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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
RelaxationRelaxation
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
↑ ↑ secretionsecretion
Profuse secretionProfuse secretion
Parasympathetic N. Parasympathetic N. S.S.
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
RelaxationRelaxation
IncreaseIncrease
GUT GUT
sphincter m.sphincter m.
bladder wall & bladder wall & detrusor m.detrusor m.
Penis, seminal v.Penis, seminal v.
MM33
MM33
MM
RelaxationRelaxation
contractioncontraction
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
↑ ↑ secretionsecretion
Profuse secretionProfuse secretion
Parasympathetic N. Parasympathetic N. S.S.
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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(Parasympathomime(Parasympathomimetics)tics)
Parasympathetic Parasympathetic AgonistsAgonists
(Parasympathomime(Parasympathomimetics)tics)
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):
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AgonistsAgonists
(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
Parasympathetic Parasympathetic AntagonistsAntagonists
(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
Parasympathetic Parasympathetic AntagonistsAntagonists
(Parasympatholytic(Parasympatholytics)s)
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
Parasympathetic Parasympathetic AntagonistsAntagonists
(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
DoseDose EffectsEffects
Parasympathetic Parasympathetic AntagonistsAntagonists
(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
Parasympathetic Parasympathetic AntagonistsAntagonists
(Parasympatholytic(Parasympatholytics)s)
DoseDose EffectsEffects
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
Parasympathetic Parasympathetic AntagonistsAntagonists
(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
Parasympathetic Parasympathetic AntagonistsAntagonists
(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
Parasympathetic Parasympathetic AntagonistsAntagonists
(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