak N rec.

effects.2- Locally on the eye rapid miosis + contraction

of ciliary muscle.The eye undergoes spasm of accommodation &

vision is fixed at particular distance.3- Potent stimulant of sweat , tears & saliva sec.4- Well abs. orally ,& excreted in urine.5-Not metabolized by CE , so has long duration of

action

Cholinomimetic Alkaloids

OPEN ANGLE GLAUCOMA

Actions of pilocarpine and atropine on the iris and CILIARY muscle of the eye

Therapeutic Uses of Pilocarpine1- In the form of eye drops to treat

glaucoma. It produces miosis better drainage of aqueous humor ↓ in IOP in both close and wide angle glaucoma.

2- Counteracts mydriasis after eye fundus examination.

3- Acts as sialagogue to treat dry mouth.4-Diaphoretic (↑ sweating) nonspecific

treatment of fever. 5- To promote hair growth.

Adverse Effects: 1- Can pass bbb and causes CNS

disturbance ( so avoid in Parkinsonism). 2- Stimulates salivation & sweat.

They inhibit both true and pseudo CE enzymes resulting in accumulation of endogenous Ach. In the synaptic space inducing both muscarinic & nicotinic actions in the ANS & neuromuscular junction and the brain.

According to the extent of enzyme inhibition they may be used either as therapeutic or life threatening agents.

Reversible Anti-cholinesterases: They weakly inhibit CE by reversible

association with the anionic site & hinder access to Ach .

B- Indirect parasympathomimetics ((Anticholinesterases

A- Carbamate Derivatives: Physostigmine , Neostigmine , Pyridostigmine.

a)They attach to both sites of the enzyme .

b) They are substrates for CE ,and then will be hydrolyzed slower than Ach.

Comparison between physostigmine & neostigminePhysostigmine(Eserine) Neostigmine(Prostigmine))

Natural (calabar beans) ,tertiary amine.

1 -Well abs. orally.2 -Pass bbb.

3-Rapid metabolism by CE.4 -Short duration

-- Stimulates M & N receptors

- - Specific on eye--CNS stimulant. -Uses:1- Eye drops: -a) Glaucoma. -b) To counter act mydriatics.

Synthetic ,quaternary amm. comp.

1-Irregular oral abs.2 -Does not pass bbb.

3-Slow metabolism by CE. 4 -Long duration .

-Stimulates M & N receptors- Specific on GIT & UB

-Direct skeletal muscle stimulant.

-Uses:1- Myesthenia gravis-Diagnosis (0.5-1 mg IM)

Treatment (15-75 mg oral)

Physostigmine NeostigmineUses:2- I.V. in atropine poisoning. 3- Alzheimer disease.Toxicity :-Exaggerated Ach-like actions.- CNS convulsions.Managed by atropine+ anticonvulsant.

2- Curare poisoning.3- Paralytic ilius. 4- Urine retention.Toxicity:-Exaggerated Ach –like actions. -No convulsions in CNS.-Managed by atropine only.

Pyridostigmine is similar to neostigmine but with longer duration of action .used in chronic management of myasthenia gravis.

Pyridostigmine

Edrophonium:Similar to neostigmine BUT more rapidly absorbed and has short duration of action.It is not hydrolyzed by CE ,excreted in urine unchanged.Used in the diagnosis of myasthenia gravis.

B-quaternary alcohols:

a) Muscarinic side Effects: 1 ↑-Salivary and bronchial secretions.

2 ↑ -GI activities &nausea , vomiting and diarrhea , &colic.

3-Bradycardia & hypotension . These side effects can be antagonized by atropine.

b) Nicotinc side effects:1 -Stimulation of autonomic ganglia .

2-Neuromuscular junction: m. twitching& spasm

General Side Effects of Parasympathomimetic:

Some side effects of cholinergic agonists

They bind covalently to CE long lasting increase in Ach at all sites.Many of them are very toxic and were developed by military as nerve agents.Parathion is an insecticide.Isoflurophate: (diisopropylfluorophosphate DFP):It permanently inactivates the enzyme ,

Restoration of the enzyme requires 3weeks for the pseudo & 3 months for the true enzyme

2-Irreversible anticholinesterases (Organophosphorous compounds)

Pharmacological Actions:1 -Generalize Ch stimulation.

2 -Paralysis of motor functions (breath difficulties & convulsions ).

3-Intense miosis so has a therapeutic application.

Atropine in high doses can reverse many of the peripheral and central effects.

Therapeutic Use:1- For chronic treatment of open angle glaucoma (Topically as ointment).

The effect lasts for one week after a single dose.

Echothiophate is similar to isoflurophate.

.

Isoflurophate (cont.)

By the use of a synthetic enzyme reactivator pralidoxime (PAM)IT has a charged group & approaches the anionic

site on the enzyme so displaces the organophosphate and regenerate the enzyme.

It is effective only before enzyme aging. Enzyme Aging : Organophosphorous comp. + enzyme

phosphorylated enzyme this complex loses an isopropyl group (Aging) this makes it impossible for PAM to break the bond bet. the drug and the enzyme

Reactivation of Acetylcholinesterase:

Impairment in the neuromuscular transmission in the skeletal muscle.CCC by inability to control voluntary movements and muscle in-coordination.Etiology :

1 -Defect rate in Ach synthesis. 2 -Excessive CE enzyme at the

neuromuscular junction.3 -An autoimmune disease destruction

of cholinergic rec. at NMJ.

Myasthenia gravis

Symptoms:-Ptosis

- Diplopia -Difficulty in chewing & swallowing .

-- Respiratory failure.Diagnosis:1- Edrophonium: (2-8 mg iv rapid inc.

in m strength & improvement in 1 min. 2-Neostigmine : (0.5 mg im) + atropine

0.5mg.

Treatment:1-Neostigmine ( 15 mg/6hrs.) also

pyridostigmine.

2- Atropine to counteract the side effects of neostigmine.

3- Ephedrine and caffeine to improve neuromuscular transmission.

4- Immune –suppressant e.g. prednisolone & antimetabolite e.g. azathioprine.

An eye disorder charachtarized by increased intraocular pressure (IOP) due to defective drainage of aqueous humaur through the canal of Schlemm.TYPES:

1 -Chronic Open-Angle Glaucoma ( simple chronic):

- Gradual painless rise in IOP with progressive loss of vision due to pressure on the optic nerve.

-- Commonly bilateral .mostly in pts. over 40 years of age .

- - The etiology is not known.-

Glaucoma:

- Common in people over 60 years & usually affects one eye.

- The lens gradually increases in size by age pushing the iris forward.

- When the pupil dilates during the dark the relaxed iris may come in contact with the cornea and closes the canal of Schlemm ↑ IOP.

2-Acute (closed )– angle glaucoma:

The angle between the iris and the cornea

is gradually reduced and the canal of

Schlemm is occluded following repeated moderate or severe attacks chronic closed –angle glaucoma.

The strategy of treatment is: 1- To facilitate the drainage of aqueous humor . 2- To decrease the production of aqueous

humor.Miotic agents pull the iris away from the filtration

angle opening of the canal↓IOP - Treatment of narrow –angle glaucoma:- A) Drainage of aq. Humour :- Pilocarpine (1-2%) + physostigmine(0.5%) B) Reduction in the Synthesis of aq. Humour : - Acetazolamide ( carbonic anhydrase inhibitor)- Mannitol iv infusion, glycerine orally (osmotic

agents) .

Treatment of glaucoma

1- Miotic eye drops : pilocarpine + physostigmine.

2- Carbonic anhydrase inhibitor : acetazolamide.

3- Sympathomimetic eye drops: a) Adrenaline 1-2%. b) Phenylephrine 10%.4- ß- blockers: timolol 0.25- 0.5 %

eye drops.(NO Change IN PUPIL SIZE)

Treatment of wide –angle glaucoma:

They are classified to:A- Anti-muscarinic agents.Selectively block peripheral muscarinic

receptors↓ of muscarinic action of Ach.

B-Ganglion Blockers:They block both sympathetic &

parasympathetic ganglia.C- Neuromuscular Blockers:They block nicotinic receptors at the neuromuscular junction.

II- parasympatholytics (cholinergic antagonists)

1- Atropine: Pharmacological actions: It blocks peripheral & central M1 , M2 , M3 – receptors.

a) Cardiovascular System- Actions on the heart (M2-rec.):- Bradycardia Tachycardia.- The initial bradycardia is due to block of

the inhibitory M1- (presynaptic rec.)↑release of endogenous Ach.

At higher doses the cardiac rec.(M2 )on the SA-node are blocked tachycardia.

A- muscarinic blockers:

Therapeutic doses do not affect the vessel tone & not affect arterial bl.p.

b) GIT: ↓ tone & motility antispasmodic effect.

No significant effect on gastric acid secretion. Pirenzepine is a selective M1 – blocker used to control peptic ulcer.

c) Urinary Tract: Relaxation of the smooth m. of the ureter

( antispasmodic ) & urinary bladder urinary retention.

d) Bronchioles: Dilatation and reduced bronchial

secretions.

Pharmacological actions of atropine

e) Exocrine Glands: Atropine↓ salivary ,lachrymal, sweat &

bronchial secretions.f) Eye :

1 -It causes passive mydriasis ( paralysis of circular muscles ).

2 -Loss of accommodation for near objects (cycloplegia ) due to relaxation of ciliary muscle.

3-loss of light reflex . Mydriasis closure of canal of Schlemm in

closed –angle glaucoma (so contra-indicated).

Pharmacological actions of atropine

1 -As pre-anaesthetic medication to: a) Decrease both salivary and bronchial

secretions. b) Protect the heart from excessive

vagal tone. c) Counteract the inhibitory effect of

morphine on the respiratory center.2 -As antispasmodic.

3 -Mydriatic and cycloplegic.4 -Treatment of sever bradycardia.

5- As an antidote for organophosphorous compounds poisoning.

:TherapeutiC uses of atropine

a) Fever. b) Glaucoma. c) Tachycardia. d) Constipation & paralytic ileus. e) Senile hypertrophy of prostate f) After neostigmine severe bradycardia. G) Allergy to atropine.

Contraindications:

Scopolamine:=atropine but with more CNS-effects ,

longer duration of action.Mainly used for motion sickness.Homatropine:Used in ophthalmology as rapidly –acting mydriatic with short duration.Propantheline:Synthetic used as antispasmodic.Ipratropium: Given by inhalation for obstructive pulmonary disease & asthma.

Other antimuscarinics:

A) Ganglionic Stimulants Stimulate cholinergic receptor sites

on autonomic ganglia. 1- Nicotine: Natural tertiary amine alkaloid of

tobacco , it does not have any clinical applications.

Absorbed from all sites , pass bbb & placental barrier metabolized in liver & lung , excreted in urine & milk .

Drugs acting on autonomic ganglia

1- CNS stimulation →anxiety , hyperreflexia , tremors convulsions and coma.

2- Stimulates the respiratory center. 3- Stimulates the VMC , CTZ and ADH

secretion. 4- Stimulation of autonomic ganglia →+ve

inotropic ,+ve chronotropic &↑CO ↑ cardiac work→↑O2 need may →angina. - Increase automaticity so may cause

arrhythmia. - Increase peripheral resistance so may

cause hypertension .

Actions of nicotine

5- GIT ↑ parasympathetic activity →↑ gastric acidity →peptic ulcer.

- increased motility →colic , stimulation of CTZ → nausea. - depress appetite.

Therapeutic Uses: limited to smoking cessation programs as skin patches or chewing gum.

B- Ganglion blockers They interfere with the transmission of

the nerve impulses from preganglionic nerve terminals to the cell bodies of of postganglionic neurons.

The end organ response may show a predominant adrenergic or cholinergic effect.

The degree of enervation by the adrenergic and

cholinergic nervous system and the extent of adrenergic and cholinergic dominance in a given organ may not be equivalent leading to a response that is characteristic of the less dominant component.

e.g. in the heart the cholinergic system dominates over the adrenergic component

,so the administration of a ganglion blocker will have the greatest effect on the cholinergic component leading to adrenergic effect.

There are two types of ganglion blockers

1- Depolarizing Ganglion Blockers They initially stimulate the ganglia by

acetyl choline –like action and then block them due to a persistent depolarization e.g. nicotine.

Prolonged application of nicotine results in desensitization of cholinergic receptors sites and continued block e.g. nicotine in high concentration.

B- Ganglion blockers (cont.)

2- Competitive Ganglion Blockers They do not cause prior ganglion stimulation , they impair transmission by:

- Competing with Ach. for ganglion receptor sites e.g. tetraethylamonium and trimethphan.

OR- Blocking the ion channel when it is open e.g. hexamethonium , and pentamethonium

1- Blocking of Sympathetic Ganglia - Hypotension , orthostatic

hypotension , inhibition of sweat secretion, supersensitivity to exogenous sympathomimetics.

Actions of ganglion blockers

2- Blocking of Parasympathetic Ganglia (atropine – like action)

- Eye : passive mydriasis cycloplegia. -GIT : dry mouth distension and

constipation . - UB : urine retention . - blocking of both ganglia → impotence. Most side effects are due to blocking of

parasympathetic ganglia. Norepinephrine or ephedrine is used to

correct hypotension. Piolcarpine or neostigmine is used to

correct the atropine –like actions.

Rarely used due to side effects.

Trimethaphane has short duration of action so used to produce

hypotension during surgery and in the treatment of hypertensive crises.

Therapeutic uses of Ganglion Blockers

They act by interrupting transmission at the junction between skeletal muscle fibers and somatic nerve.

They can produce skeletal muscle relaxation and are classified into

A) Neuromuscular blockers B) Spasmolytic agents.

A) Neuromuscular Blockers: Based on their mechanism: a) Competitive Neuromuscular

Blockers. b) Depolarizing Neuromuscular

Blockers .

Skeletal muscle relaxants Neuromuscular blockers and spasmolytic relaxants

e.g. Tubocurarine , Gallamine , Pancuronium

They inhibit Ach competitively at receptor sites , they combine with the nicotinic receptors at the motor end plate but do not activate them.

The released Ach is unable to stimulate the already occupied receptors and it will be immediately hydrolyzed by cholinesterase enzyme leading to skeletal muscle paralysis.

a) Competitive Neuromuscular Blockers.

e.g. Succinylcholine, decamethonium , and suxamethonium

They cause sustained depolarization of the motor end plate

Like Ach they react with the nicotinic receptors leading to depolarization of the muscle fiber followed by receptor

desensitization and muscle relaxation. They are given parentrally Succinylcholine has rapid onset and very short

duration (3-7 min.) it is hydrolyzed rapidly by pseudochollinesterase enzyme.

Tubocurarine and pancuronium have longer duration of action (40-120 min )

2- Depolarizing neuromuscular blockers

1- Facilitate operative manipulation. 2- maintaning controlled ventilation

during surgery. 3- Facilitate the endotrachial intubation

( laryngoscopy ,bronchoscopy, oesophagscopy ), ( succinylcholine single iv dose )

4- D-tubocurarine is used for the symptomatic treatment of tetanus and other convulsive states.

5- Diagnosis of Myasthenia gravis. 6- With electro convulsent shock

therapy.

Therapeutic uses of neuromuscular blockers

Adverse Effects: 1- Prolonged apnea. 2-Muscle pain with depolarizing blockers.

1- Competitive Blockers. Can be antagonized by cholineesterase

inhibitors e.g. neostigmine . The unwanted actions of Ach. Can be blocked by atropine.

2- Depolarizing Blockers: No antagonist ,but artificial respiration until

recovery occurs. If an anticholinesterase is given, muscle

paralysis will be increased.

Reversal of neuromuscular block

They produce skeletal muscle relaxation either by

a) Central mechanism e.g. Diazepam and baclofen.

b) Direct effect outside the CNS e.g. dantrolene.

Diazepam: IT facilitates the action of GABA in the

CNS. Its spasmolytic action is partly in the

spinal cord.

B- Spasmolytic agents

Baclofen: It reduces the release of excitatory

neurotransmitters in the brain and the S.C.

It may also inhibit the release of substance P in the S.C.

Dantroline: It interferes with excitation contraction coupling in the m fiber.

It interferes with the release of activator Ca++ from the sarcoplasmic reticulum.

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