Feu Parasympathetic Drugs

AUTONOMICSAUTONOMICS

NERVOUS SYSTEMNERVOUS SYSTEM

CENTRAL NERVOUS SYSTEM

PERIPHERAL NERVOUS SYSTEM

BRAINSPINAL CORDEFFEREN

T DivisionAFFERENT Division

AUTONOMIC N.S.

SOMATIC N.S.

Sympathetic N.S.

Parasympathetic N.S.

Enteric N.S.

Autonomic Autonomic Nervous SystemNervous System

NEUROTRANSMITTERS:NEUROTRANSMITTERS:Sympathetic: ADRENERGICSympathetic: ADRENERGIC

Central: EPINEPHRINECentral: EPINEPHRINE Peripheral: NOREPINEPHRINEPeripheral: NOREPINEPHRINE

Parasympathetic: CHOLINERGICParasympathetic: CHOLINERGIC

AcetylcholineAcetylcholine

RECEPTORS:RECEPTORS:Sympathetic: Sympathetic: ADRENOCEPTORSADRENOCEPTORS

Alpha Alpha αα1 1 , , αα2 2

Beta Beta 1 1 , , 2 2 , , 33

Parasympathetic: Parasympathetic: CHOLINOCEPTORSCHOLINOCEPTORS

MuscarinicMuscarinic NicotinicNicotinic

Dopaminergic: Dopaminergic: DD11, D, D22

Parasympathetic N. Parasympathetic N. S.S.EffeEffector Organsctor Organs ReceptorReceptor ActionAction

EyeEye

circular m. circular m.

ciliary m.ciliary m.

MM33

MM33

Contraction (miosis)Contraction (miosis)

ContractionContraction

(accomodation)(accomodation)

HeartHeart

SA nodeSA node

ATRIAATRIA

AV nodeAV node

VENTRICLESSVENTRICLESS

MM22

MM22

MM22

↓ ↓ Heart rateHeart rate

↓ ↓ contractile strengthcontractile strength

↓ ↓ conduction velocityconduction velocity

small ↓ contractilesmall ↓ contractile

strengthstrength

LungLung

bronchial m.bronchial m. MM33 contractioncontraction

Effector OrgansEffector Organs ReceptorReceptor ActionActionBlood VesselsBlood Vessels

most BV most BV

skeletal m.skeletal m.

Endothelium drug effectEndothelium drug effect

--

--

M3M5M3M5

--

--

EDRFEDRF

GITGIT

wallswalls

sphinctersphincter

secretionsecretion

MM33

MM33

MM33

ContractsContracts

RelaxationRelaxation

IncreaseIncrease

GUTGUT

sphincter m.sphincter m.

bladder wall & detrusor bladder wall & detrusor m.m.

Penis, seminal v.Penis, seminal v.

MM33

MM33

MM


IncreaseIncrease

ErectionErection

Parasympathetic N. Parasympathetic N. S.S.

Effector OrgansEffector Organs ReceptorReceptor ActionAction

Secretory glandsSecretory glands

sweatsweat

intestinalintestinal

bronchialbronchial

lacrimallacrimal

MM

MM33

MM

MM

Generalized secretionGeneralized secretion

↑ ↑ secretionsecretion


Profuse secretionProfuse secretion


SUMMARY OF SUMMARY OF NEUROHUMORAL NEUROHUMORAL

TRANSMISSION PROCESS:TRANSMISSION PROCESS:

I.I. Synthesis and Storage of Synthesis and Storage of NeurotransmitterNeurotransmitter

II.II. Release of NeurotransmitterRelease of Neurotransmitter

III.III. Interaction with Postjunctional Cell Interaction with Postjunctional Cell and Initiation of Activity and Initiation of Activity

IV.IV. DeactivationDeactivation

Drugs That Enhance Drugs That Enhance Cholinergic TransmissionCholinergic Transmission

Nicotinic Agonists (Nicotine)Nicotinic Agonists (Nicotine)Muscarinic Muscarinic

agonists(bethanechol)agonists(bethanechol)Cholinesterase Inhibitor Cholinesterase Inhibitor

(physostigmine)(physostigmine)

Drugs That Inhibit Cholinergic Drugs That Inhibit Cholinergic TransmissionTransmission

1.1. Inhibitors of vesicular storage (vesamicol)Inhibitors of vesicular storage (vesamicol)

2.2. Inhibitors of release (botulinum toxin)Inhibitors of release (botulinum toxin)

3.3. Nicotinic antagonists (trimethaphan)Nicotinic antagonists (trimethaphan)

4.4. Muscarinic antagonists (atropine)Muscarinic antagonists (atropine)

5.5. Inhibitors of high affinity choline Inhibitors of high affinity choline transport (hemicholine)transport (hemicholine)

PARASYMPATHETIC DRUGSPARASYMPATHETIC DRUGS Parasympathomimetic agentsParasympathomimetic agents Cholinergic agonistCholinergic agonist (Muscarinic/nicotinic drug)(Muscarinic/nicotinic drug) CholinomimeticsCholinomimetics

Parasympathetic blockers/antagonistsParasympathetic blockers/antagonists ParasympatholyticsParasympatholytics Cholinergic antagonist/blockerCholinergic antagonist/blocker Anticholinergics (antimuscarinic, Anticholinergics (antimuscarinic,

antinicotinic)antinicotinic)

PARASYMPATHOMIMETICSPARASYMPATHOMIMETICS

A.DIRECT ACTING CHOLINOMIMETICSA.DIRECT ACTING CHOLINOMIMETICS Binds & activates cholinoreceptorsBinds & activates cholinoreceptorsI.MUSCARINIC II. NICOTINICI.MUSCARINIC II. NICOTINIC A. Choline EstersA. Choline Esters 1. Nicotine 1. Nicotine

1.1. Acetylcholine 2. AcetylcholineAcetylcholine 2. Acetylcholine2.2. Bethanechol 3. Succinylcholine Bethanechol 3. Succinylcholine 3.3. Carbachol 4. Carbachol Carbachol 4. Carbachol 4. Methacholine 4. Methacholine BB. Alkaloids. Alkaloids 1.1. Pilocarpine Pilocarpine 2.2. MuscarineMuscarine

MUSCARINIC RECEPTORSMUSCARINIC RECEPTORSReceptor Receptor

TypeTypeLocationLocation Postreceptor MechanismPostreceptor Mechanism

MM11NervesNerves ↑↑IPIP33, DAG cascade, DAG cascade

MM22Heart, nerves, smooth Heart, nerves, smooth musclesmuscles

Inhibition of cAMP prod’n, Inhibition of cAMP prod’n, activation of Kactivation of K++ channels channels

MM33Glands, smooth muscle, Glands, smooth muscle, endotheliumendothelium

↑↑ IPIP33, DAG cascade, DAG cascade

MM44? CNS? CNS Inhibition of cAMP Inhibition of cAMP

productionproduction

MM55? CNS? CNS IPIP33, DAG cascade, DAG cascade

NNMMSkeletal muscle NMJSkeletal muscle NMJ NaNa++, K, K++ depolarizing ion depolarizing ion

channel, action potentialchannel, action potential

NNNNPostganglionic cell body, Postganglionic cell body, dendritesdendrites

NaNa++, K, K++ depolarizing ion depolarizing ion channel, action potentialchannel, action potential

B.INDIRECT ACTING CHOLINOMIMETICSB.INDIRECT ACTING CHOLINOMIMETICS

Amplifies the effects of endogenous Ach by Amplifies the effects of endogenous Ach by inhibiting acetylcholinesteraseinhibiting acetylcholinesterase

i. ALCOHOLi. ALCOHOL1.1. EdrophoniumEdrophonium ii. CARBAMATESii. CARBAMATES1.1. NeostigmineNeostigmine 2.2. Physostigmine Physostigmine 3.3. Pyridostigmine, ambemonium Pyridostigmine, ambemonium iii.ORGANOPHOSPHATESiii.ORGANOPHOSPHATES1.1. EchothiophateEchothiophate 2.2. Parathion, Malathion, Dichlorvos Parathion, Malathion, Dichlorvos

AcetylcholineAcetylcholine quarternary ammonium compoundquarternary ammonium compound muscarinic & nicotinic activitymuscarinic & nicotinic activity Actions:Actions:

↓ ↓ HR and CO, ↓ BPHR and CO, ↓ BP ↑ ↑ salivary & intestinal secretion and GI motilitysalivary & intestinal secretion and GI motility Enhances bronchiolar secretionsEnhances bronchiolar secretions↑ ↑ detrussor muscle tonedetrussor muscle tone stim. Ciliary m. → near vision/ miosis stim. Ciliary m. → near vision/ miosis

Parasympathetic Parasympathetic AgonistsAgonists

(Parasympathomime(Parasympathomimetics)tics)Direct-Acting (Choline Esters):Direct-Acting (Choline Esters):

PHARMACODYNAMICSPHARMACODYNAMICS

A. MECHANISM OF ACTIONA. MECHANISM OF ACTION1. Ach activates muscarinic receptos on 1. Ach activates muscarinic receptos on

effector cells …> directly alter organ effector cells …> directly alter organ functionsfunctions

2.Ach interacts w/ muscarinic receptors on 2.Ach interacts w/ muscarinic receptors on nerve terminals to inhibit the release nerve terminals to inhibit the release

of neurotransmitter…>indirectly alter of neurotransmitter…>indirectly alter organ functions by modulating the effects organ functions by modulating the effects of PNS & SNS or NANC systemsof PNS & SNS or NANC systems

Neuromuscular JunctionNeuromuscular Junction

Nicotinic receptors on the NM end plate Nicotinic receptors on the NM end plate apparatus : respond to Ach & nicotineapparatus : respond to Ach & nicotine

Nicotinic agonist…>depolarization of end Nicotinic agonist…>depolarization of end plates (due to increase permeability to Na plates (due to increase permeability to Na & K)>>>> flaccid paralysis of skeletal & K)>>>> flaccid paralysis of skeletal musclemuscle

Effects of dierect acting Effects of dierect acting cholinoreceptor stimulantscholinoreceptor stimulants

EffeEffector Organsctor Organs ReceptReceptoror

ActionAction

EyeEye

circular m. circular m.

ciliary m.ciliary m.

MM33

MM33

Contraction (miosis)Contraction (miosis)

Contractionfor near visionContractionfor near vision

(accomodation)(accomodation)

HeartHeart

SA nodeSA node

ATRIAATRIA

AV nodeAV node

VENTRICLESSVENTRICLESS

MM22

MM22

MM22

↓ ↓ Heart rateHeart rate

↓ ↓ contractile strengthcontractile strength

↓ ↓ conduction velocity, ↑ refractory conduction velocity, ↑ refractory periodperiod

small ↓ contractilesmall ↓ contractile

strengthstrength

LungLung

bronchial m.bronchial m. MM33 contractioncontraction

Effector OrgansEffector Organs ReceptorReceptor ActionActionBlood VesselsBlood Vessels

ARTERIESARTERIES

VEINSVEINS

--

--

Dilatation (via EDRF) Dilatation (via EDRF) constriction (high dose diredt constriction (high dose diredt

effedteffedt

Dilatation (via EDRF) Dilatation (via EDRF) constriction (high dose diredt constriction (high dose diredt

effedteffedt

GITGIT

wallswalls

sphinctersphincter

motilitymotility

MM33

MM33

MM33

ContractsContracts


IncreaseIncrease

GUT GUT

sphincter m.sphincter m.

bladder wall & bladder wall & detrusor m.detrusor m.

Penis, seminal v.Penis, seminal v.

MM33

MM33

MM


contractioncontraction

ErectionErection


Effector OrgansEffector Organs ReceptorReceptor ActionAction

Secretory glandsSecretory glands

sweatsweat

intestinalintestinal

bronchialbronchial

lacrimallacrimal

MM

MM33

MM

MM

Generalized secretionGeneralized secretion



Profuse secretionProfuse secretion


CHOLINE ESTERS P’KINETICSCHOLINE ESTERS P’KINETICS

Poorly absorbed & distributed, hydrophilicPoorly absorbed & distributed, hydrophilicHydrolyzed in the GITHydrolyzed in the GIT TERTIARY NATURAL CHOLINOMIMETICS:TERTIARY NATURAL CHOLINOMIMETICS:

(Pilocarpine, nicotine, lobeline)(Pilocarpine, nicotine, lobeline) Well absorbedWell absorbed Acidification of urine accelerates clearanceAcidification of urine accelerates clearance

Quarternary amine: MUSCARINEQuarternary amine: MUSCARINE

Less completely absorbedLess completely absorbed


(Parasympathomime(Parasympathomimetics)tics)

Susceptibility Susceptibility to to

CholinesteraseCholinesterase

Muscarinic Muscarinic EffectsEffects

Nicotinic Nicotinic EffectsEffects

Therapeutic Therapeutic Use Use

AchAch ++++++++ ++++++ ++++++ MioticMiotic

MetachoMetacho-line-line

++ ++++++++ NoneNone Dx of Dx of bronchial bronchial hyperactivityhyperactivity

Carba-Carba-cholchol

NegligibleNegligible ++++ ++++++ MioticMiotic

GlaucomaGlaucoma

Betane-Betane-cholchol

NegligibleNegligible ++++ NoneNone Non-Non-obstructive obstructive urinary urinary retentionretention

Naturally-occuring:Naturally-occuring: PilocarpinePilocarpine ArecholineArecholine MuscarineMuscarine


(Parasympathomime(Parasympathomimetics)tics)Direct-Acting:Direct-Acting:

PILOCARPINEPILOCARPINE tertiary aminetertiary amine dominant muscarinic actiondominant muscarinic action resistant to acetylcholinesteraseresistant to acetylcholinesterase Action: rapid miosis & contracts ciliary m.Action: rapid miosis & contracts ciliary m.

Potent stimulator of secretions (sweat, tears, saliva)Potent stimulator of secretions (sweat, tears, saliva)

Therapeutic Use:Therapeutic Use: DOC in emergency lowering of IOP in glaucomaDOC in emergency lowering of IOP in glaucoma

Adverse Effects: CNS disturbances, profuse sweating Adverse Effects: CNS disturbances, profuse sweating and salivationand salivation





ARECOLINEARECOLINE

chief alkaloid of areca or betel nutschief alkaloid of areca or betel nuts muscarinic & nicotinic receptorsmuscarinic & nicotinic receptors enhances salivary secretionenhances salivary secretion no therapeutic indicationno therapeutic indication

Direct-Acting (Choline Esters):Direct-Acting (Choline Esters):


(Parasympathomime(Parasympathomimetics)tics)MUSCARINEMUSCARINE

quarternary aminequarternary amine muscarinic receptorsmuscarinic receptors found in mushrooms found in mushrooms (Amanita muscaria)(Amanita muscaria)

small amounts small amounts edible edible large amounts large amounts poisonous poisonous

effects: fall in BP, temporary cessation effects: fall in BP, temporary cessation of heart beat, diaphoresisof heart beat, diaphoresis

antidote: ATROPINE antidote: ATROPINE


(Parasympathomime(Parasympathomimetics)tics)Indirect-Acting :Indirect-Acting :

PhysostigminePhysostigmineNeostigmineNeostigminePyridostigminePyridostigmineAmeboniumAmeboniumEdrophoniumEdrophoniumTacrine, Tacrine, Donezepil, Donezepil, Rivastigmine, Rivastigmine, GalantamineGalantamine

Organophosphates Organophosphates IsoflurophateIsoflurophateEchothiophateEchothiophateMalathion, Malathion, ParathionParathion

Chemical WarfaresChemical WarfaresSarin, SomanSarin, Soman

A. ALCOHOLSA. ALCOHOLSReversibly bind electrostically & by Reversibly bind electrostically & by

hydrogen bonds to the active site hydrogen bonds to the active site thus preventing access of thus preventing access of acetylcholineacetylcholine

Enzyme inhibitor complex short livedEnzyme inhibitor complex short lived(2-10 minutes)(2-10 minutes)

B. CARBAMATES ESTERSB. CARBAMATES ESTERSUndergo two step hydrolysis Undergo two step hydrolysis

sequence analogous to that of sequence analogous to that of aceylcholineaceylcholine

The covalent bond of the The covalent bond of the carbamolated enzymes is more carbamolated enzymes is more resistant to the seond hydration resistant to the seond hydration rocessrocess

More prolonged (30 min to 6 hours)More prolonged (30 min to 6 hours)

C. ORGANOPHOSPHATESC. ORGANOPHOSPHATES Initial binding & hydrolysis by the Initial binding & hydrolysis by the

enzymesenzymes>>>phosphorylated active site>>>phosphorylated active siteMay undergo AGING (breaking of one May undergo AGING (breaking of one

of the O2-phosphorus enzyme bond)of the O2-phosphorus enzyme bond)Extremely stable & hydrolyzes in water Extremely stable & hydrolyzes in water

at a very slow rate (hundreds of hours)at a very slow rate (hundreds of hours)

ORGAN SYSTEM EFFECTSORGAN SYSTEM EFFECTSof Cholinesterase Inhibitorsof Cholinesterase Inhibitors

1. CNS1. CNS Low dose: EEG alerting responseLow dose: EEG alerting response High dose: convulsions, coma, resp deprnHigh dose: convulsions, coma, resp deprn

2.2. Eye, Resp tract, GIT, UTEye, Resp tract, GIT, UT Miosis, Contraction, IncreaseMiosis, Contraction, Increase

3. CVS3. CVS Incr in both sympathetic & Incr in both sympathetic &

parasympathetic ganglia supplying the parasympathetic ganglia supplying the heart heart

Heart: parasympa predominateHeart: parasympa predominate (-) chrono, dromo & inotropic effects…> (-) chrono, dromo & inotropic effects…>

CO fallsCO fallsMinimal effect on vascular smooth muscle Minimal effect on vascular smooth muscle

4. NEUROMUSCULAR JUNCTION4. NEUROMUSCULAR JUNCTIONLow therapeutic conc: incr strength Low therapeutic conc: incr strength

of contractionof contractionHigh doses: fibrillation of muscle High doses: fibrillation of muscle

fibers, fasciculationfibers, fasciculationPhysostigmine: direct nicotinic effect Physostigmine: direct nicotinic effect

at the NMJ at the NMJ

CLINICAL PHARMACOLOGY OF CLINICAL PHARMACOLOGY OF THE CHOLINOMIMETICSTHE CHOLINOMIMETICS

A. THE EYEA. THE EYEGLAUCOMAGLAUCOMAContraction of the ciliary body>>>facilitate Contraction of the ciliary body>>>facilitate

outflow of a. h.outflow of a. h.Pilocarpine, methacholine, carbachol,Pilocarpine, methacholine, carbachol,Physostigmine, demecrium, echothiophatePhysostigmine, demecrium, echothiophate

B. GIT/UTB. GIT/UTPostoperative ileus, urinary retention,Postoperative ileus, urinary retention,Reflux esophagitisReflux esophagitisRx; Bethanechol, neostigmineRx; Bethanechol, neostigmine

c. NEUROMUSCULAR JUNCTIONc. NEUROMUSCULAR JUNCTION

MYASTHENIA GRAVIS: autoimmuneMYASTHENIA GRAVIS: autoimmune

Antibodies reduce nicotinic receptors function: Antibodies reduce nicotinic receptors function: cross-lining receptors, causing lysis of the cross-lining receptors, causing lysis of the postsynaptic membrane & binding to postsynaptic membrane & binding to nicotinic receptors & inhibiting function,nicotinic receptors & inhibiting function,

MYASTHENIA GRAVISMYASTHENIA GRAVIS

Ptosis, diplopia, difficulty in speaking & Ptosis, diplopia, difficulty in speaking & swallowing & extreme weaknessswallowing & extreme weakness

Rx : cholinesterase inhbitorsRx : cholinesterase inhbitors Immunosuppresive agents, thymus gland Immunosuppresive agents, thymus gland

removal, Immunoglobulins, removal, Immunoglobulins, plasmapheresisplasmapheresis

Edrophonium: dxEdrophonium: dxLont term: pytidostigmine, neostigmineLont term: pytidostigmine, neostigmine

D. HEARTD. HEARTEdrophonium: paroxysmal SVTEdrophonium: paroxysmal SVT

E, ANTIMUSCARINIC DRUG E, ANTIMUSCARINIC DRUG INTERACTIONINTERACTION

Atropine/ Tricyclics overdoseAtropine/ Tricyclics overdoseRx Physostigmine w/ cautionRx Physostigmine w/ caution

F. CNSF. CNS

Tacrine, donezepil, gallanthamine, Tacrine, donezepil, gallanthamine, rivastigminrivastigmin


(Parasympathomim(Parasympathomimetics)etics) PHYSOSTIGMINEPHYSOSTIGMINE

Alkaloid, tertiary amineAlkaloid, tertiary amine Enters the CNSEnters the CNS DOA: O.5 to 2 hrs.DOA: O.5 to 2 hrs. Therapeutic Uses:Therapeutic Uses:

1.1. Atony of intestines and bladderAtony of intestines and bladder2.2. Glaucoma Glaucoma lowers IOP lowers IOP3.3. Antidote Antidote atropine, phenothiazines, TCA atropine, phenothiazines, TCA4.4. NDMR (tubocurarine) reversalNDMR (tubocurarine) reversal

Adverse effects: convulsions, bradycardia, Adverse effects: convulsions, bradycardia, ↓ CO↓ CO


(Parasympathomim(Parasympathomimetics)etics)NEOSTIGMINENEOSTIGMINE

Quarternary nitrogenQuarternary nitrogen Does not enter the CNS Does not enter the CNS peripheral peripheral DOA: 0.5 to 2 hrsDOA: 0.5 to 2 hrs Therapeutic Uses:Therapeutic Uses:

1.1. Atony of intestines and bladderAtony of intestines and bladder2.2. Myasthesia gravisMyasthesia gravis3.3. NDMR (tubocurarine) antidoteNDMR (tubocurarine) antidote

Adverse effects: salivation, flushing, Adverse effects: salivation, flushing, ↓ BP, ↓ BP, nausea, abdominal pain, diarrhea, bronchospasmnausea, abdominal pain, diarrhea, bronchospasm


(Parasympathomim(Parasympathomimetics)etics) PYRIDOSTIGMINE and PYRIDOSTIGMINE and

AMEBONIUMAMEBONIUM

DOA: DOA: PYRIDOSTIGMINE - 3 to 6 hrsPYRIDOSTIGMINE - 3 to 6 hrsAMEBONIUM – 4 to 8 hrsAMEBONIUM – 4 to 8 hrs

Therapeutic Uses:Therapeutic Uses:1.1. Myasthesia gravisMyasthesia gravis2.2. NDMR (tubocurarine) antidoteNDMR (tubocurarine) antidote

Adverse effects: salivation, flushing, Adverse effects: salivation, flushing, ↓ BP, ↓ BP, nausea, abdominal pain, diarrhea, nausea, abdominal pain, diarrhea, bronchospasmbronchospasm


(Parasympathomim(Parasympathomimetics)etics) EDROPHONIUM EDROPHONIUM

Quarternary amineQuarternary amine DOA: DOA: 5 to 15 mins5 to 15 mins Therapeutic Uses:Therapeutic Uses:

1.1. Diagnosis of Myasthesia gravisDiagnosis of Myasthesia gravis2.2. NDMR (tubocurarine) antidoteNDMR (tubocurarine) antidote3.3. Arrhythmias (SVT)Arrhythmias (SVT)

Antidote: Antidote: AtropineAtropine Adverse effects: salivation, flushing, Adverse effects: salivation, flushing, ↓ BP, ↓ BP,

nausea, abdominal pain, diarrhea, bronchospasmnausea, abdominal pain, diarrhea, bronchospasm


(Parasympathomim(Parasympathomimetics)etics) Tacrine, Donezepil, Tacrine, Donezepil,

Rivastigmine, GalantamineRivastigmine, Galantamine

Alzheimer disease Alzheimer disease deficiency of deficiency of cholinergic neurons in the CNScholinergic neurons in the CNS

TacrineTacrine – hepatotoxic – hepatotoxic Adverse effect: GI distressAdverse effect: GI distress


(Parasympathomim(Parasympathomimetics)etics)A.A. ORGANOPHOSPHATESORGANOPHOSPHATES

ISOFLUROPHATEISOFLUROPHATE- tx of open angle glauctx of open angle glaucomaoma

ECHOTHIOPHATEECHOTHIOPHATE- Produce intense miosis Produce intense miosis tx of open tx of open

angle glaucangle glaucomaoma

PARATHION, MALATHIONPARATHION, MALATHION- InsecticidesInsecticides

ORGANOPHOSPHATE ORGANOPHOSPHATE POISONINGPOISONING

1.1. MiosisMiosis

2.2. salivation, frothy secretionssalivation, frothy secretions

3.3. sweatingsweating

4.4. bronchial constrictionbronchial constriction

5.5. vomiting and diarrheavomiting and diarrhea

6.6. muscle fasciculationmuscle fasciculation

maintenance of VS maintenance of VS respiration respiration DecontaminationDecontamination Drugs: Atropine + Pralidoxime Drugs: Atropine + Pralidoxime

ATROPINE sulfateATROPINE sulfate 1 to 2 mg IV 1 to 2 mg IV every 5-15 min until signs of every 5-15 min until signs of effect appears (maximum of 1 gm effect appears (maximum of 1 gm per day)per day)PRALIDOXIMEPRALIDOXIME A cholinesterase A cholinesterase enzyme regenerator compoundenzyme regenerator compound

- 1 to 2 gm given over 30 - 1 to 2 gm given over 30 min by IV min by IV infusioninfusion

Organophosphate Organophosphate Poisoning TreatmentPoisoning Treatment

TOXICITY WITH DIRECT ACTING TOXICITY WITH DIRECT ACTING MUSCARINIC STIMULANTSMUSCARINIC STIMULANTS

OVERDOSAGE: nausea, vomiting, OVERDOSAGE: nausea, vomiting, diarrhea, urinary urgency, salivation, diarrhea, urinary urgency, salivation, sweating, cuatneous vasodilation, sweating, cuatneous vasodilation, bronchial constrictionbronchial constriction

Rx: Atropine Rx: Atropine

TOXICITY W/ DIRECT ACTING TOXICITY W/ DIRECT ACTING NICOTINIC STIMULATIONNICOTINIC STIMULATION

1.ACUTE TOXICITY1.ACUTE TOXICITYFatal dose of Ncotie: 40 mgFatal dose of Ncotie: 40 mgMay cause CNS stimulation, skeletal May cause CNS stimulation, skeletal

muscle end plate depolarization, muscle end plate depolarization, hypertension & cardiac arrtyhmiashypertension & cardiac arrtyhmias

RX: symptomaticRX: symptomatic

2. CHRONIC NICOTINE TOXICITY2. CHRONIC NICOTINE TOXICITY

Increase risk of vascular disease & Increase risk of vascular disease & sudden coronary deathsudden coronary death

High ulcer recurrenceHigh ulcer recurrenceRx nicotine gum. Transdermal patch, Rx nicotine gum. Transdermal patch,

inhaler & sprayinhaler & sprayVARENICLINE: partial agonist action at VARENICLINE: partial agonist action at

a4B2 nicotine receptorsa4B2 nicotine receptors

Parasympathetic Parasympathetic AntagonistsAntagonists

Parasympathetic Parasympathetic AntagonistsAntagonists A. ANTICHOLINERGIC DRUGSA. ANTICHOLINERGIC DRUGS

i. Antimuscarinici. Antimuscarinica. M1 Selective : Pirenzepinea. M1 Selective : Pirenzepineb. Non Selective: Atropine b. Non Selective: Atropine Scopolamine, glycopyrolate, ipratropium, Scopolamine, glycopyrolate, ipratropium,

tropicamide, oxybutynin, tropicamide, oxybutynin, benztropine,tolterodine benztropine,tolterodine

ii. Antinicotinicii. Antinicotinica.a. Ganglion Blockers : HexamethoniumGanglion Blockers : Hexamethoniumb.b. Neuromuscular Blockers: TubocurarineNeuromuscular Blockers: Tubocurarine B. CHOLINESTERASE REGENERATORB. CHOLINESTERASE REGENERATOR Oximes: PralidoxineOximes: Pralidoxine


(Parasympatholytic(Parasympatholytics)s)

ATROPINEATROPINE prototypeprototypeBelladona alkaloidBelladona alkaloid high affinity for muscarinic receptorshigh affinity for muscarinic receptors central and peripheral muscarinic central and peripheral muscarinic

blockerblockercauses reversible (surmountable) causes reversible (surmountable)

blockade of the actions of cholino-blockade of the actions of cholino-mimetics at muscarinic receptorsmimetics at muscarinic receptors



Actions:Actions:1. CNS1. CNS

– – minimal stimulant effect for atropineminimal stimulant effect for atropineMarked for scopolamineMarked for scopolamineAntiparkinsons agentsAntiparkinsons agents2. Eye 2. Eye

- mydriasis, unresponsiveness to light- mydriasis, unresponsiveness to light- - cycloplegiacycloplegia inability to focus for inability to focus for near-visionnear-vision

Dry eyesDry eyes

Parasympathetic Parasympathetic Antagonists Antagonists

Parasympathetic AntagonistsParasympathetic Antagonists

(Parasympatholytics(Parasympatholytics))

3. GIT3. GIT

- antispasmodic - antispasmodic reduce GIT activity reduce GIT activity

4. GUT4. GUT

- reduce urinary bladder hypermotility - reduce urinary bladder hypermotility

5. SECRETIONS5. SECRETIONS

- blocks salivary glands - blocks salivary glands antisialogogue antisialogogue

- - ↓↓ lacrimal & sweat glands secretion lacrimal & sweat glands secretion

ATROPINEATROPINE

Parasympathetic Parasympathetic AntagonistsAntagonists(Parasympatholytic(Parasympatholytics)s)ATROPINEATROPINE

6. CVS6. CVS

- divergent effects - divergent effects depending on dosedepending on dose

Low dose – (-) MLow dose – (-) M11 ↑ Ach ↑ Ach

releaserelease

Higher dose – (-) MHigher dose – (-) M22 on SA on SA

node node ↑ CR ↑ CR

Parasympathetic AntagonistsAParasympathetic AntagonistsATROPINE KINETICSTROPINE KINETICS

Well absorbed fr the GIT & conjunctivaWell absorbed fr the GIT & conjunctivaWell distributedWell distributedHydrolysis and conjugationHydrolysis and conjugation50% excreted unchanged thru the urine50% excreted unchanged thru the urineEffects on the eye persist for 72 hoursEffects on the eye persist for 72 hours

Therapeutic Uses:Therapeutic Uses:1. Ophthalmic1. Ophthalmic- Permits measurement of EOR Permits measurement of EOR 2. Antispasmodic2. Antispasmodic3. Antidote for cholinergic agonists3. Antidote for cholinergic agonists- Organophosphate poisoningOrganophosphate poisoning- Mushroom poisoningMushroom poisoning- acetylcholinesterase inhibitorsacetylcholinesterase inhibitors4. Antisecretory agent4. Antisecretory agent


(Parasympatholytics)(Parasympatholytics)ATROPINEATROPINE

DoseDose EffectsEffects

Parasympathetic AntagonistsParasympathetic Antagonists(Parasympatholytics)(Parasympatholytics)

ATROPINEATROPINE

0.5 mg0.5 mg Slight cardiac slowing Slight cardiac slowing

some dryness of mouth some dryness of mouth

inhibition of sweatinginhibition of sweating

1.0 mg1.0 mg Definite dryness of mouth; thirst Definite dryness of mouth; thirst acceleration of heart, sometimes acceleration of heart, sometimes preceded by slowingpreceded by slowing

mild pupillodilatationmild pupillodilatation



(Parasympatholytic(Parasympatholytics)s)ATROPINEATROPINE

2.0 mg2.0 mg Rapid HR; palpitations Rapid HR; palpitations

marked dryness of mouth marked dryness of mouth

Dilated pupils; some blurring of visionDilated pupils; some blurring of vision

5.0 mg5.0 mg All of the above symptoms marked; All of the above symptoms marked; difficulty in speaking and swallowing;difficulty in speaking and swallowing;

Restlessness and fatigue;Restlessness and fatigue;

Headache; dry, hot skinHeadache; dry, hot skin

Difficulty in micturitionDifficulty in micturition

Reduced intestinal peristalsisReduced intestinal peristalsis




ATROPINEATROPINE

10.0 mg 10.0 mg and moreand more

Above symptoms more markedAbove symptoms more marked

Pulse rapid and weakPulse rapid and weak

Iris practically obliteratedIris practically obliterated

Vision very blurredVision very blurred

Skin flushed, hot, dry, and scarletSkin flushed, hot, dry, and scarlet

Ataxia, restlessness and excitementAtaxia, restlessness and excitement

Halluciantions and deliriumHalluciantions and delirium

ComaComa


(Parasympatholytic(Parasympatholytics)s)SCOPOLAMINESCOPOLAMINE

Belladona alkaloidBelladona alkaloid Peripheral effects similar to atropinePeripheral effects similar to atropine Greater and longer CNS actionGreater and longer CNS action Action:Action:

Anti-motion sicknessAnti-motion sickness Blocks short-term memoryBlocks short-term memory Produces sedation, Produces sedation,

excitementexcitement

Therapeutic Uses:Therapeutic Uses:

anti-motion sicknessanti-motion sickness adjunct in anesthesia procedures adjunct in anesthesia procedures

> in obstetrics, + morphine > in obstetrics, + morphine sedation sedation

& amnesia & amnesia


(Parasympatholytic(Parasympatholytics)s)SCOPOLAMINESCOPOLAMINE

Quarternary derivative of atropineQuarternary derivative of atropineDoes not enter CNS Does not enter CNS Therapeutic Uses:Therapeutic Uses:

Treat asthma in patients who are unable to Treat asthma in patients who are unable to take adrenergic agoniststake adrenergic agonists

Management of COPDManagement of COPD


(Parasympatholytic(Parasympatholytics)s)IPRATROPIUMIPRATROPIUM

NICOTINIC BLOCKERSNICOTINIC BLOCKERS

A. GANGLION BLOCKER:A. GANGLION BLOCKER: HexamethoniumHexamethonium TrimethaphanTrimethaphan MecamylamineMecamylamineB. NEUROMUSCULAR BLOCKERSB. NEUROMUSCULAR BLOCKERS1.Nondepolarizing: 1.Nondepolarizing: Long Acting:TubocurarineLong Acting:Tubocurarine Short Acting: MivacuniumShort Acting: Mivacunium Depolarizing: SuccinylcholineDepolarizing: Succinylcholine

Ganglionic Blocking AgentsGanglionic Blocking Agents Competitive pharmacologic anagonistsCompetitive pharmacologic anagonists Block the entire output of the ANS at the Block the entire output of the ANS at the

nicotinic receptorsnicotinic receptors NICOTINENICOTINE Component of cigarette smokeComponent of cigarette smoke Depolarizes ganglia, resulting first in stimulation Depolarizes ganglia, resulting first in stimulation

& then paralysis of all ganglia& then paralysis of all ganglia ↑↑ in BP & CR, in BP & CR, ↑↑ peristalsis & secretion…> peristalsis & secretion…> ↑↑↑↑↑↑

doses : drop in BP, actv of GIT, bladder doses : drop in BP, actv of GIT, bladder musculature ceasesmusculature ceases

TRIMETHAPHANTRIMETHAPHAN Short acting competitive nicotinic ganglionic Short acting competitive nicotinic ganglionic

blocker blocker : IV, malignant hypertension: IV, malignant hypertension

MECAMYLAMINEMECAMYLAMINE Competitive nicotinic blockade of the gangliaCompetitive nicotinic blockade of the ganglia Ten hours durationTen hours duration Oral administrationOral administration Postural hypotensionPostural hypotension Dry mouth, blurred vision, constipationDry mouth, blurred vision, constipation Severe renal dysfunctionSevere renal dysfunction

NEUROMUSCULAR BLOCKERSNEUROMUSCULAR BLOCKERS

A.A. NON DEPOLARIZINGNON DEPOLARIZING

a. Long Acting: Tubocurarinea. Long Acting: Tubocurarine

b. Short Acting: Mivacuriumb. Short Acting: Mivacurium

B. DEPOLARIZINGB. DEPOLARIZING

SuccinylcholineSuccinylcholine

NONDEPOLARIZINGNONDEPOLARIZING NEUROMUSCULAR NEUROMUSCULAR BLOCKERS (NDNMB)BLOCKERS (NDNMB)

TUBOCURARINETUBOCURARINECombine with the nicotinic receptor & Combine with the nicotinic receptor &

prevent the binding of Achprevent the binding of AchPrevent depolarization of the muscle cell Prevent depolarization of the muscle cell

membrane & inhibit muscular contractionmembrane & inhibit muscular contractionCompetitive blockersCompetitive blockersHigh doses: can block the ion channels of High doses: can block the ion channels of

the end platethe end plate

NDNMBNDNMBUSE: as adjuvant in anesthesia during USE: as adjuvant in anesthesia during

surgery to relax skeletal musclesurgery to relax skeletal muscleGiven by IVGiven by IVUndergo redistributionUndergo redistributionTubocurarine: induce histamine release & Tubocurarine: induce histamine release &

promote ganglionic blockade, lower BPpromote ganglionic blockade, lower BPDrug Interaction: cholinesterase inhibitors, Drug Interaction: cholinesterase inhibitors,

halothane,aminoglycosides andhalothane,aminoglycosides and Ca channel blockersCa channel blockers

DEPOLARIZING NEUROOMUSCULAR DEPOLARIZING NEUROOMUSCULAR BLOCKERS (DNMB)BLOCKERS (DNMB)

SuccinylcholineSuccinylcholine Attaches to the nicotinic receptor & acts like Attaches to the nicotinic receptor & acts like

ACh to depolarize the junctionACh to depolarize the junction Persist at high conc in the synaptic cleft, Persist at high conc in the synaptic cleft,

remaining attached to the receptor remaining attached to the receptor Fasciculation…> flaccid paralysisFasciculation…> flaccid paralysis Half life: few minutes, by IV infusionHalf life: few minutes, by IV infusion Hydrolyze by plasma docholinesteraseHydrolyze by plasma docholinesterase Use: rapid endotracheal intubation/ in Use: rapid endotracheal intubation/ in

electroconvulsive shock Rxelectroconvulsive shock Rx Adverse effect: hyperthermia, apneaAdverse effect: hyperthermia, apnea

CHOLINESTERASE CHOLINESTERASE REGENERATORS(Pralidoxime)REGENERATORS(Pralidoxime)

Chemical AntagonistsChemical AntagonistsContain oxime group, has an extremely Contain oxime group, has an extremely

high affinity for the phoshorus atom in high affinity for the phoshorus atom in organophosphate insecticidesorganophosphate insecticides

Because the affinity of the oxime grp for Because the affinity of the oxime grp for phosphorus exceeds the affinity of the phosphorus exceeds the affinity of the enzyme active site for phosphorus, these enzyme active site for phosphorus, these agents are able to bind the inhibitor & agents are able to bind the inhibitor & displaces the enzyme,displaces the enzyme,

Delight yourself also in the Lord,Delight yourself also in the Lord,

And HE will give you the desires And HE will give you the desires of your heart.of your heart.

Psalms 37:4Psalms 37:4

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