2

. ..*. Basic &.clinical pharmacology-Katzung* Examination &. board review

, ;.

pharmacology -Katzung .* Lippincott illustrated review­

Pharmacology'*Goodman & Gillman :Pharmacological

basis of therapeutics'.

REFERENCES ...

Dr.Zheen A. Mutabchi

Autonomic Nervous.System DRUGS

.CANS)

UNIVERSITY OF SULAIMANICOLLEGE OF PHARMACYDEPARTMENT OF PHARMACOLOGY &TOXtCOLOGY

4

Classification• Natural Alkaloids: Atropine,

L-Hyoscine( Scopolamine).

• ·Semisynthetic derivatives: Homatropine,atropine methonitrate, Hyoscinebutyl bromide, ipratropiumbromide, tiotropium bromide.

• Synthetic compounds:myd ri ati cs....tropicamide, cyclopentholate.

antisecretory -antispasmodics ...30 oxybutinin, dicyclomine, pirenzipine, telenzipine,flevoxate.40 propantheline, clidinium, pipenzolate, isopropamide.anti parkinsonian .....Trihexypheniyl, procyclidine,biperidine, benztropine, cycrimine.

3

ANTICHOLINERGICDRUGS

Parasympatholytics- Muscarinic antagonists- Nicotinic antagonists

6

Glyoopyrrol ate (Roblnul)Ipranopnnn (Atrovent)Mepenzolate (Cantil)Methscopolamlne (Pamlne)Propantheline bromide

(Pro-Banth ine)

.AtropineBenztmplne (Cogentln)Blperlden (Aklneton)Dlcyclomlne hydrOChlorIde (Bentyl)Flavoxate (unspas)...Hyoscyamlne (Anaspaz)Oxybutynln (Dltropan)Procyclidine (Kemadrln)Scopolam.lneTolterodlne (Detrol and Detrol LA)rnhexyphen~dyl(Trlhexy)

Quarternary Amlnes

CHEMISTRYThe best known of the muscarinic blocking drugs are

the belladonna alkaloids, Atropine and scopolamine.They are tertiary amines that contain an ester linkage.Atropine is a racemic mixture of D L-hyoscyamine,of which only the levorotatory isomer ispharmacologically active.

Atropine and scopolamine are parent compounds forseveral semisynthetic derivatives, and somesynthetic compounds with little structural similarityto the belladonna alkaloids are also in use. All of theantimuscarinic compounds are amino alcohol esterswith a tertiary amine or quaternary ammoniumgroup. 5

8

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Effects on body tissues andorgans

• Central nervous system (CNSTstimufationfollowed by depression, sedation, reduction ofmotion sickness, and, as previously noted,reduction of some of the signs ofparkinsonism ..

• Bronchodilation and decreased respiratorytract secretions.

• Antispasmodic effects in the GI tract due todecreased muscle tone and motility.

These drugs act by occupying receptorsites at parasympathetic nerve endings,thereby leaving fewer receptor sites free. to respond to acetylcholine .Parasympathetic response is absent ordecreased, depending on the number ofreceptors blocked by anticholinergicdrugs and the underlying degree ofparasympathetic activity.

MECHANISM OF ACTION

,10

.1\1i'scellaneouseffectsinclude decreased secretionsfrom salivary and sweat glands;relaxation of ureters, urinarybladder, and the detrusormuscle: and relaxation ofsmooth muscle in theqaHbiadder and bile ducts._"

9

• The pupil is dilated (mydriasis) by atropineadministration and becomes unresponsive tolight. Relaxation of the ciliary muscle causesparalysis of accommodation (cycloplegia); as

..a result, near vision is impaired. Indescending order of duration of

• action, these drugs are atropine (>72 h),homatropine (24 h),

• cyclopentolate (2-12 h), andtropicamide (0.5-4 h).

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.Atropine makes you:"dry as a bone,red as a beet,hot as a pistol,blind as a bat,and mad as a hatter."

• Effects on heart rateAtropine causes tachycardia through block ofcardiac muscarinic receptors. The tachycardia is .modest, up to 80-90 beats/min in humans. This isbecause there is no effect on the sympatheticsystem but only inhibition of the existingparasympathetic tone.At very low doses, atropine causes a paradoxical

. bradycardia, which results from a central action,increasing vagal activity.The response of the heart to exercise is unaffected.Arterial blood pressure is unaffected, since mostresistance vessels have no cholinergic innervation.

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In genitourinary disorders• Oxybutynin, tolterodine, or similaragents may be used to reduce urgency inmild cystitis and to reduce bladder spasmsafter urologic surgery .

• Tolterodine, darifenacin, solifenacin,and fesoterodine are promoted for thetreatment of stress incontinence.

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• In genitourinary disorders .•.••., • In ophthalmology •••••••• In respiratory disorders ••.••.••.• In cardiology ••••••••.• In Parkinson's disease ••..•• Before surgery ..•••...• In Organophosphates poisoning •••.••...

Indications for Use

Same as adUltdose

Not approvedIn children.

Not approvedfor POuse <6 y.Parenteral: 0.006 mgjkg.

Maxlmumdose: 0.3 mg.

:2 sprays/nostril of 0.03%spralbId-tid.

Children 2-10 y: PO0.062-0.125 mgq 6-8h.Children <2 y: half Qf thepreVIousdose.

Forretradtlon: Instill 1 drop of2% soluUonInto eyebeforeprocedure.Mayrepeat q 10.min as needed. For uveitis:Instill 1 drop of 2% solutionbid to tid.

Rr~fi\m;~1"2_~afi~OII)tlIJ:! rw1-$~~~.

FO.IA.SC,ft1-16b': 0.1nv1'"'24~:Oj5q24-40 [~:().2 ~~S~:O.3~t~1bs.:O.4~.>90 lt$(l,44>.eqo.:l~(~_)m(ll.~ mg(12)Il_~SC3i!l".fm:&llg9q.

For refraction: Instill 1-2 dropsof 2% solution or 1 drop5% solution Into eye beforeprocedure.May repeat at5-10 min Intervals asneeded.

For uveitis: Instill 1-2 drops of2% or 5% .solutlonbid to tidor every3-4 n as needed.

PO,Sl 0.125-0.2.5 mg tid orqld, ae and ns, PO(tlmed­release formula):0.375-0.75 q12h. 1M,IV;SC:0.25-0.5 mgq6h.

2 puffs (36 mcg)of aerosol qld.Additl0n3llnhalatlons maybe needed.Do not exceed12 puffs/24h. Solution forinhalation: 500 meg, tld-qld.

2 sprays/nostril of 0.03%spraybld-tld.

2 sprays/nostrll of 0.06%spraytld-qld.

PO0.4-0.8 mgqd.SC,IMO.32-O.65 mgIV 0.32-0.65 mg clllutedInsternewater for l!'!lection.

Transderm81:Applydisc 4 11before antiemetic effect Isneeded. Replaceq 3 days.

For refmmon: In5t1l11-2dropsJnto eye1n before refracting.

For uveitis: Instill 1-2 dropsIntoeyers) up to tid.

1M.$C,mIVi).~c6 __m~.UstO.__d~~a.

I(.OA"1q(4Ipm2'mJ)ql..a~.

Wtfl.t.~.(ta..$~.as·.~ wlll sip fIa~._~~iIJ~~I$~~

.fof~dl ...2d~ot1'~~.$')1 ~ware·~

fof~~Bl...;2·_1;If11:~Imtt~$)_l

Mydrlatlc/cyCIOPlegla/Inflammationof uvealtract

Antiemetic

SystemiCuseScopolamine

Nasal spray for rhinorrhea

BronchodllatlonIptatroplum (Atrovent)

Antispasmodic Antlsecretoryfor gastrointestinal (GI)andgenitOUrinary(GU)disorders

Hyoscyamine (Anaspaz)

Mydrlatlc/cycloplegla/Inllammationor uveal tract

Homatropine (Homapln)

OIItfta1M~f~) ~~I~~ot~!bCt

-.~-.~AO'\1IIf. ~-

Drug..lnduced extrapyramidalsymptoms

Parkinsonism

Drug-Induced extrapyramidalsymptoms

ParkinsoniSm

Drug-lnduced extrapyramIdalsymptoms

Parkinsonism

Drug-lnduced extrapyramIdalsymptoms

ro, 1M, IV0.5-1 mg ns, MayInorease up to 6 mg given I1Sor in 2--4 divided doses.

For acute dystonia: 1M, IV 1....:2mg. May repeat if needed.For prevention: PO 1-2mg.

PO 2 mg tld-qld. Maximumdose 16mg/day.

PO 2 mgtld-qld1M, IV 2 mg. Repeat q12h

until symptoms are resolved.Do not give more than4doses/24h

PO2.5 mg tid pc, May Increase. t05mgtld.PO 2.5 mg tid. Increase by

2.5-mg increments untll symp­toms are resolved. Usualmaximum dose 10-20mg,td.

po 1-2 mg. Increase by 2 mgIncrements at 3-5-d intervalsuntil a total of 6-10 mg Isgiven qd In divided doses34 tlmes/d at mealtimesand bedtimes.

PO 1 mg Initially. Increase asneeded to control symptoms.

200mCgjkg ac & hSPO25--50 mg Qld ao& fisPO2.5~5mg 30 min ao& hsPO7.5,.15 mg 30 min 80& fis

<2 y: 0.004 mgJlb 1M30--60 min beforeanesthesia,

2-12y:OiOO2~,004mgjIb1M3(}"60 min beforeanesthesia.

< 12~ not recommended

Trlhexyphenldyl (Trlhexy)

Ptocyclfdine (Kemadrln)

Blperlden {Aklneton}

Antlchollnerglcs Used III Parkinson's DiseaseBenztropll16 (Cogentln) Parkinsonism

Antlsecreto~jantlspasmodlcAntlsecreto~jantispasmodloAntlsecreto~ jantlspasmodlo

Antlsecreto~/antlspasmodlC PO20..40 mg ao& hs1M20 rug ae & hs

Antlsecreto~/antlspasmodlo PO182 mg bld41d1M; IVO,l~,2mg

Preanesthetic 1M0,004 mg/kg 3Q..60 minbefore anestMsla

Mepenzolate (Cantil)Methsoopolamlne (pamlne)Propanthellne bromide (Pro-Banthlne)

'.

Glycopyrrorate (Roblnul)

Dlcyclomlnehydrochloride(Ben~l)AnHsecretolYlAntlspasmodlC AntlChollnerglcs for 61 Dlsofders

. ChildrenMults

Routes and D~sage Ranges

USeGenerlcjTrade Name

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Contraindications to Useprostatic hypertrophy, myasthenia

gravis, hyperthyroidism, glaucoma,tachyarrhythmias, myocardial infarction,and heart failure unless bradycardia ispresent. They should not be given in hiatalhernia or other conditions contrlbutinq to refluxesophagitis because the drugs delay gastricemptying, relax the cardioesophageal sphincter, andincrease esophageal reflux.

Safezy and efficac~ not

.establlslleo.

>5 ~ 5 ml PO biOi Maximum

dose 5 mi tid.

<12y: safew ana Bmcacy notestaDlls~ed

Toltero~m9 (Detrol and Detrol LA)

O~~uqnm (Druo~n andDltro~anXl)

PO1~200 ~tl~~iReaveswnens~m~tomsIm~rov9i

PO5mi Din or tldiMa~mumdose5 m~~[di

EMende~reJease5 mi PO~du~to30nwd,

PO 2 m~biOi Ma~ decrease to1 ~wnen s~~toms 1m·~rovei Reduce doses to

11li PO bid In ~resenoo of

ne~a~cIm~lmlent

unna~Rayoxat9IUns~as) .

22

Physostigmine, an acetylcholinesteraseinhibitor, is a specific antidote. It is usuallygiven (IV) at a slow rate of injection.Neostigmine?? !!!!!! !

• Diazepam or a similar drug may be givenfor excessive CNS stimulation.

• Ice bags, cooling blankets, and tepidsponge baths may. help reduce fever.

• Artificial ventilation and cardiopulmonaryresuscitative measures are used ifexcessive depression of the CNS causescoma and respiratory failure.

·Toxicity of AnticholinergicsThe anticholinergic overdose syndrome ischaracterized by hyperthermia; hot, dry,flushed skin; dry mouth; mydriasis;

< delirium; tachycardia; ileus; and urinaryretention. Myoclonic movements andchoreoathetosis may be seen. Seizures,coma, and respiratory arrest may also occur.Treatment involves use of activated charcoalto absorb ingested poison. Hemodialysis,hemoperfusion, peritoneal dialysis, andrepeated doses of charcoal are not effectivein removing anticholinergic agents. 21

24

-Hexamethonium I

Mecamylamine 1&

.Trimethaphan are useful intreatment of Hypertension.

Ganglion-Blocking Drugs

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• Ganglion-Blocking Drugs• Neuromuscular Blocking Drugs

NicotinicAntagonists

26

·Nicotine (gum or. Transdermal Patches),Mecamylamine &

Varenicline (Orally) areuseful in smoking cessation"programs.

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Nondepolarizing Drugs.• Tubocurarine: it produces a

competitive block at the end platenicotinic receptor, causing flaccidparalysis that lasts 30-60 min.

". Pancuronium, attracuronium,vecuronium are short actingdrugs.

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Neuromuscular BlockingDrugs

=These agents are useful inprod ucinqcomplete skeleta IMuscle·Relaxation in surgery.

_.Nondepolarizing Drugs: Tubocurarine• Depolarizing Drugs: Succinylcholine

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• Half life of these drugs is only fewminutes.

• Genetic Factors contributes toabnormal production ofpsudocholinesterase that dose notmetabolize these drugs effectively

, resulting in prolonging in duration ofaction of these drugs.

• Incidence is: 1:2500 .

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Depolarizing Drugs-They are nicotinic agonists, not.antagonists.-Causing flaccid paralysis.• Mainly deactivated by plasmacholinesterase.DecamethoniumSuxamethonium.

1! .

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PralidoximeObidoxime

. Cholinesterase Regenerators

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• Increased intraocular pressure• Prolonged paralysis• Muscle pain (Succinylcholine)

• Malignant hyperthermia>65%

• Potassium release• Bradycardia

Unwanted effects ofdepolarising drugs

---- ..~