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PARASYMPATHETIC DRUGS(Cholinomimetic Drugs)
. . . .
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Objectives
1. Cholinoceptor-Activating Drugs
1.1 Direct-acting cholinergic receptor agonists
1.2 Indirect-acting cholinergic receptor agonists
2. Cholinoceptor-Blocking Drugs
2.1 Muscarinic-blocking drugs2.2 Nicotinic-blocking drugs
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1. Cholinoceptor-Activating Drugs
1 2
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Cholinergic NT & Sites of Drug ActionCholinergic NT & Sites of Drug Action
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ACh + NMR Na + influx + EPSP (excitatory postsynaptic potential )
EPSP
depolarizes muscle membrane
action potential+muscle contraction .
Ex: NMJ
Nicotinic agonist
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Na +, K+ depolarizingion channel
Pentamer CNSpostganglioniccell body,dendrites
NN
Na +, K+ depolarizingion channel
Pentamer Neuromuscular junction
NM
-IP 3,-DAG cascade
Seven transmembranesegments,Gq/11 protein-linked
Glands,smooth muscle,endothelium
M3
-Inhibition of cAMPproduction,-Activation of K +
channels
Seven transmembranesegments,G i/o protein-linked
Heart,nerves,smooth muscle
M2
-IP 3,-DAG cascade
Seven transmembranesegments,Gq/11 protein-linked
NervesM1
Postreceptor Mechanism
Structural FeaturesLocationReceptor Type
Cholinoceptor Subtypes and Characteristics
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Drugs that inhibit ChE: edrophonium, neostigmine Drugs that augment effects of ACh: sildenafil (Viagra )
1.1 Direct-acting cholinergic receptor agonists Directly bind to muscarinic and nicotinic receptors
Types1. Choline esters:
- Acetic acid esters: ACh, methacholine
- Carbamic acid esters: carbachol, bethanechol
2. Plant alkaloids: pilocarpine, nicotine, lobeline
1.2 Indirect-acting cholinergic receptor agonist
1. Cholinoceptor-Activating Drugs
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Quaternary NH 4-cpdspoorly absorbed from GI tract & -/-> CNS
ACh & carbachol activate both M & N receptors ,Bethanechol activates only M receptors
Due to non- specificity for M receptor subtypeswide range of effects on many organ systems
ACh: choline ester of acetic acid, rapidly hydrolyzed by AChEextremely short duration
Bethanechol & carbachol , choline ester of carbamic acidresistant to AChE lasting for several hours
1.1.1 Chemistry & Pharmacokinetics:1.1.1.1. Choline esters
1.1 Direct-Acting Cholinergic Receptor Agonists
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found in mushrooms, can cause diarrhea, sweating, salivation & lacrimation, no medical use
1.1.1.2. Plant Alkaloids:
derived from Nicotiana plants &
contains in cigarettes & tobacco products, use for smoking cessation
is tertiary amine well absorbed, use as second-line drug for chronic glaucoma use for xerostomia (dry mouth), low dose,
oral pilocarpine stimulates salivary secretion(high sensitivity of salivary gland)
Nicotine,
Muscarine,
Pilocarpine,
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ANS Effects on Organs
1.1.2 Drugs acting on muscarinic receptors
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Parasympathetic effects Sympathetic effects
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St t f th t i h b f th
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Aqueous humor is secreted by the epithelium of the ciliary body ( ) flows in front of the iris trabecular meshwork-->canal of Schlemm (arrow ).
Blockade of the adrenoceptors: - secretion of aqueous. Blood vessels (not shown) in the sclera are also under autonomic control and
influence aqueous drainage
Structures of the anterior chamber of the eye(Show ANS receptors)
A t i Eff t th E
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Autonomic Effects on the Eye
Suspensoryligament(M) ( )
( ) (M)
Iris; para + constrictor muscle pupil size = miosissym + dilator muscle pupil size = mydriasis
Ciliary muscle constrictrelax suspensory ligament eye accommodation for near visionTrabecular meshwork increase aqueous humour drainage
Effects of pilocarpine and atropine on the eye
Effects of pilocarpine and atropine on the eye
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Effects of pilocarpine and atropine on the eyeEffects of pilocarpine and atropine on the eye
A. Normal eye: Relationshipbetween iris sprincter & ciliary muscle
B. Muscarinic agonist(:pilocarpine)
- iris sprincter contraction->pupil constrict ( miosis)
- ciliary contraction-> relax suspensory ligament-> len thickness
-> focus on close object .C. Muscarinic antagonist
(:atropine)
- iris sprincter relax->pupil dilate (mydriasis )
- ciliary muscle relax
-> suspensory ligament contraction-> len thickness-> blurred vision (cycloplegia).
D g th t l i t l
Drugs that lower intraocular pressure
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Muscarinic agonist Prostaglandins -antagonist & -agonist Carbonic anhydrase inhibitor
Muscarinic agonist (:pilocarpine) ciliary muscle contraction
open trabecular spacedrainage
Drugs that lower intraocular pressureDrugs that lower intraocular pressure
h l l
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Drugs that lower intraocular pressureDrugs that lower intraocular pressure
Can cause ocular pigmentationProstaglandinanalogue
Latanoprost
Used as eye drops2-Adrenoceptoragonist
Clonidine,apraclonidine
Acetazolamide is given systemically.Side effects include diuresis, loss of appetite,tingling, neutropenia.Dorzolamide is used as eye drops.
Side effects include bitter taste and burningsensation.
Carbonic anhydraseinhibitor
Acetazolamide,dorzolamide
Given as eye drops but may still causesystemic side effects: bradycardia,bronchoconstriction.
-Adrenoceptor antagonist
Timolol
Widely used as eye dropsCan cause muscle spasm & systemic effects
AnticholinesteraseEcothiopate
Widely used as eye dropsMuscarinic agonistPilocarpineNotesMechanismDrugs
Effects of Direct Acting Cholinoceptor Stimulants
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19SecretionSweat, salivary,lacrimal, nasopharyngeal
Glands
RelaxationTrigone and sphincter
ContractionDetrusor Urinary bladder
StimulationSecretion
RelaxationSphinctersIncreaseMotilityGI tract
StimulationBronchial glands
Contraction (bronchoconstriction)Bronchial muscleLung
Dilation (via EDRF). Constriction (high-dosedirect effect)
Veins
Dilation (via EDRF). Constriction (high-dosedirect effect)
ArteriesBlood vessels
Small decrease in contractile strengthVentricles
Decrease in conduction velocity (negativedromotropy). Increase in refractory periodAV node
Decrease in contractile strength (negativeinotropy). Decrease in refractory period
Atria
Decrease in rate (negative chronotropy)Sinoatrial nodeHeartContraction for near visionCiliary muscle
Contraction (miosis)Sphincter muscle of irisEye
ResponseOrganEffects of Direct-Acting Cholinoceptor Stimulants
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20Glaucoma ,xerostomia
Topical ocular,oral
NoM > NPilocarpine
Smokingcessation
Oral,transdermal
NoNNicotine
NoneNoMMuscarine
Plant Alkaloids
Glaucoma
Miosis duringophthalmicsurgery
Topical ocular,
Intraocular
NoM & NCarbachol
Stimulate GI &bladder motility
Oral, scNoMBethanechol
Miosis duringophthalmicsurgery
Intraocular YesM & N AcetylcholineCholine esters
Clinicaluse
Route ofadministration
Hydrolyzedby ChE
Receptor specificity
Drug
1 1 3 D A ti Ni ti i R t
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1.1.3.1 Drugs acting on autonomic ganglia: nicotine
Stimulate both sym & parasym ganglia complex effects- tachycardia and- increase of blood pressure;- variable effects on GI motility and secretions;- increased bronchial, salivary and sweat secretions.
Ganglion stimulation may be followed by depolarisation block .
Nicotine also has important CNS effects .
No therapeutic uses,(Except for nicotine to assist giving up smoking)
1.1.3 Drugs Acting on Nicotinic Receptor: Autonomic ganglion & NMJ1.1.3 Drugs Acting on Nicotinic Receptor: Autonomic ganglion & NMJ
1 1 3 2 Drugs acting on neuromuscular junction (NMJ)
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1.1.3.2 Drugs acting on neuromuscular junction (NMJ)
SCh + N MR (postsynaptic site)prolong depolarizationunresponse to subsequent impulse
neuromuscular block= Depolarizing neuromuscular blocking agents
ACh + Receptor (alpha site)
Open Na ion channel
Na + influx
Depolarization
Muscle contraction
Succinylcholine ( SCh or suxamethomium )
Acetylcholine ( ACh)
1 2 Indirect acting cholinergic receptor agonists
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1.2.1 Drugs that Inhibit ChE (Anticholinesterase drugs)1.2.1 Drugs that Inhibit ChE (Anticholinesterase drugs)
2. Butyrylcholinesterase (BuChE or pseudocholinesterase)- occurs in plasma and many tissues (liver),
- non-selective
Cholinesterase : Two main forms of ChE :
1. Acetylcholinesterase (AChE): membrane-bound, specific for AChrapid ACh hydrolysis at cholinergic synapses
1.2.1 Drugs that inhibit ChE1.2.2 Drugs that augment effects of ACh
1.2 Indirect-acting cholinergic receptor agonists
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Reversible antiChE Irreversible antiChE
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(2-PAM)
: Organophosphates(:parathion)
formed covalent bondvery slow hydrolysis
: Carbamates (:neostigmine )formed carbamoylated enzyme
slow hydrolysis
Pharmacologic Effects of antiChE Drugs
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cholinergic transmission at synapses
-CVS: bradycardia, hypotension
-RS: excessive secretions, bronchoconstriction-GI: gastrointestinal hypermotility-Eye: intraocular pressure
Pharmacologic Effects of antiChE Drugs
Autonomic actions:
CNS effects:
-muscle fasciculation and-can produce depolarisation block
Neuromuscular action:
- convulsion: physostigmine, organophosphates(antiChEs that cross BBB)
- AntiChE poisoning may occur from exposureto insecticides or nerve gases
Clinical Uses of Anticholinesterases
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1. Anaesthesia : neostigmine + atropine
Clinical Uses of Anticholinesterases
-to reverse action of non-depolarisingneuromuscular-blocking drugs
:donepezil,galantamine,rivastigmine
-to test : edrophonium-treatment : neostigmine &
pyridostigmine
2. Myasthenia gravis
: ecothiopate
(eye drops)
3. Glaucoma
4. Alzheimers
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Physostigmine, Neostigmine & Pyridostigmine
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Ester of carbamic acid slow hydrolysis, duration 0.5-2 h
Physostigmine-Tertiary amine well absorbed & penetrates BBB- Use in the treatment of anticholinergic drug overdose
(atropine, phenothiazine, tricyclic antidepressant) Neostigmine & Pyridostigmine ,
- Synthetic quaternary amine cpds absorbed -/-> BBB.- Clinical uses:
- treatment of MS,- antidote of nondepolarizing blocking agent- stimulate bladder & GI tract (SC)
Are centrally acting, reversible ChE inhibitors that readily cross BBB &increase brain ACh conc, treat Alzheimers disease
Donepezil, galantamine, rivastigmine
. . rugs a ugmen ec s o: Sildenafil (Viagra ) Used in erectile dysfunction
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Erection requiresrelaxation of thenonvascular smooth
muscle of the corporacavernosa
In response to therelease of NO fromNANC associated withparasympatheticdischarge.
Sildenafil cGMP(- phosphodiesteraseisoform 5)
: Sildenafil (Viagra ), Used in erectile dysfunction
2. Cholinoceptor-Blocking Drugs
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2. Cholinoceptor Blocking Drugs
2.1 Muscarinic-Blocking Drugs- Compete with ACh for M-receptors parasympatholytic drugs- Obtained from:
- Plants (Belladonna alkaloids): atropine, scopolamine, hyoscyamine- Synthesis: ipratropium, dicyclomine, tropicamide, pirenzepine
- Have similar effect, differ in pharmacokinetics & clinical uses
2.2.1 Ganglionic blocking agents2.2.2 Neuromuscular blocking agents
- Nondepolarizing Neuromuscular blocking agents: Tubocurarine
- Depolarizing Neuromuscular blocking agents: Succinylcholine
2.2 Nicotinic-Blocking Drugs
l k
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Pharmacological effects (: atropine )
HR tachycardia
Eye mydriasis, cycloplegia, & intraocular pressure
Relax smooth muscle: bronchial, biliary & urinary tract
CNS : atropine + CNS
GI: GI motility & gastric acid secretion
Secretion dry mouth
2.1 Muscarinic-Blocking Drugs
Dose Dependent Effect of Atropine
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Low dose of atropine inhibits salivation & sweating , The effects are dose-dependent. Higher doses tachycardia, urinary retention & CNS effects
(Brenner 2006 p 66)
Clinical uses of muscarinic antagonists
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-CVS : sinus bradycardia-Eye : dilate pupil
-CNS : motion sickness (scopolamine),parkinsonism (benztropine, biperiden)
-RS : asthma (ipratropium, used in combination with 2 agonists in the management of chronic asthma )
anasethetic premedication (atropine)-GI : antispasmodicpeptic ulcer
Clinical uses of muscarinic antagonists
Muscarinic-Blocking Drugs
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Fewer side effects than othermuscarinic antagonists
Largely superseded by otherantiulcer drugs
Peptic ulcerSelective for M1 receptorsInhibits gastric secretion
by action on ganglion cellsLittle effect on smoothmuscle or CNS
Pirenzepine
As tropicamide (long acting)Similar to tropicamideCyclopentolate
Ophthalmic use to producemydriasis and cycloplegia (as eyedrops)Short acting -
Similar to atropineMay raise intraocularpressure
Tropicamide
Quaternary ammonium compoundTiotropium is similar
By inhalation for asthma ,bronchitis
Similar to atropinemethonitrateDoes not inhibitmucociliary clearance frombronchi
lpratropium
Quaternary ammonium derivativeMainly for GI hypermotilitySimilar to atropine butpoorly absorbed & lacks CNSeffectsSignificant ganglion-blocking activity
Atropinemethonitrate
Belladonna alkaloidCauses sedation;other side effects as atropine
As atropineMotion sickness
Similar to atropineCNS depressant
Hyoscine(Scopolamine )
Belladonna alkaloidMain side effects:
urinaryretention, dry mouth, blurred visionDicycloverine, similar & used mainlyas antispasmodic agent
Adjunct for anaesthesia(reduced secretions, bronchodilatation)AntiChE poisoningBradycardiaGI hypermotility (antispasmodic)
Non-selective antagonistWell absorbed orallyCNS stimulant
Atropine
NotesClinical usesPharmacological propertiesCompound
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2.2.2 Neuromuscular-blocking drugs
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- NMR at postsynaptic site-/-> depolarization
neuromuscular blockflaccid paralysis= Non-depolarizing blocking
drug
Succinylcholine (nChR agonist)
+ N MR (postsynaptic site)prolong depolarizationunresponse to subsequent impulse
neuromuscular blockparalysis
= Depolarizing blocking agents
Tubocurarine (nChR antagonist)
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QuestionsQuestions