*

Cholinergic neurons and receptors

Cholinergic neurons and receptors

Adrenergic neurons and receptors

*

*

*Most organs receive dual sympatheticand parasympathetic innervation

However, some organs only receivesympathetic innervation:

SpleenSweat GlandsPiloerector MusclesMost Blood VesselsVascular smooth muscle is a prime example of a target organ that does not have dual innervationBlood pressure and peripheral resistance are controlled by the sympathetic nervous system

*

Mydriasis & MiosisMydriasisDilatation of pupil

MiosisConstriction of pupil

*Sympathetic: Contraction of radial muscle produces dilation (mydriasis)Parasympathetic: Contraction of circular muscle produces constriction (miosis)

Sympathomimetic drugs Adrenomimetic drugsAdrenergic agonistsAdrenoceptor agonists

Sympathetic Agonists (Sympathomimetics) EPINEPHRINENOREPINEPHRINEDOPAMINEIBOPAMINEAMPHETAMINEMETHAMPHETAMINEEPHEDRINEPSEUDOEPHEDRINEDOBUTAMINEISOPROTERENOL

12 and 12

1 and 21 and 2

Sympathetic Agonists (Sympathomimetics) PHENYLEPHRINEMETHOXAMINEMEPHENTERMINEMETARAMINOLMITODRINE

12 and 12

1 and 21 and 2

Sympathetic Agonists (Sympathomimetics) METHYLDOPACLONIDINEGUANABENZGUANFACINE

12 and 12

1 and 21 and 2

Sympathetic Agonists (Sympathomimetics) NAPHAZOLINETETRAHYDROZOLINEOXYMETAZOLINEXYLOMETAZOLINE

12 and 12

1 and 21 and 2

Sympathetic Agonists (Sympathomimetics) METAPROTERENOLTERBUTALINE, ALBUTEROLRITODRINEISOETHARINE, PILBUTEROLBITOLTEROL, FENOTEROLFORMOTEROL, SALMETEROLPROCATEROL

12 and 12

1 and 21 and 2

* Signal Transduction by 1 - Adrenergic Receptors

*Signal Transduction by 2 - and - Adrenergic Receptors

*Adrenergic (Sympathomimetic): DrugsCathecholaminesCannot cross Blood Brain BarrierEndogenous: Epinephrine, NE, DopamineExogenous (synthetic): Dobutamine (post-heart failure) and Isoproterenol (Bronchodilators)

Non-CathecholaminesCross the Blood Brain BarrierEphedrine (Metabolife diet pills), albuterol (anti-asthma), and phenylephrine (decongestant)

*Adrenergic (Sympathomimetic): UsesPrimarily used for emergency drugsCardiac arrest stimulates the heartHypotension increase BPCHF increase force and contraction of heartAsthma bronchodilatorURT Congestion decongestantAllergic reaction vasoconstriction and decongestantHypoglycemia glycogenolysis Local bleeding vasoconstriction Obstetrics uterine relaxantEye disorder vasoconstriction

*Adrenergic (Sympathomimetic): Adverse EffectsCathecholaminesNervousness and restlessnessAnginaHypertensionTachycardiaHyperglycemiaNausea and vomitingNon-CathecholaminesSevere anxiety and insonmiaTachycardia and palpitationsDysrhythmiasMuscular weakness and cramps

*

*Adrenergic (Sympathomimetic): ContraindicationsCardiac dysrythmiaAnginaHypertensionGlaucomaPregnant women

*Adrenergic (Sympathomimetic): Cathecholamine DrugsEpinephrine hydrochloride (Adrenalin Chloride)Drug of choice for Anaphylaxis Active ingredient in OTC (over-the-counter) asthma preparationEffects: (+) Alpha and Beta recepts BP and HR blood flow to brain, heart, and skeletal musclePeripheral vasoconstriction(-) GIT motility

*Adrenergic (Sympathomimetic): Cathecholamine DrugsNorepinephrine (Levophed)Strong vasoconstrictorUsed for Hypotension and Cardiac Arrest

Dopamine Hydrochloride (Intropin)Precursor to NEDosage effects:Low dose causes renal perfusionLow to moderate dose causes increased COHigher doses increased peripheral resistance and BP

*Adrenergic (Sympathomimetic): Cathecholamine DrugsDobutamine hydrochloride (Dobutrex)Synthetic cathecholamineActs directly on heart muscle to increase the contraction

Isoproterenol hydrochloride (Isuprel)Synthetic cathecholamineBronchodilator(+) Beta1 and Beta2 receptors

*Adrenergic (Sympathomimetic): Anti-Cathecholamine DrugsEphedrine and Pseudoephedrine (Sudafed)Less potent but longer acting than epinephrineBronchodilator and Nasal decongestant (allergic reaction)

Phenylephrine hydrochloride (Neo-Synephrine)(+) Alpha receptorVasoconstrictor, decongestant, and bronchodilator

Albuterol (Proventil)Bronchodilator

*Clonidine (Catapres) Centrally acting alpha 2 receptor agonist

Effects Reduces blood pressure and produces inhibition of sympathetic vasomotor centers

Indications Hypertension

*

*AmphetamineActions - CNS stimulant and cardiovascular stimulant (increased BP and heart rate and contraction)Mechanism of action Releases catecholamines from presynaptic storage vesicles. Indications - narcolepsy, appetite controlAdverse effects Restlessness, tremor, irritability, insomnia, tachycardia, hypertension

*Anti-Adrenergic (Sympatholytic)Block the effect of sympathetic nervous system

Treatment goal is to reduce pathologic response to activity, stress, and other stimuli

Two major types:Alpha-adrenergic blocking agentBeta-adrenergic blocking agent

Selective 1-blockers Selectively block 1 receptors Ie. Alfuzosin, doxazosin, prazosin, terazosin, tamsulosinUsed in the treatment of chronic hypertension Also used to treat urinary retention in men with benign prostatic hyperplasia

Non-selective -blockersBlock both 1 and 2 receptors phentolamine and phenoxybenzamine Chemical sympathectomyHypertensive Episodes - decreases vascular resistance - lowers BP - smooth muscle relaxation in the bladderUsed to treat hypertensive episodes of Pheochromocytoma

*Anti-Adrenergic (Alpha-adrenergic blocker): UsesMild to moderate hypertensionBenign prostatic hypertrophy (BPH)Migraine headachesPheochromocytoma tumor of the adrenal glandsIncreased secretion of Epinephrine and NECHF with diuretics Peripheral vascular disorders (frostbites)

*Anti-Adrenergic (Alpha-adrenergic blocker): Adverse EffectsNasal congestionNauseaVomitingPostural hypotension

*Anti-Adrenergic (Alpha-adrenergic blocker): ContraindicationsHypersensitivitySepsisHepatic or renal diseaseAtherosclerosis (alpha 2 blocker)Hypertension (alpha 2 blocker)AnemiaPregnancy and lactatingCaution to children and elderly

*Anti-Adrenergic (Alpha-adrenergic blocker): Important DrugsPhentolamine mesylate (Regitine)Prevents tissue necrosis after extravasation of IV NEPrevents and controls hypertension caused by Pheochromocytoma

Doxazosin (Cardura), Prozosin (Minipress), and Terazosin (Hytrin)Acts on the peripheryTreats hypertension or BPH

*Anti-Adrenergic (Beta-blockers)

-Nonselective blocker: propranolol*, timolol, nadolol-Combined a - and b - blocking:Carvedilol, labetalol -b 1 selective blocker: metoprolol, atenolol -b 2 selective blocker: butoxamine

*Anti-Adrenergic (Beta-Adrenergic)Block the effect of Adrenergic stimulation of Beta1 or Beta2

Competes with NE receptor site

Beta blockers Decrease in BP, heart contraction, and COBeta2 blockers causes vasodilation in skeletal muscles

Treatment for Angina pectoris and decrease BP

*Anti-Adrenergic (Beta-Adrenergic): Uses Angina decrease in O2 demand, heart contraction, HR, BPDysrhythmias slow sinus node, prolongs AV conductionHypertension lowers BPMI to decrease Cathecholamin-induced dysrhythmiasGlaucoma decreases IOPMigraine unclearPalpitation and Tremor unapproved anti-anxiety

*Anti-Adrenergic (Beta-Adrenergic): Adverse EffectsBradycardiaShortness of breathEdemaReduced tolerance to exerciseHypoglycemiaCHFOrthostatic hypotensionFatigue NauseaVomitingBronchospasmImpotenceDepressionSleep disorders

*Anti-Adrenergic (Beta-Adrenergic): Contraindication Diabetes with insulinKidney and liver disease (metabolism and excretion)Alcohol, CNS depressant, and OTC decongestant

*Anti-Adrenergic (Beta-Adrenergic): Important DrugsPropranolol hydrochloride (Inderal)Treats hypertrophic subaortic stenosis, hypertension, angina, dysrythmias, and MI

Metoprolol tartrate (Lopressor)Treats hypertension and dysrythmias

Atenolol (Tenormin)Treats hypertension, angina, and MI

Timolol maleate (Timoptic)Eye drop for treatment of Glaucoma

Drugs for GlaucomaMultiple medication classes used to treat glaucoma-several are autonomic drugs

Alpha 2 adrenergic agonists (Apraclonidine) [Iopidine]; (Bromonidine) [AlphaganP]

Topical carbonic anhydrase inhibitors (Dorzolamide) [Trusopt]

Beta blockers (Betaxolol, Timolol)

Prostaglandin analogs (Latanoprost) [Xalatan]

Cholinergic agonists - Direct (Pilocarpine)

Sympathomimetics (Dipivefrin)*

PARASYMPATHOMIMETIC DRUGSPARASYMPATHOLITIC DRUGS*

*

Cholinergic receptors*

*Amanita muscaria L.

*

Cholinoceptor-activating drugs Para sympathomimetics Cholinomimetics

*Direct Cholinergic AgonistsCholine EstersAcetylcholineMethacholineCarbacholBethanechol

AlkaloidsMuscarinePilocarpineAlkaloids are notmetabolized bycholinesterases

Properties of choline esters

Choline EsterSusceptibility to CholinesteraseMuscarinic ActionNicotinic ActionAcetylcholine++++++++++Methacholine+++++NoneCarbacholNegligible+++++BethanecholNegligible++None

Acetylcholinesterase inhibitorsThree chemical groups:*

AlcoholsEstersOrganophosphates1- Edrophonium1- Neostigmine 2- Physostigmine1- Echothiophate2- IsoflurophateNeostigmine is not absorbed and does not enter CNSPhysostigmine is absorbed from all sites including conjunctiva and enters CNSAll organophosphorous compounds are well absorbed from all sites of administration and enter the CNS except echothiophateReversible inhibition after 2-10 min.Reversible inhibition after 30 min to 6 hoursIrreversible inhibition (can be reversed by pralidoxime)

Therapeutic uses of cholinoceptor stimulants*

DiseaseMechanism of actionDrug1- GlaucomaContraction of the ciliary muscle and increasing the outflow of the aqueous humorPilocarpinePhysostigmine echothiophate2- Postoperative ileusBethanechol or neostigmine3- Reflux esophagitis4- Urinary retention5- Myasthenia gravisneostigmine, pyridostigmine, or ambenonium.

*Cholinergic (Direct-acting): DrugsBethanechol chloride (Urecholine)Treats urinary retention and glaucoma

Pilocarpine hydrochloride (Pilocar)Decreases IOP in Glaucoma

Carbachol intraocular (Miostat)Treats Glaucoma

Metoclopramide hydrochloride (Reglan)Prevents chemotherapy-induced nausea and vomitingTreats Acid-reflux disease

*Cholinergic (Indirect-acting): Important drugsNeostigmine bromide (Prostigmin)Treats urinary retention

Edrophonium chloride (Tensilon)Diagnoses Myasthenia gravis

Pyridostigmine bromide (mestinon)Drug of choice for Myasthenia gravis

*Edrophonium (Tensilon)Clinical indication diagnosis of myasthenia gravis

More rapidly absorbed and shorter duration of action than neostigmine

Toxicity of cholinoceptor stimulants*

Direct acting muscarinic stimulants (ex. Pilocarpine) meiosis, nausea, vomiting, diarrhea, salivation, sweating, cutaneous vasodilation, and bronchial constriction. These effects are all blocked by atropine.Cholinesterase inhibitorsAcute toxicity: Treated by atropine and pralidoxime)1- meiosis, nausea, vomiting, diarrhea, salivation, sweating, cutaneous vasodilation, and bronchial constriction 2- These manifestations are followed by:central stimulation, which cause convulsions and may progress to coma and respiratory arrest; skeletal muscle paralysishypertension and cardiac arrhythmias.

CHOLINOCEPTOR-BLOCKING DRUGSPARASYMPHATOLITIC DRUGS ANTICHOLINERGIC DRUGS

Antimuscarinic Antinicotinic

M1-selective Nonselective Ganglion Neuromuscular (Pirenzepin) blockers blockers

Muscarinic receptor blockers(antimuscarinic or parasympatholytic because they block the effects of parasympathetic autonomic discharge)I- Natural: 1. Atropine 2. Scopolamine (hyoscine)

II- Synthetic Substitutes a) Tertiary amines :1. Propantheline2. Pirenzepine3. Dicyclomine4. Tropicamide5. Benztropin6. Oxybutynin b) Quaternary amines 1. Ipratropium 2.Trospium

Antimuscarinic drugs used in ophtalmology

DrugDuration of Effects (days)Usual Concentration (%) Atropine7-100.5-1 Scopolamine3-70.25 Homatropine1-32-5 Cyclopentolate10.5-2 Tropicamide0.250.5-1

Atropine & Scopolamineplant origin atropine - Atropa belladonnascopolamine - Hyoscyamus nigerwell absorbed from mucous membranes or skincompetes with Ach for muscarinic receptorsorgans differ in sensitivity to these drugs

*Atropa belladonna

*Hyoscyamus niger

Atropinemost sensitivesalivary glandsbronchial glandssweat glandsintermediate sensitivity - heart tissuesleast sensitive - parietal cellshighly selective for muscarinic receptors

*Atropine SulfateGeneral Pharmacological Effects - A belladonna alkaloid competitively blocks muscarinic receptors from acetylcholine - ability to cross the CNS

IndicationsEye - Diagnostic use only - Causes mydriasis (pupil dilation) and cycloplegia (inability to focus). Increases intraocular pressure in patients with glaucomaGI - Antispasmodic agent for GI tract and bladder - Reduces motility and slightly reduces hydrochloric acid secretion.Antidote for cholinergic agonists - organophosphate overdosesCardiovascular applications

Adverse Reactions - (autonomic)- dry mouth, blurred vision, dry eyes, tachycardia, and constipation; (CNS) - confusion, and hallucinations

*Anticholinergic ContraindicationsContraindications - Narrow angle glaucoma, Tachycardia, GI or GU Obstructive disease, Myasthenia gravis, Asthma (Atropine only)

Myasthenia gravis - Anticholinergics contraindicated however (Atropine and propantheline) may be used in conjunction with Anticholinesterase medications to reduce GI side effects

Atropine in asthma - Systemic absorption and CNS penetration results in side effects and toxicity

Therapeutic uses of atropine1- Preanesthetic mediction:Given half an hour before general anesthesia to:Decrease salivary and bronchial secretionProtect the heart from excessive vagal tone which may occur during anesthesiaCounteract the depressant effect of morphine on the respiratory center2- Antispasmodic3- Treatment of severe bradycardia4- Antidote to parasympathomimetics5- Hyperhidrosis6- Treatment of poisoning with cholinoceptor stimulants (as cholinesterase inhibitors)

*ScopolamineBelladonna alkaloid with similar peripheral effects and greater CNS effects compared to atropineIndicationsMotion Sickness Surgery; block short-term memory, reduce the flow of saliva (antisialagogue). Adverse Reactions - Similar to atropine: drowsiness (17%), dry mouth (67%), blurred vision, pupil dilation.

*Ipratropium (Atrovent) Indication Bronchospasm

Available as an inhaler, solution for nebulization, and nasal spray (for rhinorrhea)

Bronchodilation - caused by inhibiting cyclic guanosine monophosphate in the lungs

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