Neurology

Adrenergic System

Adrenoceptors

Adrenergic receptors:

Alpha 1 – Most vascular smooth muscles – Activate PLC => ca++ => contraction Alpha 2 – Mostly presynaptic – Inhibit adenylate cyclase Beta 1 – Mostly heart – Activate adenylate cyclase Beta 2 – Respiratory and uterine smooth muscle – Activate adenylate cyclase Beta 3 – Mostly adipocytes – Activate adenylate cyclase => lipolysis (Dopamine)

•

• • •

•

•

Alpha

Beta

Generally Excitatory

Generally inhibitory

Exception: intestinal smooth muscle

Exception: beta1 in the heart

Mechanisms of Action and Effects

Mechanisms of Action and Effects

Adrenergic or sympathomimetic drugs have three mechanisms of action

• Drugs that activate alpha 2 receptors on presynaptic nerve fibers do not produce a sympathetic effect. In fact, these drugs inhibit the release of the neurotransmitter norepinephrine.

1.

2.

3.

Direct adrenergic drug action. Adrenergic drugs interact directly with postsynaptic alpha1 and beta receptors on target effector organs, activating the organ like norepinephrine does. Indirect adrenergic drug action occurs by stimulation of postsynaptic alpha1, beta1 and beta2 receptors by adrenergic medications. These drugs increase the release of norepinephrine into the synapse from storage sites in nerve endings or inhibit the reuptake of norepinephrine from the synapse. Mixed action. Is a combination of direct and indirect receptor stimulation.

• Stimulation of alpha2 receptors in the CNS (central) is helpful in treating hypertension but peripheral stimulation has no effect. Exact mechanism not clear. • Most body tissues have both alpha and beta receptors so the effect produced depends on the type of receptor activated and the number of affected receptors in a particular body tissue.

Adrenergic Agonist = Sympathetic Indirect Acting MOA= ↑ NE Release

Amphetamine

Direct Acting

Mixed Action

MOA= ++ α & β

MOA= Both

Alpha

Affinity of the Adrenergic Agonist

Ephedrine

Beta

Tyramine Beta 1

Beta 2

Alpha 2

Alpha 1

Isoproterenol < EPI < NE

NE < EPI < Isoproterenol

Clonidine

Phenylephrine

Guanfacine

Methxamine

Guanabenz

Midodrine

Methylnorepin ephrine

Metaraminol

Dobutamine

Albuterol

Denopamine

Salbutamol

Xameterol

Terbutaline Clenbutarol

α-methyldopa

Receptor Selectivity

Clinical Aspects of Adrenoceptor α1 adenoceptor effects • • • • • • • •

Eye ------------------------ Mydriasis. Arterioles --------------- Constriction. Uterus ------------------- Contraction. Skin ---------------------- Sweat. Platelet ------------------ Aggregation. Male --------------------- Ejaculation. Bladder Sphincter---- Contraction. Hyperkalaemia.

α2 adrenoceptors on nerve endings mediate negative feedback which inhibits noradrenaline release.

Clinical Aspects of Adrenoceptor β2 Adrenoceptor Effects

Direct acting; Epinephrine • Epinephrine: interacts with both alpha and beta

• • • • • •

Bronchi -------------- Relaxation. Arterioles ----------- Dilatation. Uterus --------------- Relaxation. Skeletal Muscle -- Tremor. Hepatic ------------- Glycogenolysis. Hypokalaemia.

• Low dose: mainly beta effects (vasodilation) • High dose: alpha effects (vasoconstriction)

• Pharmacological effects include:

• Increased BP • Vasoconstriction in peripheral blood vessels which allows for shunting of blood to heart and brain • Increased heart rate • Relaxation of GI smooth muscle • Relaxation and dilation of bronchial smooth muscle • Increased glucose, lactate, and fatty acids in the blood due to metabolic effects • Inhibition of insulin secretion • Increased leukocyte count and increased coagulation

Da – Phenylephrine (α1)

Direct acting; Epinephrine • Therapeutic Effects • • • •

Bronchospasm (emerg TX of asthma) Glaucoma Anaphylactic shock Promotes vasoconstriction

Da – Phenylephrine (α1) • Therapeutic effects: • Used in hypovolaemic shock as pressor agent. • Sinusitis & Rhinitis as nasal decongestant. • Mydriatic in the form of eye drops and lowers intraocular pressure. • Does not cross BBB, so no CNS effects. • Actions qualitatively similar to noradrenaline. • Postural Hypotension (Midodrine) • To prolong spinal anesthesia

Mixed Action; Ephedrine • Therapeutic Effects: – Treatment of bronchial asthma – As a nasal decongestant – As a mydriatic agent

Phenylephrine: Selective, synthetic and direct α1–agonist • Long duration of action. • Resistant to MAO and COMT. • Administered parenteraly & topically (eye, nose)

Pharmacological effects include: • • • • • • •

To produce vasoconstriction It decreases cardiac output and renal perfusion No activation of beta1 or beta2 Used to raise blood pressure in hypotension and shock Longer lasting than epinephrine May cause a reflex bradycardia Produces mydriasis and nasal decongestion.

Mixed Action; Ephedrine Ephedrine: Plant alkaloid, directly act on adrenoceptor & (indirectly) release of stored cathecolamine •Effects appear slowly but lasts longer (t1/2-4h) • Tachyphylaxis on repeated dosing • Pseudoephedrine is similar. • It resistant to COMT & MAO • It has a high bioavailability •A long duration of action

Pharmacological Effects include:

•Centrally – Increased alertness, anxiety, insomnia, tremor and nausea in adults. Sleepiness in children. •Used as bronchodilator, mydriatic, in heart block,mucosal vasoconstriction & in myasthenia gravis.

α2 Agonist - Clonidine Clonidine - Agonist to postsynaptic α2 adrenoceptors in brain, stimulation suppresses sympathetic outflow and reduces blood pressure. – High dose activates peripheral presynaptic autoreceptors on adrenergic nerve ending mediating negative feedback suppression of noradrenaline release. – Onset may be rapid (a few hours) or delayed for as long as 2 days and subsides over 2-3 days. – Treatment is to reinstitute clonidine, i.m or treat for phaeochromocytoma (is a tumor that produces norepinephrine and epinephrine and is equivalent to overfunction of the adrenal medulla)

– Never use Clonidine with β-adrenoceptor blockers.

Pharmacological Effects Include: – Clonidine reduces blood pressure.

Adrenergic System - Agonists b1 - receptors • Mostly in heart • Increase contractility = “positive inotrope” • Increase heart rate = “positive chronotrope” b2 - receptors • Respiratory system – located in bronchial smooth muscle • Short acting : Salbutamol, Metaproterenol, Terbutaline,pirbuterol. • Used for acute inhalational treatment of bronchospasm. – – – – –

Onset of action within 1 to 5 minutes. Bronchodilatation lasts for 2 to 6 hours. Duration of action longer on oral administration. Directly relax airway smooth muscle. Relieve dyspnea of asthmatic bronchoconstriction

β1 Agonists - Dobutamine

β2 Agonists - Isoproterenol Isoproterenol : β1=β2>> α

Dobutamine • Resembles dopamine & it is directly activates β1-receptor. Pharmacologic & Therapeutic effects: • Strong inotropic effect with little chronotropic effect => increase in cardiac output without significant increase in heart rate (Minimal changes in HR and systolic BP) • Short-term treatment of impaired cardiac function after cardiac surgery, MI etc. • Also used in “Dobutamine Stress Test” = Heart sonogram: Dobutamine mimics exercise • Adverse effects: Increases atrioventricular conduction, Atrial fibrillation, Increased myocardial oxygen demand that may worsen post-infarct myocardial damage

β2 Agonists - Albuterol • Albuterol: – Effective following inhalation. – Onset within 15 minutes, – Duration last about 3-4 hours.

• Pharmacologic effects: – (β2) Relax bronchial smooth muscle. – Therapeutic uses: Chronic and acute asthma, Bronchi asthma,Bronchospasm.

Pharmacologic effects: – (ß1) Increased cardiac contractility and heart rate – (ß2) Vasodilation in peripheral (skeletal muscle, Renal and mesenteric vascular beds ) Slight decrease in mean BP, marked drop in diastolic BP. – (ß2) Muscle relaxation (Bronchial and GI smooth) – (ß2) Inhibit antigen-mediated histamine release – Adverse effects: Palpitations, Tachycardia,Coronary insufficiency – Therapeutic uses: As a bronchodilator & cardiac stimulant for heart block or severe bradycardia, ventricular arrhythmia)

β2 Agonists - Albuterol • Albuterol: – Effective following inhalation. – Onset within 15 minutes, – Duration last about 3-4 hours.

• Pharmacologic effects: – (β2) Relax bronchial smooth muscle. – Therapeutic uses: Chronic and acute asthma, Bronchi asthma,Bronchospasm.

Indirect Sympathomimetics Amphetamines

β2 Agonists – Metaproterenol & Terbutaline

– These are synthetic compound having the same pharmacological profile as ephedrine. – Orally active long duration of action 4-6hrs – Displace norepinephrine in storage vesicle => forced epinephrine release – Also inhibit norepinephrine re-uptake and degradation by MAO (“triple action”)

Metaproterenol (β2>>β1>>>>α) Terbutaline – ß2selective – Terbutaline has a longer duration of action. – Metaproterenol has less ß2 selective compared to terbutaline and albuterol. – Resistant to COMT metabolism – Rapid onset and Long-duration

Pharmacological & Therapeutic effects

– On CNS: alertness, increase conc. Euphoria, talkativeness, increase work capacity, Athletic performance is increased temporarily. – Stimulated resulting in wakefulness and postponement of sleep, they stimulate respiratory centre. Hunger is suppressed as result of inhibition of hypertension feeding centre. – They also week anticonvulsant, analgesic.

Pharmacologic effects: – Relaxing effect on bronchial smooth muscle (β2) – Show little effect on cardiac β1 receptors. – Therapeutic uses: Bronchi asthma or bronchospasm

Indirect Sympathicomimetics Amphetamines • Drug abuse: Generally teenagers, seeking thrill/kick which obtained on rapid IV infusion, high dose produce Euphoria. • The central actions of amphetamine are largely mediated by release of noradrenaline in the brain.

Indirect Sympathicomimetics • Siburtamine

– This recently introduced anti-obesity drug inhibits the reuptake of both NA as well as 5HT, but does not have clinically useful antidepressant property. – It cans loss of 3-9 kg.wt. – Side effects: dry mouth, constipation, anxiety, insomnia, chest pain

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Fenfluramine – It affects food intake by enhancing serotonergic transmission in the hypothalamus and has tranquillizing rather than stimulant property. Appetite suppressant (now banned in US) (combined with Phentermine = “FenPhen”) – The plasma half life is 20hr. – Treatment beyond 3 months are not recommended. – Side effects: drowsiness, depression, loss of libido, dry mouth diarrhea.

•

Metamphetamine/MDMA

– Effectiveness disappears due to catecholamine depletion of vesicles => post-use depression => urge for re-administration!

DOPAMINE • It is alpha1 and beta1 agonist. When large doses are infused it will produce vasoconstrictions (alpha 1 action). • At normal doses it raises cardiac output and systolic blood pressure. • Dopamine is used in patient of cadiogenic or septic shock and severe congestive heart failure, (CHF) where it increase the blood pressure and urine outflow.

Therapeutic Usage of Adrenergic Agonist Drugs 1. Pressor agents: Nor adrenaline, Epedrine, Dopamine 2. Cardiac stimulants: Adrenaline, Isoprenaline 3. Branchodilators: Adrenaline, salbutamol, Terbutaline 4. Nasal decongestants: Xylometazoline, Pseudoehedrine 5. CNS Stimulants; Amphetamine, Dexamhetamine 6. Anorectics: Fenfluramine, Dexafenfluramine 7. Uterine relaxant: Ritodrine, salbutamol.

Therapeutic Usage of Adrenergic Agonist Drugs • Emergency drugs in treatment of acute cardiovascular, respiratory and allergic disorders

– In children, epinephrine may be used to treat bronchospasm due to asthma or allergic reactions. – Phenylephrine may be used to treat sinus congestion but rebound congestion can occur. – Use in older adults. Used to treat asthma, hypotension, shock, cardiac arrest and anaphylaxis. Careful monitoring required as elderly often have chronic cardiovascular conditions which may be aggravated by adrenergics. In ophthalmic preparations, caution as systemic absorption can likewise increase BP. – In shock as second line once volume has been replaced – In allergic disorders, used for vasoconstricting or decongestant effects – Inhibition of uterine contractions – For vasoconstriction and hemostatic effects

Contraindications to Use Cardiac dysrhythmias, angina pectoris Hypertension Hyperthyroidism Cerebrovascular disease Narrow angle glaucoma—dilation increases IOP In distal areas with a single blood supply such as fingers, toes, nose, ears • In those with urinary retention • In renal impairment • • • • • •

Toxicity of adrenergics Vasopressor action can affect renal perfusion Can induce cardiac dysrhythmias Increases myocardial oxygen consumption May decrease perfusion of liver w/resultant damage • Hyperglycemia, hypokalemia, and hypophosphatemia 2ndary to B1 stimulation • Tissue necrosis w/extravasation • Do not give epinephrine and isoproterenol at the same time or within 4 hours of each other. Could result in serious dysrhythmias. • • • •

Organ System Effects

Adrenergic Agonist Drugs

What is the treatment of choice for anaphylactic shock? Epinephrine

Why? It is the only drug that addresses the most serious manifestations: • β1 increases cardiac output • β2 relaxes constricted bronchioles • α1 constricts capillaries

Indirect Sympathicomimetics: MAO - Inhibitors: – Inhibition of MAO causes increase in free Norepinephrine – In the CNS, MAO also metabolizes dopamine and serotonin => MAO inhibitors trigger increase in these “happy hormones” => uses as antidepressants – Irreversible inhibition of MAO => long-lasting effect (weeks!) •

Tranylcypromine

•

Moclobemide Possibility of severe adverse interactions of MAO inhibitors with numerous other drugs => fatal hypertension

NEUROPHARMACOLOGY SBD 3034 / SPH 3014

CHAPTER FOKUS • This chapter describes the basic pharmacology of drugs that affect the parasympathetic nervous system. It also explains how cholinergic drugs increase parasympathetic activity and anticholinergic drugs decrease it. CHAPTER OBJECTIVES • After studying this chapter, you should be able to :

Muscarinic Drug

• • • • • •

CHOLINOMIMETIC DRUGS Direct Acting MAO=Receptor Agonist Choline Esters Acetylcholine Bethanecol Carbachol Methacholine

Alkaloids Pilocarpine Muscarine Nicotine

Indirect Acting MAO= Cholinesterase inhibitors Reversible/ Carbamates

Irreversible/ Organophosphate

Physostigmine Neostigmine Pyridostigmine Edrophonium

Isoflurophate Echothiophate Iodide, Parathion Malathion

describe the neuronal release and inactivation of acetylcholine list the three types of cholinergic receptors and the tissues where they are located explain the effects of acetylcholine on the major internal organs and glands of the body name two direct and two indirect acting cholinergic drugs and the effects they produce name three anticholinergic drugs and the main effects they produce on the major body system list the most frequently observed adverse effects of both cholinergic and anticholinergic drug therapy

• MUSCARINIC DRUGS • Muscarinic receptors are present in the brain, in ganglia, and on some cells such as those in blood vessels. Cholinergic agonists mimic the effects of acetylcholine at these sites. • Muscarnic receptor Agonists: • Acetylcholine and several synthetic choline esters. • Naturally occurring cholinomimetic alkaloids. ( Pilocarpine, muscarine) • • • •

Acetyl choline produces effects on many tissues include : dilation of blood vessels Contraction of spleen Contraction of smooth muscle

• Acetyl choline and drugs that mimic its actions may combine with muscarnic or nicotinic receptors or both • Acetyl choline (20-100mg I.V) has found occasional therapeutic use to terminate attacks of tachycardia.

Cholinergic Response

Cholinergic Response

Responses Mediated by Nicotinic Receptors Responses Mediated by Muscarinic Receptors Type of Receptor

Principal Locations

Mechanism of Signal Transduction

Effects

M1 – Neuron

Autonomic ganglia, presynaptic nerve terminals and CNS

Increased inositol triphosphate (IP3) and diacylglycerol (DAG)

Modulation of neurotransmission

M2- Cardiac

Cardiac tissue (sinoatrial Increased potassium & efflux or decreased cAMP atrioventricular nodes)

M3- Glandular

Smooth muscle & gland

Increased cGMP due to NO stimulation

Slowing of heart rate and conduction Vasodilatation

Cholinergic Receptor Agonists Cholinomimetics = Parasympathomimetics • Direct acting agonists – bind and activate cholinergic receptors - Act on the cholinergic receptors • Indirect-acting agonists – increase synaptic [ACh] by either inhibiting AChE or increasing the release of ACh from terminals - Act on the receptor of Ach

Type of Receptors

Principle location

Mechanism of Signal Transducer

Effect

Nm (In muscle)

In somatic neuromuscular junction

Increased sodium influx

Contraction of muscle

Nn (In neurons)

Autonomic ganglia

Increased sodium influx

Excitation of postganglionic neurons

Muscarinic Parasympathomimetics

R emember!!! • Cholinergic agonist => cholinomimetics => parasympatomimetics Organ system effects for cholinomimetics drugs = parasympathetic effects Adverse effects = SLUD/DUMBELS

SLUD: salivation, lacrimation (crying), urination, defecation, true for all Ach agonists DUMBELS - Diarrhea, Urination, Miosis, Bronchoconstriction, Excitation (of skeletal muscle & CNS), Lacrimation, and Salivation and Sweating

The extremely short half-life of Ach makes it therapeutically useless Ach is rapidly hydrolysed following oral ingestion and rapidly metabolized following intravenous administration

*All symptoms can be blocked by ATROPINE

Direct Acting- Choline Ester

• PARASYMPATHOMIMETIC DRUGS: • DRUGS that exert direct muscarinic actions or stimulate the muscarinic receptors. • Pharmacological effects: • • • • •

ON CVS: Ach has 4 effects on CVS : vasodilation, Decreased in cardiac rate Decreased in the rate of conduction Decreased in the force of cardiac contraction

• ON GIT: • All of the compounds of this class are capable of producing increasing in tone. Contraction of stomach and intestine. • The enhanced motility may be accompanied by nausea, vomiting intestinal cramps. • Urinary Tract: • Ach contracts muscle of urinary bladder, increase the maximal voluntary voiding pressure, and decrease the capacity of the bladder.

Drug

Therapeutic Use

Organ System Effects

Acetylcholine -Miochol(N&M) AchE=Yes

Eye: Intraocular – Miosis during opthalmic surgery. Cardio: Intracoronary – Coronary angiography

Eye: contraction of iris sphincter & ciliary muscle; facilitate outflow of aqueous humor in canal of schlemn decrease intraocular pressure

Bethanechol -Urecholine(M) AchE= No

GU: Oral/ Subcutaneuos/iv – Postoperative/ postpartum urinary retentionPromote emptying of bladder

CNS: does not cross BBB GI: increases tone & motility GU Contraction of destrusor muscles of bladder & relaxation of trigone & sphincter

GI: Salivary & gastric gland ++, salivation, nausea, abdominal pain. Diarrhea: (X acid-pepsin diseaseacid stimulation will aggravate) Resp: Bonchospasm (X asthma) Skin: Sweating, flushing Cardio: ↓BP (X coronary insufficiency & hyperthyroidism)

Carbachol -Miostat(N&M) AchE=No

Eye: Topical ocular – glaucoma Intraocular – Miosis during opthalmic surgery

CNS: does not cross BBB Cardio& GI: Significant activity at N& M

.

Ocular Effects

Muscarinic receptor agonist Pilocarpine Miosis-Pupillary constriction

Muscrinic receptor antagonist Atropine Mydriasis - Pupillary dilatation

Others/ Adverse Effect

X= contraindication DX= Diagnose TX= Treatment ++= Stimulates

Direct Acting- Alkaloids Drug

Therapeutic Use

Organ System Effects

Others/ Adverse Effect

Pilocarpine -Isoptocarpine(M>N) AchE= No

Skin: Oral – xerostomia Eye: ↓intraocular pressure in narrow /wide angle glaucoma GI: ↑Salivary secretion to ease swallowing &hydration of oral cavity

CNS: Cross BBB Eye: Rapid miosis contraction of iris sphincter & ciliary muscle; facilitate outflow of aqueous humor in canal of schlemn decrease intraocular pressure

Skin: Profuse sweating, cutaneous vasodilation Resp: bronchoconstriction GI: Profuse salivation

None

Muscurine (M) AchE= No Nicotine (N) AchE= No

Oral or transdermal – smoking cessation programme

CNS: ++ Ganglia initially- high doses produces ganglionic blockade. (desensitization of N) Cardio:↑ HR &BP GI: ↑ tone& motility

CNS: Convulsions, followed by coma & respiratory arrest Cardio: Hypertension & cardiac arrythmia

Precautions, Toxicity, and Contraindications •ACh and its agonist analogs should be administered only by the oral or subcutaneous route for systemic effects; they also are used locally in the eye. •Antidote - atropine. •Epinephrine may be used to overcome severe cardiovascular or bronchoconstrictor responses. •Among the major contraindications to the use of the choline esters are asthma, hyperthyroidism, coronary insufficiency, and acid-peptic disease. •Bronchoconstrictor action could precipitate an asthmatic attack •Hyperthyroid patients may develop atrial fibrillation. •Hypotension induced by these agents can severely reduce coronary blood flow, especially if it is already compromised. •The gastric acid secretion produced by the choline esters can aggravate the symptoms of acidpeptic disease. •Other possible undesirable effects of the cholinergic agonists are flushing, sweating, abdominal cramps, a sensation of tightness in the urinary bladder, difficulty in visual accommodation,headache, and salivation.

• Reversible inhibitors : - to reverse the effects of drugs that block cholinergic and nicotinic receptors (excessive anticholinergic blockade) - water soluble • Irreversible inhibitors - long duration because form irreversible bonds with the AchE enzyme - lipid soluble - cross skin, BBB and membrane.

CHOLINOMIMETIC DRUGS Direct Acting MOA=Receptor Agonist Choline Esters Acetylcholine Bethanecol Carbachol Methacholine

• Antidotal therapy of the toxic effects of cholinesterase inhibitors used as insecticide and chemical warfare agents is directed to blocking the effects of excessive acetylcholine stimulation. • The function of AchE in terminating the action of Ach at the junctions of various cholinergic nerve endings with the effector’s organs. Drugs that inhibit AchE are called anticholinesterase (anti-ChE) agents. Pharmacological Properties: The anti- ChE agents potentially can produce the following effects. • Stimulation of muscarinic receptor response autonomic effect or organs • Stimulation followed by depression of all autonomic ganglia and skeletal muscle. • Stimulation with occasional depression of cholinergic receptor sites in the CNS

Pilocarpine Muscarine Nicotine

MOA= Cholinesterase inhibitors Reversible/ Carbamates

Irreversible/ Organophosphate

Physostigmine Neostigmine Pyridostigmine Edrophonium

Isoflurophate Echothiophate Iodide, Parathion Malathion

Indirect Acting Cholinergic Agonists = IRREVERSIBLE Drug

Therapeutic Use

Organ System Effects

Others/ Adverse Effect

Isoflurophate (Floropryl)

Eye: TX of glaucoma (long acting)

Eye: Intense miosis

Generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties) & convulsions.

Echothiphate (Phosphline)

Eye: TX of glaucoma (long acting & low lipid solubility); reserved for cases when intraocular pressure cant be controlled by other drugs An insecticide that is converted in the body of insects & fish to acive compound

Cannot be detoxified in vertebrates

Malathion Parathion

ANTICHOLINESTERASE DRUG • These agents inhibit acetylcholinesterase, which is concentrated in synaptic regions and is responsible for the rapid hydrolysis of acetylcholine. Anticholinesterase agents have therapeutic utility in the treatment of glaucoma and other ophthalmologic indications.

Alkaloids

Indirect Acting

• The main action of anti-ChE agents are of therapeutic importance are concerned with eye, the intestine and neuromuscular junction of skeletal muscle and other actions of toxicological interest. • EYE : • When applied locally on eye it will produce miosis. It will become pinpoint in size, it generally contracts further when exposed to light. • GIT : • Neostigmine enhances gastric contractions and increases the secretion of gastric acid. The drug tends to counteract the inhibition of gastric tone motility induced by atropine. • SKELETAL NEUROMUSCULAR JUNCTION : • Treatment of Myasthenia Gravis • The anti-ChE agents will reverse the antagonism caused by competitive neuromuscular blocking agents. Neostigmine can be used for the skeletal muscle paralysis. • Action on other sites : Anti-ChE agents cause contraction of muscle fibers of the bronchioles and ureters.

smooth

• Treatment :

• ABSORPTION, FATE AND EXCRETION : • Physostigmine is absorbed readily from the g. i. t., subcutaneous tissues and mucous membranes. • Poorly absorbed after oral administration. Following their absorption, most organophosphorus compounds are excreted almost entirely as hydrolysis product in the urine. • TOXICOLOGY : • Organophosphorus compounds are used as agriculture insecticides, these agents have been used frequently for homicidal and suicidal purpose largely because of their accessibility.

• Atropine in sufficient dose effectively antagonizes the action at muscarinic receptors sites. • Pralidoxime 1 – 2g infused intravenously is recommended. • THERAPEUTIC USES : • Used in Glaucoma – is a disease characterized by an increase in intraocular pressure in eye leads to damage to the optic disc. • Used in Myasthenia gravis – is a neuromuscular disease characterized by weakness and marked fatigability of skeletal muscle. • Used in the peripheral and central effects of poisoning by atropine and related antimuscarinic drugs.

• The broad spectrum of effects on the CNS includes confusion, ataxia, slurred speech, convulsion, coma and death due respiratory failure may occur less than 5 min- 24 hours depending upon the dose, route, agent and other factors.

What is the difference between direct acting cholinergic agonists and indirect acting agonists? Direct-acting agonist: bind and activate cholinergic receptors Indirect-acting receptors: Increase the synaptic concentration of Ach

Cholinergic Antagonist => Cholinolytics => Parasympatholytics • Muscarinic receptor blockers: – Competitive antagonists – Widespread medical applications: • • • •

Inhibition of bronchial and gastric secretion Relaxation of smooth muscles (Bronchii, pupillary sphincter…) Cardioacceleration CNS-altering effects

• Nicotinic receptor blockers: – Ganglion-specific blockers: no clinical applications – Neuromuscular blockers: Muscle relaxants

Cholinergic Antagonist

CHOLINERGIC ANTAGONISTS

=> Cholinolytics => Parasympatholytics • Muscarinic receptor blockers: – Competitive antagonists – Widespread medical applications: • • • •

Inhibition of bronchial and gastric secretion Relaxation of smooth muscles (Bronchii, pupillary sphincter…) Cardioacceleration CNS-altering effects

• Nicotinic receptor blockers: – Ganglion-specific blockers: no clinical applications – Neuromuscular blockers: Muscle relaxants

MUSCARINIC ANTAGONISTS

Ach Inhibitor (Botulinum Toxin)

NEUROMUSCULAR BLOCKING AGENTS Non- Depolarising

Depolarising

MAO = Bind to NR and competes with Ach

MAO = Acts as nicotinic agonist depolarization

Short Duration (vecuronium, pancuronium)

Long Duration (tubocurarine)

(succinylcholine)

NICOTINIC ANTAGONISTS

GANGLIONIC BLOCKING AGENTS MOA = Interfere with postsynaptic transmission of Ach

Mecamylamine Nicotine Trimetaphan

CHOLINERGIC ANTAGONISTS MOA = Blocks Muscarinic Receptor MUSCARINIC ANTAGONISTS

Atropine Scopolamine Ipratropium Pirenzipine

Blocks muscarinic receptors MOA = Blocks Release of Ach Ach INHIBITOR

(Botulinum Toxin)

ANTI MUSCARINIC DRUG (MUSCARINIC RECEPTORS ANTAGONISTS) Muscarinic receptors antagonists prevents the effects of Ach by blocking its binding to muscarinic cholinergic receptors at neuro effectors sites on smooth muscle, cardiac muscle, and gland cells. •

• •

In general muscarinic receptors antagonists cause little blockade of the effects of Ach on nicotinic receptor sites, Atropine produces partial block only at relatively high doses. MECHANISM OF ACTION: Atropine and related compounds are competitive antagonists of the actions of Ach and other muscarinic agonists; they compete with such agonists for a common binding site on the muscarinic receptors. All muscarinic receptors are blocked by atropine.

•

NATURALLY occurring muscarinic receptors antagonist are the alkaloids of the belladonna plants. The most important of these are atropine, and scopalamine

•

SOURCES: The belladonna drugs are widely distributed in nature in the solanaceae plants. Atropa belladonna, yield the alkaloid atropine. The same alkaloid is found in Datura stramonium.

•

MUSCARINIC ANTAGONISTS

CHEMISTRY: Atropine and scopolamine are organic esters formed by combination of an aromatic acid, tropic acid, and complex organic bases either tropine or scopine.

Drug

Therapeutic Use

Others/ Adverse Effect

Ipratropium (Atrovent)

Resp: TX of asthma & chronic obstructive pulmonary disorder

Aerosol targets bronchiolar tissue locally to minimize systemic effects

Benztropine (Cogentin) Trihexyphnidyl (Artane)

CNS: Effective against Parkinsons tremor (often taken with drugs enhancing dopaminergic activity)

Scopolamine

CNS: Motion sickness (p.o/iv), blocking short term memory. Eye: Mydriasis & cycloplegia Resp: Used prior to admin of inhalant anaesthetic to reduce secretions & possibility of laryngospasm

GI: Post-op urinary retention & intestinal hypomobility

Methscopolamine (Pamine)

GI: large doses required to treat peptic ulcer disease (least sensitive to muscurinic blockade)

Such large doses-> Eye: blurred vision GI: Dry mouth; usually contraindicated in gastric peptic ulcer disease because of slow gastric emptying time, ↑exposure to acid GU: urinary hesitancy

Flavoxate (Urispas)

GU: overactive bladder: inappropriate urination

Dicylomine (Bentyl)

GI: Irritable bowel syndrome; spastic colon

Intermediate Responsiveness

Sensitive to Atropine

Salivary, bronchial, & sweat glands

Smooth muscle & heart

EFFECTS OF ANTI-MUSCARINIC DRUGS = Sympathetic • GLANDS • HEART • GU • GI • BRONCHI • EYE

Decrease of secretion Initial bradycardia, then tachycardia Relaxation of bladder wall, urinary retention Relaxation, slowed peristalsis Bronchodilation Cycloplegia*, mydriasis, reduction of lacrimal secretion (sandy eyes)

• Drowsiness, anti-motion sickness action, antiparkinson action, amnesia, delirium CNS

Adverse Effects/Toxicity "DRY AS A BONE, RED AS A BEET, MAD AS A HATTER“ 1. "Dry as a bone" is a result of decreased sweating, salivation, and lacrimation. 2. "Red as a beet" is a result of dilation of cutaneous vessels of the arms, head, neck and trunk - "atropine flush". 3. "Mad as a hatter" is a result of CNS effects, including sedation, amnesia, delirium or hallucination.

ABSORPTION, FATE AND EXCRETION: Atropine rapidly absorbed from the g.i.t. Atropine has half life of 4 hrs. Half of a dose excreted unchanged in the urine. • Poisoning by muscarnic receptors antagonists like Atropine, and other antidepressants amitriptiline : For the treatment Physostigmine 1-4mg given slowly by I.V .

• •

Therapeutic uses: Muscarnic receptor antagonists were once the most widely used drugs for the management of peptic ulcer.

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Although these drugs reduce the gastric motility and secretion of gastric acid it does produced many side effects like dry mouth, loss of visual accommodation usage of these drugs in peptic ulcer is poor.

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Belladonna alkaloids can induce bronchial dilation it was used in the treatment of bronchial asthma.

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Atropine occasionally is useful in reducing the severe bradycardia.

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Belladonna alkaloids were used in the prevention of motion sickness.

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Uses in Anesthesia: The belladonna alkaloids commonly were used to inhibit excessive salivation and secretions of the respiratory tract induced by administration of general anesthetic agents.

• •

Anticholinestrase and Mushroom poisoning: Atropine is only useful as an antidote for the symptoms of mushroom poisoning due to the cholinomimetic alkaloid muscarine found in certain mushroom species.

•

Classification of Blockers Agent

Pharmacological Properties

Onset time (min)

Duration (min)

1-1.5

6-8

Elimination

Succinylcholine

Ultra short acting; Depolarizing

Plasma cholinesterase

D-tubocurarine

Long duration; Competitive

4-6

80-120

Renal and liver

Atracurium

Intermediate duration; Competitive

2-4

30-40

Plasma cholinesterase

Mivacurium

Short duration; Competitive

2-4

12-18

Plasma cholinesterase

Pancuronium

Long duration; Competitive

4-6

4-6

Renal and liver

Rocuronium

Intermediate duration; competitive

1-2

1-2

Renal and liver