principles of pharmacology rn

7/25/2019 principles of pharmacology RN

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LIFE 207 Revision Notes Drugs and the peripheral nervous system

Modifcation o these allow the ormation o drugs in pharmacology


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Somatic Nervous system

Somatic nerves innervate skeletal (voluntary) muscles

One single axon all the way rom the spinal cord to the muscle (noganglia)

Acetylcholine (A h) is the neurotransmitter Acts on nicotinic Ach receptors located on s!eletal muscle mem"ranes

Nicotinic receptors are lin!ed to a Na + ion channel#

Autonomic nervous system

Parasympathetic (rest an i!est" $ long pre$ganglionic nerve% shortpost$ganglionic nerve

Sympathetic (fght and &ight)$ short pre$ganglionic nerve% long post$ganglionic nerve

'oth pre$ganglionic nerves release A#h to act on nicotinic receptors onpost$ganglionic nerve

Parasympathetic $ post$ganglionic nerves release A#h to act onmuscarinic receptors on e ector cells

Sympathetic $ most post$ganglionic nerves release NA to act on a and "adrenoceptors on e ector cells

A!onists an Anta!onists in the Somatic System

Nicotinic (receptor ion channel controlled "y A h) agonists


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$ Acetylcholine$ Nicotine$ ar"achol

Nicotinic antagonists$ d $*+'O +,A,-N.

$ /AN +,ON-+M$ S+0AM.*1ON-+Mo Cholinergic;

1. Synthesis in nerve terminalAcetyl oA and choline( rom diet)com"ine to orm acetylcholinecatalysed "y holine acetyltrans erase

2. A h stored in vesicle 2 3esamicol

4# Action potential cause therelease o Ach rom presynapticmem"rane 2 'otulinum toxin(prevent contraction "y "loc!ingrelease o Ach)

4. ACh acts on nicotinic receptor on postsynaptic membrane

opening ion channel5. ACh action terminated by

acetylcholinesterase enzyme/ Anticholinesterases inhibit the

!unction o! acetylcholinesterase"5# holine reclaimed "y nerveending (rate limiting step in A hsynthesis) through cholinecarrier2 1emicholinium "loc!supta!e o choline "y NM6

7# .mpty vesicles reflled with Ach

o adrenergic;


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synthesis in noradrenergic nerves (rate limiting step) tyrosine ( romdiet) hydrolyses "y tyrosine hydrolase

o $IS%LFIRA& (Anta"use8) inhi"its dopamine 9$hydroxylase%causing some depletion o NA stores treat alcoholics mainlyused or its action on meta"olism o alcohol

Storage NA in nerve terminals is contained in vesicles% with A*/(neurotransmitter unction co$transmission) and chromogranin A

o RESERPINE "loc!s mechanism that transports NA into vesicles

,elease a:;

enters the nerve ending and activates exocytosis o NArom storage vesicleso ' RA&INE) A&P*E'A&INE (indirectly acting

sympathomimetics) -ncrease release o NA rom vesicleso NI&,$IPINE reduces release "y "loc!ade o a :; channels in

nerve terminalso AN - 2 .A/,NIS'

NA can act on $% $adrenoceptor,educed synthesis "y action o released NA on pre$synaptic a : $adrenoceptors

$ negative feedback inhibition of transmitter release

$ autoinhibitory feedback mechanism


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'he role o a renoceptors

1 2 1IS,PRENALINE(isoproterenol"

2 .l n!sIS,PRENALINE(isoproterenol"

3 .a renoceptors

A$RENALINE (epinephrine"

N,RA$RENALINE (norepinephrine"

(non.selective anta!onist"P*EN',LA&INE)

P*EN,4 5EN6A&INE

PR,PRAN,L,L (non.selectiveanta!onist" car iovasc lar) !la coma)thyroto icosis) tremor) mi!raineprophyla is) an iety


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contractiono smoothmusclegenerally(not gut)

e#g# "loodvessels%uterus

relaxationo gutsmoothmuscle

salivarysecretion

hepaticglycogenolysis

inhi"itiono transmitterrelease

plateletaggregation

contraction o vascularsmoothmuscle

insulinrelease

cardiac rateand

orce

"ronchodilation

vasodilation relaxation o

gut smoothmuscle

hepaticglycogenolysis

muscletremor

,egulationo lipidmeta"olism

lipolysis

PRA6,SIN $antihypertensive

,*I&5INE

A'EN,L,L 5%',4A&INEcar iovasc lar(antihypertensive)

antian!inal)antiarrhythmic"

P*EN LEP*RINE

#L,NI$INE .hi!h 8loopress re

$,5%'A&INE heart

ail re

SAL5%'A&,L)'ER5%'ALINE)$ asthma

'ermination o Nora renaline Action

%ptake 1 (ne ronal re. ptake 8y active transport intopresynaptic" relatively selective or noradrenaline (tyramine) rapidreupta!e2 monamine o i ase (&A," a8 n ant in sympathetic nerveen in!s meta"olises noradrenaline into inactive meta"olites

%ptake 2 (e tra ne ronal re. ptake 8y active transport intopostsynaptic" ta!es up noradrenaline% adrenaline and isoprenaline2

catechol.,.methyl trans erase (#,&'" in e ector cells and


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extracellular space important or meta"olism o circulating adrenaline andsome drugs% e#g# isoprenaline

$r !s A9ectin! %ptake an &eta8olism o Nora renaline

%ptake 1

"loc!ed "y

#,#AINE) $ESIPRA&INE

%ptake 2 (e trane ronal re. ptake"

"loc!ed "y

P*EN,4 5EN6A&INE

#,R'I#,S'ER,NE (and other steroid hormones)

&eta8olism

MAO inhi"ited "y

'RAN L# PR,&INE

IPR,NIA6I$

MAO-s used in treatment o depression

o structure activity relationships;

*radition SA, altering the chemical structure o a r ! changes the

pharmacological responseMolecular SA, Altering the chemical structure o a target macromolec lechanges the pharmacological response

*arget macromolecule

#rotein

$eceptor

%on channel

&nzyme

D'A

A drug will not wor! unless it is "ound /aul .hrlich


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o (A$ in the cholinergic system;

Traditional SAR (drug)Enhancin! #holiner!ic E9ects at the Ne ro & sc lar : nction

'reatment o &yasthenia !ravis a toimm ne isease characteri;e8y pro!ressive &%S#LE Pharmacolo!ical options?Increase Ach in the N&: to stren!thens m scle contractions 8y sin!

1> Anticholinesterase r !s? Increase concentration o A#h in theN&: stren!thens m scle contractions

2> ,r mimic the e9ect o Ach @ith selectivity to nicotinic a!onistsnot a rener!ic at the N&: @ith Nicotinic A!onists

SAR at Nicotinic an & scarinic ReceptorsA!onist &I&I# action provi es selectivity> So 8y sin! a r ! @hich is?


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Nicotinic a!onist or &yasthenia !ravis @ith no *R&%S#ARINI# AN'A/,NIS'S re ce ! t motility no skeletalm scle tension

Lo@ E# 0 B hi!h potency

*i!h E# 0B lo@ potency

2 system to meas re m scarinic response an nicotinicresponse>'estin! selectivity @ith a 8ioassay Acetylcholine an Relate#ompo n s

#omparin! E&R at nicotinic an m scarinic receptor tell s a8o t

r ! selectivity>'o etermine @hich part o the molec le is important or itsinteraction @ith nicotinic an m scarinic receptor


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1. A molecule must possess a nitrogen atom capable of bearing a

positive charge, preferably a uaternary ammonium salt.!. "or ma#imum potency, the si$e of the alkyl groups substituted

on the nitrogen should not e#ceed the si$e of a methyl group.%. The molecule should have an o#ygen atom, preferably an ester&

like o#ygen capable of participating in a hydrogen bond. '. A t o&carbon unit should occur bet een the o#ygen atom and

the nitrogen atom.

%se ri!i analo! e to comCrm the pharmacophores


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In ce make a molec le ri!i (prevent the rotation o molec les"8y intro cin! a rin!

&ethyl rtrethoni m se to conCrm that the methyl !ro p(pharmacophore" is the important or m scarinic selectivity ratherthan hy ro yl !ro p>

o (A$ o! anticholinesterases

olecular SAR (target macromolecule)*icotinic Acetylcholine receptor (nA+hR)=eatures o nicotinic (ionotropic)receptors

ligand gated channels -nvolved in ast2rapid synaptic transition 1eteromenic assem"ly o ? su"units with transmem"rane helices (@

(M %M:%M4) in each su"unitB:C in total) arranged around centrala>ueous channel

Digand "iding $$E channel opening $ process ta!e milliseconds


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Nicotinic receptor is the frst type o receptor to "e ully pharmacologicallycharacterised using

$ .lectric organ o *orpedo fsh "ecause it is a rich source o receptors( CC pmol2mg protein cared to C# in human)

$ Sna!e venom toxins contain high aFnity ligands (a$"ungarotoxinG"inding to alpha su"unit o nicotinic receptorH%o"ratoxin) specifc or nicotinic acetylcholine receptor which acts as

a good mar!er in pharmacology#Acetylcholine "inding site was determine rom

$ *he "inding o a competitive molecule DDF/N,N Dimethylaminobenzenediazonium fluoroborate

$ Covalently binds to binding site under UV light allowingextraction/ urification/investigation of !Ch binding site

'he str ct re o nicotinic receptor

$ /entameric -on channel made o ? su"units proteins ( )$ frst :CC amino acids o gene represent extracellular protein (most o

the proteins are extracellular)$ 2 su"unit with @ transmem"rane domains$ M: (alpha$helix protein) on "oth su"unit mediate gating

mechanism

$ At the "inding site A h2


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"inding o venon toxin without restricting "inding o A h$ SA, can "e carried out on the extracellular aa or drug "inding$ NO N.IA*-3. 1A,I.$ -ntricate networ! o 1$"onds 2 no ionic interation (strong enough to

"ound with >uaternary amonium on A h)

$ 'inding site #? nm rom cell sur ace'he Acetylcholine 5in in! Site

Muscarinic receptor (mA h,)

I$protein coupled receptor ommon type o mem"rane "ound protein

*o "e continue $eceptor theory/pharmacodynamics

o (tructure activity relationships;

&rlich loc) and )ey model

o agonist/receptor theories;

o competitive antagonism;


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o non*competitive antagonism;o drug binding;o drug targets

#harmaco)inetics


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Pharmacokinetics Bthe "odyJs action on the drug

Pharmaco ynamics B the action o the drug on the "ody

o +ey pharmaco)inetic parameters;

5ioavaila8ility? =raction o unchanged drug2 ingested drug reaching thesystemic circulation a ter administration# =or -#3# = B 2 CCK =or oral = o ten L

2 CCK

'ioavaila"ility B A+ (oral)2 A+ (-23) x CC


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Dol me o istri8 tion? *he apparentP volume in which drug is distri"uted#,elates amount o drug in the "ody to the concentration o drug in "lood (inliters) 2 in orms you on where the drug is in the "odyD B$oseB amo nt in 8o y

# 0 initial concentration

- there is tissue "ound drug ("lue) concentration in plasm is low 3dmay greatly exceed total "ody water#

- drug "ound in plasma (yellow) 3d will approach plasma volume

#learance? D,L%&E o plasma (or "lood) rom which drug is removed perunit time (ml2s) (volume2unit time)


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ii) clearance is the rate o elimination o a drug (!) rom the volume in whichdrug is distri"uted (3d)

learance and "lood &ow are lin!ed

*al .li e? the time ta!en or the plasma concentration o the drug to all to a hal 2tQ B time ta!en or drug conc to decline "y hal 21al li e B C#5R42!

! B rate constant o elimination (h $ )

Area n er the plasma concentration time c rve? (A%#" total druge#posure over time

. that A%# is proportional to the total amount of drugabsorbed by the body +


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Plasma concentration? # p B # o (concentration at time 0" e .kt

o oral absorption;


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1al $li e o drug can "e calculated rom a"sorption phase 2 elimination phase

,ral A8sorption the 8arriers @hich a9ect 8ioavaila8ility?# poor dissolution

:# . ux proteins (' ,/% M,/% /$glycoprotein) removes drugs rom theinside o the enterocytes into the intestinal lumen (causing reduced drugconcentration reduced drug a"sorptions)

$ -n&ux protein orm intestine lumen (OA*/ organic anion )$ e ux protein into portal vein (M,/$ T4)

4#


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" First Pass E9ect denotes the K o drug which is lost on the ,rst passthrough the gut and the liver ollowing Oral A"sorption# - "ioavaila"ilityis ?CK then ?CK is lost on =irst /ass#


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o hepatic clearance;

#learance rom the liver

An e ective drug should have high "ioavaila"ility very low oral clearance and lowhepatic clearance

.xtraction ratio .B what actually gets into the "ody which re&ects "ioavaila"ility=

. ( $C)is inversely proportional to = (C$ )

,easons or varia"ility in systemic availa"ility

$ /harmacologist wants to get right concentration o drug into the "odythis concentration is called the &E# B &inim m E9ective #onc

$ hanges in meta"olism might a ect M. drug conc

Daria8ility in orm lations !eneric pro cts vs innovator

5ioe ivalence implies that i one ormulation o a drug is su"stituted oranother no clinically unwanted conse>uence will arise#


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5ran e r !s A=A innovator r !? produced "y innovator companies 2rigorously researched received necessary regulatory approval2 intellectualproperty protected

G aliCe !eneric r ! (o ten !iven"? re>uires proo o "ioe>uivalence2 orcomparisons with "randed drug2 clinical trial is not mandatory

%n aliCe !eneric r ! an co nter eit r ! are unwanted drugs whichdo not have supporting evidence

o renal clearance;


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o

pharmaco)inetic variability;o drug interactions. Drug disposition and metabolism- Describe early biochemical

events a!ter drug administration that are o! to icological andbiochemical signi,cance

o #aths o! drug absorption and distribution

'erminolo!ies?


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A$&E? process "y which an ade>uate concentration o the drug in target tissuesis achieved in order or the drug to wor!#

. A "sorption rom site o administration

. $ istri"ution within the "ody to target tissues

. & eta"olism

. E xcretion

'opical a ministration on s!in e#g# cream

Systemic a ministration into the "ody e#g# pill% inVection% inhaler

. Enteral a ministration? via I- tract e#g# ta"let2capsuleo Feat res?

,e>uires gastrointestinal a"sorption$r ! has to cross tho !h or 8et@een cellmem8ranes to reach tar!et

*hrough cells achieved "y paracellularo passive di usiono acilitated di usiono active transporto pinocytosis

'etween cells achieved "y transcellularo A>ueous pores

. Parental a ministration not via I- tract inVection inhaler o Feat res

uire gastrointestinal a"sorptionallow localised e ect

rapid distri"ution depending on type o "lood &owaster a"sorption which depends on di usion through local

tissue% removal "y local "lood &owrapidly produce a high concentration in plasma(parental administration) -nVection astest route or thedrug to get into the systemic circulation


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-ncreasing Dog< 7#@ a"ove C will decrease renal clearance and increasemeta"olic clearance#1igh Dog < 7#@ compounds will tend to "e meta"olised "y phase - (/@?C)enUymes in the liver#


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$ /lasma al"umin is the most importantW glo"ulin and acid glycoproteinalso "ind some drugs

$ /lasma al"umin (with : "inding sites) "inds mainly acidic drugs#$ 'asic drugs may "e "ound "y glo"ulin and acid glycoprotein$ .xtensive protein "inding slows drug elimination (meta"olism or 2and

glomerular fltration)o #hase % o idation;

/re$systemic


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system in the SMOO*1 .N


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*ype o /@?Coxidations

=unctionalgroup

.nUyme o actor /roduct

AliphatichydroxylationAromatichydroxylation

.poxidation


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uired or cellsurvival and growth# =olate2thymidylate pathway leading to


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& /oo tar!et Y( TR- T/0 R- 2 S34fonamides )althoughidentical pathway 2 !ey enUyme shows di erential sensitivity ( olateantagonism sensitivity higher in "acteria)

$ =olate2thymidylate pathway leading to


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Penicilline resistance

'ypes o Penicillins. 5en;ylpenicillin (P#./">

o Naturally occurringo Destroyed by beta lactamases/#oor and irregular absorption/

Destroyed by acid and adsorbed by !ood/ ive by in0ection / (hort duration o! action

$ 'eta lactamase resistant /enicillins# #lo acillin) H clo acillin)iclo acillin) naCcillin

o Acid stable.o ive orally.o $apid absorption.o Cma appro . 1 hour.o Also give parenterally.o $enally e creted.o al!*li!e appro . 3 * min.

Protein synthesis inhi8itors (tetracyclines) macroli es" Ri8osome 30s 0s


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#lassiCcation o resistance in 8acteria

-nherent Resistance

$ e#g# a I$ve "acterium has an outer mem"rane that esta"lishes apermea"ility "arrier against the anti"iotic

Ac uired Resistance ?

1> 3ertical evolution "y mutation and selection

haracterised "y spontaneous mutation impartsresistance to a mem"er o the "acterial population

2> 1oriUontal evolution "y exchange o genes "etween strains andspecies

ac>uisition o genes or resistance rom another organism"y

#onJ !ation involves cell$to$cell contact as


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5iochemical mechanisms o resistance

Anti8iotic &echanism o resistance

#hloramphenicol reduced upta!e into cell

'etracycline active e ux rom the cell

K.lactams)

Erythromycin)Lincomycin

eliminates or reduces "inding o anti"iotic to cell target

K.lactams)Amino!lycosi es)#hloramphenicol

enUymatic cleavage or modifcation toinactivate anti"iotic molecule

S l onami es)

'rimethoprim

meta"olic "ypass o inhi"ited reaction(


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$ *hese have a higher aFnity or "eta$lactamase active site that thedrug itsel

A !mentin (anti"acterial com"ination o amoxicillin and potassium clavulanate)

o anti!ungals;

ommon ungal in ections in the u! Candida albicans6 Aspergillus !umigatus6Cryptococcus

'ar!ets or chemotherape tic a!ents a!ainst n!al in ections

# =ungi are eu!aryotic% unli!e "acteria

# ell walls composed o chitin% a polymer o N$acetylglucosamine (in"acteria $peptidoglycan)

# ell mem"rane contains ergosterol (cholesterol in mammalianmem"ranes)

# =ungi resistant to anti"acterial agents

Feat res o anti n!als? A;oles# ZetoconaUole

# Orally active#

# =irst aUole to treat systemic in ections#

# ,are "ut possi"ly atal liver toxicity#

# -nhi"itor o ungal cytochrome ( X/) /@?C ? A

# =luconaUole

# an "e given orally or intravenously#


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# oncentrated in S= so drug o choice in ungal meningitis#

# S!in lesions in 1-3 patients on multiple therapy

# -traconaUole

# an "e given orally or (most importantly) intravenously (in aormulation with 9$cyclodextrin)#

E ample o anti n!als

'er8inaCne

$ =ungicidal allylamine#$ -nhi"its ergosterol synthesis$ *reats ungal in ection o nails due to selective accumulation#

/riseo lvin

# Anti ungal anti"iotic produced "y /enicillium griseo ulvum## Active in vitro against most dermatophytes and has "een the drug o

choice or chronic in ections caused "y these ungi (e#g# nail in ections)#

# Still used in such cases% "ut is "eing superseded "y some o the neweraUole anti ungal agents#

# =ungistatic inhi"its mitosis in ungi#

# /oorly solu"le a"sorption dependent upon particle siUe# oncentrated in!eratin o newly ormed s!in

o antivirals;o anticancer therapy;o basic pharmacogenetics

principles of pharmacology rn

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