references· - · pdf file2 * basic&clinical pharmacology-katzung * examination it...

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* Basic & clinical pharmacology-Katzung* Examination It boardreview I pharmacology ....

-;

Katzung ,* Lippincott illustrated review­

Pharmacology

REFERENCES·.,~

Dr.Zheen A. Mutabchi

Autonomic NervousSystem DRUGS

CANS)

UNIVERSITY OF SULAIMANICOLLEGE OF PHARMACYDEPARTMENT OF PHARMACOLOGY

4

3

Objectives- Divisions of Nervous System._.Functions & Importance of the differentparts of ANS & SNS.

- Neurotransmitters in the ANS (synthesis,storage, release, effects, & deactivation) .

- Studying cholinergic agonists &antagonists I adrenergic agonists &antagonists I & their clinicalapplications.

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AutonomiC NS vs. Somatic NS

The ANS differs from the SNS in thefollowing areas:

• Effectors.-Efferent pathways.• Neurotransmitter.

Parasympathetic 5Sympathetic

These neuronsbring informationfrom the peripheryto the eNS .(input)

e. g. sensorynerves

Afferent division

Somatic

I

They carry signals away from thebrain and spinal cord to the peripheraltissues.(output) e.g. motor nerves

Efferent division

Central Nervous System Peripheral Nervous SystemI .. ......I .\. , ~

Brain Spinal cord

Nervous SystemI . .

8

Motor (Efferent) Pathways• Axons in the Somatic NS have

A single, myelinated axon extending fromthe eNS to the effector.

, • Axons in the Autonomic NS havetwo-neuron chain

The preganglionic (first) neuron extends toganglion.The postganglionic (second) neuron extendsfrom ganglion to an effector organ.

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Effectors• The effectors of the

SNSare:skeletal muscles.

• The effectors of theANSare:Cardiac muscles,smooth muscles,adipocytes,

&glands.

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9

• All somatic motor neurons release:Acetylcholine (ACh) ,

• ANS neurons release:. Norepinephrine (Sympathetic division)Acetylcholine (Sympathetic and

.Parasympathetic divisions)

, Neurotransmit,ter Effects

-The two divisions counterbalance eachother's activity .

...Most organs receive both sympathetic& parasympathetic innervations.

- SOME organ receive only sympatheticinnervations like:

SWEAT GLANDSPLEEN

MOST BLOOD VESSELS

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• Sympathetic mobilizes body during extreme

situations "fig ht-or-flight".

• Parasympathetic performs maintenance activities"Housekeeping" or " Rest &. Digest".

ParasympatheticSympathetic

Two divisionsDivisions of the ANS.

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• Shunts blood away from the skin andviscera to the skeletal muscles, brain, andheart.

• Inhibits peristalsis in the GIT.• Inhibits contraction of the bladder andrectum.

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• Stimulates heart beat ..,. Raises blood pressure.• Dilates the pupils.• Dilates the trachea and bronchi.• Stimulates the conversion of liverglycogen into glucose.

Sympathetic. Effects

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• Slowing down of the heart beat,• Lowering of blood pressure.• Constriction of the pupils.• Increased blood flow to the skin andviscera.

• Peristalsis of the GI tract.

Parasympathetic .Effects

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• Rest & digest.

• Preganglionic Fibers ernergefrom brain and sacral. 1973;52-54

• Long preganglionic fibers;short postganglionic,Limited to head, neck, 8r.trunk.

• Ganglia found in visceral.effectors

• Minimal preganglionicbranching

• All cholinergic fibers use(Ach), rapidly destroyedlocally.

athetic

• Extensive preganglionicbranching

• All preganglionicfibers useACh, MOSTpostganglionicuse NE.NE is more stable &diffuses for wider action.

• Fight or flight.

• Preganglionic Fibers arisefrom thoracolumbar.Is. T128r. Ll- Ls.

• Short ••.•preganglionicfibers; long •••••••••••••••postganglionic ,WideDistribution.

• Ganglia near spinal cord.

Sympathetic

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Ul'inary'bladdi'

R0:

1...1',•. inte_ineSmal•.intestine.4drenat.glandandkldne,'

.E,e~acri.IJ'lII•.gllnd.and naS8[muooa.$ubmandlbu1ti'and.lublingual.•glands..Parotid glandLung .

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21

NormetancphrilW

CH30 HO HHO'n '~-~-NH"~- I I ~

H H

COMT· ,...

3-Methoxy - 4-hydroxymandclicacid(VnniIlylmandeHc acid)

CH=o-'p. . yH nHO V '\ C -- C -- OH

- IH

COMT

Metanepnrtne

CH=O-.30 ... . yH fHO 7 '\ .. C-C-NHCH~

- I I "H H

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VMWIar s)'Stem

Norepmephrine

HO OH H

HO ~ , .~--~:-NH2

H H

MAO

3,4-Dihydmxymandelic acid

MAO

Bpi nephrtne

HO ·OH H

HO (' i - f -NHCH;1.

H H

.Adre:t'llllineOH..... I

HO('r.... CH-CHcNH-CHa

HOV·

Dopamine

DOPA

Tyrosine

synthesis, storage, release, &deactivation of N E

NANCTransmission• Neurotransmitters rather thanAch ,NE, and Dopamine may be.stored in nerve vesicles with thepreviously mentioned ones oralone like: ATP, Substance P,. Enkiphalines, Neurotensin .• They are acting as a modulatorof neurotransmitter release.. . 25

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Examination & board review by Katzung:chapter 6, page 52, 9th edition.

See:

Question ..?••••

•Complex organ control: theEYEas an example.

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Sites of Ach release1.Ganglia. All Sympathetic &

Parasympathetic ganglia.2. Post ganglionic parasympathetic

nerve endings.3. Sweat Gland.4.Somatic nerve endings supplying

Skeletal Muscles.5. Adrenal medulla.6. eNS.

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- Cholinoceptor activating- Cholinesterase inhibitors

Cholinergic Drugs

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AGetyk;hgfine~ •

DiliGd;..aciin'QctUJ~~nergicdruS

.Presynaptic V~L<:~EiiIS,contaniing aeel:yBcJ'tOIine

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CHOLINERGIC AGONIST DRUGSI

Direct~cting Indirect lacting1 I ·1 • I .

• • •Muscarinic Nicotinic : : :.. . .1 Edrophonium ~ ~

Alkaloids Choline ester Carbamate ~Pilocarpine Ach,Methacholine, :MlISCCIine carbachol, ' organOPhosPha~esArecoline bethanicol

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MUSCARINIC NICOTINIC

2

REFERENCES ...* Basic& dinical pharmacology­Katzung* Examination &. board review

pharmacology --Katzung* Lippincott illustrated review­

Pharmacology

1

Dr.ZheenA. Mutabchi

Drugs affectingAutonomic Nervous

..SystemCANS)

UNIVERSITY OF SULAIMANICOLLEGEOF PHARMACYDEPARTMENT OF PHARMACOLOGY& TOXICOLOGY

4

Sites of Ach release1.Ganglia. All Sympathetic &

Parasympathetic ganglia.2. Post ganglionic parasympathetic, nerve endings.

3. Sweat Gland.4. Somatic nerve endings supplying

Skeletal Muscles.5. Adrenal medulla.6. eNS.

3

- Cholinoceptor activating- Cholinesterase inhibitors

Cholinergic Drugs

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•AG8tYfd1glin&~

Oire:cl-aclil.ngcholinergic dn.JS

Presynaptic ve(~.dcles.mntaining aosi;yk;holine

5

tOrganophosphates

.Ach, Methacholine,. carbachol,bethanicol

Choline ester

• • •• • •• • •.. : :Edrophonium ~ ~

T :..Carbamate ~

•••

INicotinic

IMuscarinic

1

Indirect lacting· I .

D•· .t J t·. Ifec ac IngI

CHOLINERGIC AGONIST DRUGSI

IAlkaloiijPilocarpine·MuscarineArecolineLobeline

7

MUSCARINIC NICOTINIC

MlM

M3

,

msN

10

Subtypes Locations

Ml;,

M _..

G"'PCR M3

mS

N..

Ligandlon- .,

channel 9

12

11

14

Eyes .

R.T.S .

Blood vessels .... parasympathetic innervations ..??!G.1. T .

Heart ... vagal stimulation

Tissue & Organ effects

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on, H3C-.c -0 ~;CH2-cH2-~ -'CH3Ace Ichollne . CH:l; I

Quaternary ammonium compound.Has both muscarinic & nicotinic activity.Has NO therapeutic application

rapid inactivationlack of specificity

H31

ACETYLCHOLINE

DIRECT ACTING DRUGS

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* S/E .

Bethanechol* similar to Ach. quaternary ammonium. compound.. .* Not hydrolyzed by AChE.* Has STRONG MUSCARINIC but nonicotinic activity.

c, * Mainly acts on smooth muscle of bladder&GIT.

'* Therapeutic value in Post partum &postoperative atonic bladder .

+Ilmcreased b400d,' flCPA"for incr_s~ngheet dfss4patlon

IBronchllal sec:.-etiondecreasedBrol"lchodillatfon

Bronchllal secretionBrol"lchocol"IstrJction

REJlStiessne_frrimbilmtyHall!UclrnatlonsAntfpftridnsonfaneffectAntietnetfe, effect:IRaba'"AV oondUotion t r-'-----

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• Glaucoma.

Pll~1f1W1lJW• Contraction of the ciliary muscles& MIOSIS. IPu~1wlda

, • Tertiary amine structure.• Stable to hydrolysis by AChE.

Pilocarpine• Natural alkaloid.

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Glaucoma.

DOA is tonq 1 hr.

Similar to bethanicol in its resistance to AchE.

Similar to Ach in its affinity to M,N Receptors.

CARBACHOL

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II,'.ml'"m~'~~'~~t!~~~!~~l~,~d/...~~eJJ~~I_m'awJ,'~I'D~m~~m&lili'I, .~~i

ra; 111~~fJhltll(illlm " fl~j~ni~~, ~.r~~m~~I.·:.;g]]l~,,

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Adverse. reactions.. ftlxldtl Iellflm itllB ttl~lnlmil_mDn'\V1lIl •_ ,Dl;_~f__ ~!_titio~I_~_m alipi.sntdt Il1Id acnYil1, J , >' ,

u ,i '. 'maet)" IfiQ ' 'Hallen. :accUl1·.Jol- .I ..'""'"..V,. .",,>' . ..~

I~. '.J ' ill ~ ~.. 1Il,~;]inl~ou~131~,~bl

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CLASSIFICATIONDURATION OF ACTION-- Very short actingedrophonium-- intermediate -long actingcarbamates( carbaryl, propoxure,aldicarb)

-- very long- actingorganophosphates( malathion,parathion, sumithion, sarin , &tabun),

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CLASSIFICATIONCHEMICAL STRUCTURE:-- Esters of carbamic acid:

carbamates neostigmine-- Esters of phosphoric acid:

phosphates organophosphates-- R-OH:

. Edrophonium

INDIRECT ACTING CHOLINERGICAGONISTS

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•Acafylcht)lina"__~;

lDire,d..,actingcholinergic drug

, Presynaptic \fesicleHSmntaining aosl¥lcholine

.Acstylcoolinesterass

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-- Irreversible: organophosphates(parathion, malathion, echothiophate,nerve gases [tabun, sarin, soman];diazinon, dyflos). '

--Reversible: Physostigmine,neostigmine,pyridostigmine, rivastigmine,donepezil, edrophonium, ambinonium.

CLASSIFICATIONREVERSIBILITY .

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There are two major types ofcholinesterases

.acetylcholinesterase (AChE) alsoknown as true, specific I and are foundmai.nlyat(cholinergic neuroeffector junction)

pseudocholinesterase (pseudo-ChE)(liver, skin, plasma)

PreSYnipticvesi~,~oonmining acetylchol'ine

IndnGt"adingcholnergic

drug bound toacetylchoUnMtems~

(S9; nut box)

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• There are two main forms ofcholinesterase both enzymes belong to thefamily of serine hydrolases:-acetylcholinesterase (AChE), which ismainly membrane bound, relativelyspecific for ACh and responsible forrapid ACh hydrolysis at cholinergic

..synapses.- butyrylcholinesterase (BuChE) orpseudocholinesterase, which is relatlvelvnon-selective and occurs in plasma andmany tissues.

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o1.1

-C-O-H

, .~Ph'J4':R.''; •• DiI'Je

Physostigmine

REVERSIBLE ANTICHOLINESTERASES

29

Clinical applications of indirect actingcholinomimetics

32

··HaG

NEOSTIGMINE

REVERSIBLE ANTICHOLINESTERASES·

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sU1

Uses-GLUCOMA-OVERDOSES of ATROPINE ,TCA.-Intestinal & bowel atony.-ACCOMMODATIVE ESOTROPIAADVERSE· EFFECTS

34I.V. in diagnosis of Myasthenia Gravis

USES

. EDROPHONIUM

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Antidote for Tubocurarine

Urinary Retention & paralytic ileus

...Myasthenia Gravis direct stimulation Nmindirect effect on AchE

USES

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, - Chronic management of Myasthenia Gravis- DOA: 3-6 hrs 4-8 hrs

PYRIDOSTIGMINEAMBENONIUM

The drug is well absorbed after oraladministration and absorption is unaffectedby food. It is highly bound (96%) to plasmaproteins. It is metabolized in the liver toseveral metabolites, some of which arepharmacologically active; metabolites and

- some unchanged drug are excreted mainlyin urlne,Adverse effects include nausea, vomiting,diarrhea, bradycardia, and possibleaggravation of asthma, peptic ulcerdisease, and chronic obstructive pulmonarydisease. Jaw tremor 38

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• is used to treat mild to moderateAlzheimer's disease. In long term studies,donepezHdelayed the progression of thedisease for up to 55 weeks. Donepezilincreases acetylcholine in the brain byinhibiting its metabolism.

DONEPEZIL