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7/21/2019 FACTORS MODIFYING DRUG EFFECTS.ppt
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FACTORS MODIFYING
DRUG EFFECTS/DRUGVARIATIONS
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On administration of a drug ,a r!di"t!d r!sons! is o#tain!d #utsom! tim!s
Indi$idua%s ma& $ar& "onsid!ra#%& in t'!ir r!sonsi$!n!ss
Su"' as( r!sond diff!r!nt%& to drugs #ot' from tim! to tim!and from ot'!r indi$idua%s)
Som! *ou%d s'o* %!ss t'an t'! usua% r!sons! , and som!ma& s'o* mor! t'an usua% r!sons!
O""asiona%%& indi$idua%s !+'i#it unusua% r!sons!
IDIOSYNCRACY
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Physiological factors
AGE:
Pregnancy Sex/gender
Body weight
Food
Timings
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AGE
In new born there occurs
D!"r!as!s a"id s!"r!tion
D!"r!as!d mi"rosoma% !n&m!s
D!"r!as!d %asma rot!in #inding D!"r!as!d G)F)R
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T'!r! is in"r!as! in G)I)T a#sortion in n!*#orns %i-!ami"i%%in du! to d!"r!as!d a"idit&)
T!tra"&"%in!s rodu"! t!!t' staining in "'i%dr!n
Corti"ost!roids "aus! gro*t' and d!$!%om!nta% r!tardation
Anti'istamin!s "aus! '&!ra"ti$it& inst!ad of '&oa"ti$it&)
T'!s! ar! a%% diff!r!nt r!sons!s t'an adu%ts
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S!$!ra% !n&m!s ar! imortant for drug m!ta#o%ism ,. '!ati" mi"rosoma% o+idas!, g%u"uron&% and a"!t&%transf!ras! 'a$! %o* a"ti$it& in n!onat!s
C!rtain drugs ma& %!ad to s!rious "ons!0u!n"!s
e.g) "'%oram'!ni"o% "ausing gra& #a#& s&ndrom!)
su%'onamid!s "ausing -!rni"t!rus
A"ti$it& of '!ati" mi"rosoma% !n&m! a%so
d!"r!as!s *it' ag! %!ading ro%ong!d 'a%f %if! of
som! drugs !%d!r%& !o%!
e.g. 1!nodia!in!s, t'!o'&%%in!s
T'is ma& %!ad to a""umu%ation of drug on r!!at!d dos!s)
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rug e!imination is !ess e""icient in new born babies # and in
o!d $eo$!e so that drug $roduces greater and more $ro!ongede""ects at extremes o" age .es$ecia!!y drugs which areexcreted through %idneys as
there is decrease in G.F.&
Tubu!ar "unction is a!so diminished. e.g. 'orma! $!asma ha!" !i"e o" gentamicin is ()* hrs# in
babies it is (+ hrs and in $remature babies it may be u$ to (,hrs.
G.F.& dec!ines to - #in $erson o" + years o" age and +in $erson 0 years o" age.
Gentamycin #igoxin #Penci!!ins are contraindicated in o!d$eo$!e.
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Pregnancy
Caus!s s!$!ra% '&sio%ogi"a% "'ang!s t'at inf%u!n"! drug disosition)
Vo%um! of drug distri#ution is in"r!as!d.tota% #od& *at!r ma&in"r!as! #& u to 2 %it!rs ro$iding %arg! sa"! for *at!r so%u#%!drugs)
Mat!rna% %asma a%#umin "on"!ntration is r!du"!d,mor! fr!! drugs*i%% #! a$ai%a#%!
M!ta#o%i" rat! is in"r!as!d, so t'! fr!! drugs *i%% #! a$ai%a#%! for!%imination)
Cardia" out ut is in"r!as!d, %!ading to in"r!as!d r!na% #%ood f%o*and g%om!ru%ar fi%tration and in"r!as!d r!na% !%imination of drugs)
3io'i%i" mo%!"u%!s r!adi%& tra$!rs! %a"!nta% #arri!r) Drugs t'at ar!
transf!rr!d to f!tus ar! s%o*%& !%iminat!d) 8
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Gender Evidences show that men and women may responddifferently to same drugs
This may be due to body size, and amount of bodyfats.
But there are also some less easily explaineddifferences in gender –specific drug response
Aspirin shows greater benefit in men than womenin cardiovascular diseases
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There appears to be diference in the activity oliver enzymes b/w men and women
Since the activity o enzymes vary that can resultin major diference in drug response
This diference in liver activity may explain whywomen routinely waes up rom generalanesthesia several minutes beore a man givenan e!ual dose"
#t has been observed that women with red hairand air sin are particularly responsive to efectso the analgesic Pentazosine than man o samecharacter"
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Temperature
$ddition o mild to moderate hypothermiadecreases the systemic clearance o %&'()metabolizes drugs between *+,,- per degree
%elsius below .*c during cooling" The additiono hypothermia decreases the potency andecacy o certain drugs "
The therapeutic index o certain drugs is
narrowed during hypothermia" Therapeutic hypothermia has shown decrease
in neurologic damage in patients experiencingcardiac arrest"
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Timings
#t has been observed that endogenous bodycloc 0circadian cycle1 may afect the
response o the drug"e"g"
#n %230coronary heart dieseases1 shortacting calcium channel blocers seem to be
less efective than beta blocers in reducingischemic events during the night and earlymorning
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4ood 4r!s!n"! of fatt& food in stoma"' d!%a&s gastri"
!mt&ing,t'! %asma "on"!ntration of rifami"in and
ami"i%%in ma& #! mu"' r!du"!d if ta-!n on fu%%
stoma"'
Ca%"ium in mi%- int!rf!r!s *it' a#sortion of
t!tra"&"%in!s and iron)
Su#stituting rot!in for fats and "ar#o'&drat!s in di!t
,in"r!as!s drug o+idation rat!s)
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C'ar"oa% gri%%!d #!!f, "a##ag!, a%"o'o% in"r!as!s
m!ta#o%ism
4rot!in ma%nutrition aff!"ts 'arma"o-in!ti"s of
s!$!ra% drugs)
Citrus f%a$inoids in gra! fruit .#ut not in orang!
5ui"! signifi"ant%& in"r!as!s a#sortion of"&"%osorin "a%"ium antagonists and ro#a#%& ot'!r
drugs
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P$T2565G#%$6 4$%T57S
DISEASES can cause individual variations in drugresponse"
Pharmacokinetic variations8
Absorption:
Gastric and intestinal stasis during an attac o9igraine intereres absorption o drugs
7esection o gut may lead to malabsorption o iron:olicacid and at soluble vitamins and o vit ;<, ater ilealresection
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Diarr'!a in"r!as!s t'! moti%it& of t'! gut and d!"r!as!sa#sortion)
6&oa%#umina!mia from an& "aus! su"' as n!'roti"
s&ndrom!, #urn,ma%nutrition,s!sis a%%o*s 'ig'!r
roortion of a%#umin fr!! drug in %asma *'i"' isr!adi%& a$ai%a#%! for m!ta#o%ism and !%imination #ut
t'!r! "an #! ris- *it' initia% dos! for drugs *'i"' ar!
to #! 'ig'%& rot!in #ound
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Metabolism:
A"ut! and "'roni" dis!as!s of %i$!r aff!"ts t'! #%ood f%o* andfun"tion of '!ato"&t!s ,%!ading to d!"r!as!d drug "%!aran"!,and ro%ong 'a%f %if!)
Drug m!ta#o%ism is in"r!as!d in '&!rt'&rodism anddiminis'!d in '&ot'&roidism
Excretion
In a"ut! and "'roni" r!na% imairm!nt ,"on"!ntration of drugsis a%t!r!d)
.
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Pharmacodynamic variations:
Ast'ma "an #! r!"iitat!d #& #!ta #%o"-ing drugs
Rais!d intra"raina% r!ssur! ,s!$!r! u%monar& insuffi"i!n"&
"uas!s ati!nt to #! intto%!nt to oioids r!"iitat! r!sirator&
fai%ur!
%hange in receptors 09yasthenia gravis1"person
becomes intolerant to !uinine : !uinidine and
aminoglycoside
#ncreased sensitivity o adrenergic receptors in
hyperthyroidism" 18
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Genetic factors:These are %nown as idiosyncratic res$onse
These are rare but 1ery harm"u!. Acetylator stats .imortant for m!ta#o%ism S%o* a"!t&%ators(. isoniaid "ausing !ri'!ra% n!uroat'& on standard
dos! and &rido+in! is add!d to T)1 r!gim!
Raid a"!t&%ators( '!atoto+i"it& .'!ato"!%%u%ar n!"rosisin fast a"!t&%ators
3eective carbon oxidation ma& "aus! oor o+idation of som! drugs %!ading to som! ad$!rs! !ff!"ts
*it' standard dos!s of drugs %i-! #!ta #%o"-!rs)
Psedocholine estrase de!ciency Fai%ur! to raidina"ti$ation of Su+am!t'onium, %!ading to mus"u%ar #%o"- ,r!su%ts ara%&sis)
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G"#"PD de!ciency: . 'a!mo%&sis #& rima0uin!
G74D is n!"!ssar& to maintain r!du"!d g%utat'ion! inr!d "!%%s and to r!$!nt t'!ir '!mo%&sis)
T'is o""urs in sma%% ortion of !o%!
Su"' as "'%oram'!ni"o% "aus!s a%asti" an!mia 8 in
9:,:::)
9alignant hyperthermia= "aus!d #& su+am!t'onium
in ron! !rson du! to in'!rit!d a#norma%it& in Ca ;< r!%!as! from sar"o%ami" r!ti"u%um in striat!d
mus"%!s)
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Envoirmental and diet:
4o%%utants ar! "aa#%! of indu"ing 4=9: !n&m!s, su"' as'&dro"ar#ons r!s!nt in to#a""o smo-!, "'ar"oa% #roi%!d m!atindu"! CY4 8A)
Cigar!tt! smo-!rs m!ta#o%i! som! drugs mor! raid%& t'an
non smo-!rs)
Industria% *or-!rs !+os!d to som! !sti"id!s m!ta#o%i!"!rtain drugs mor! raid%& t'an *'o ar! non !+os!d
4o%&"'%orinat!d #i'!n&%s us!d in industr&, "ru"if!rous$!g!ta#%!s a%so indu"! CY4 8A
Gra!fruit 5ui"! indu"! CY4>A
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5ther variations0!uantitative 1
Mor! "ommon Mor! "%ini"a%%& imortant
4ati!nt ma& #!6&o r!a"ti$!(
6&!r?r!a"ti$!( to drug to a gi$!n dos! 6&!rs!nsiti$it&(
a%%!rgi" or ot'!r immuno%ogi" r!sonsi$!n!ss todrugs
!)g) 4!ni"i%%ins
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$olerance *it' som! drugs int!nsit& of r!sons! to gi$!ndos! ma& "'ang! during "ours! of t'!ra&,usua%%& d!"r!as! in r!sons! to "ontinu!d
administration of drug)!)g) Sa%#utamo% .@?adr!n!rgi" agonist
Oium ,#ar#iturat!s , A%"o'o% $achyphylaxis:
*'!n r!sonsi$!n!ss diminis'!s raid%& aft!radministration of drug
!)g) !'!drin!
Am'!tamin! 23
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#diosyncrasy(
Is an a#norma% g!n!ti" r!sons! and is usua%%&'armfu%
It o""urs in sma%% ortion of ou%ation)
!)g) a%asti" ana!mia du! to "'%orma'!ni"o%
'a!mo%&sis #& rima0uin! in G?7?4D d!fi!n"& 6!ati" or'&ria #& "ar#amaiin!
Ma%ignant '&!rt'!rmia #& su+am!t'onium
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$naphylaxis
It is an imm!diat! '&!rs!nsiti$it& r!a"tion on
!+osur! to s!"ifi" antig!n %!ading to %if!
t'r!at!ning r!sirator& distr!ss fo%%o*!d #&$as"u%ar "o%%as!
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%hange in response due to altereddrug concentration
T'is ma& #! du! to "'ang! in rat! of a#sortion
,distri#ution and !%imination of drug) a%t!ration in
drug "on"!ntration t'at r!a"'!s r!%!$ant r!"!tor ma&
a%t!r "%ini"a% r!sons! )
Variation in r!sons! ma& #! du! to $ariation in
"on"!ntration of !ndog!nous r!"!tor %igand,a%t!ration in num#!r of fun"tiona% r!"!tors, "'ang!
in "omon!nts dista% to r!"!tors)
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variability in response to
pharmacologic antagonist as rorano%o% *i%% mar-!d%& s%o* t'! '!art rat! of
ati!nt *'os! !ndog!nous "at!"'o%amin! ar! !%!$at!d .in
'!o"'romo"&toma #ut *i%% not aff!"t t'! r!sting 6)Rof *!%% train!d marat'on runn!r
A artia% agonist SARA3ACIN at angiot!nsin II %o*!rs
#%ood r!ssur! in ts *it' '&!rt!nsion "aus!d #&
in"r!as! in angiot!nsin II rodu"tion and rais!s #%ood r!ssur! in ati!nts *'o rodu"!s %o* amount of
angiot!nsin
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$lteration in number o receptors
t'!r! o""urs "'ang! in r!sonsi$!n!ss "aus!d #&in"r!as! or d!"r!as! in num#!r of r!"!tor sit!s ora%t!ration in !ffi"i!n"& of "ou%ing of r!"!tor to dista%!ff!"tors m!"'anism)
!)g) 8 R!"!tors for 'ormon!s
T'&roid 'ormon!s "aus! in"r!as! in num#!r of @?adr!n!rgi" r!"!tors and '!n"! in"r!as! in "ardia"s!nsiti$it& to "at!"'o%amin!s
ii Agonist %igand indu"!s a d!"r!as! innum#!r. do*n r!gu%ation or "ou%ing !ffi"i!n"& of itsr!"!tors)!)g sa%#utamo%)
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3rug resistance
'!n drug %oos!s t'! !ff!"ti$!n!ss)
usua%%& t'is 'a!ns *it' t'! imro!r us! of
anti#a"t!ria% drugs
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Synergism=
*'!n t*o drugs ar! administ!r!d at t'! sam! tim! , t'!!ff!"t in"r!as!s)
Summation( t'! !ff!"t of t*o drugs 'a$ing sam! a"tion
ar! add!d 'a$! aditi! !ff!"t)
!)g) #!ta #%o"-!r < diur!ti" 'a$! additi$! anti'&!rt!nsi$!
!ff!"t
4ot!n"iation( *'!n on! drug in"r!as!s t'! !ff!"t of
ot'!r drug !)g) %!$odoa <"a#idoa
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DRUG B DRUG INTERACTION when one drug is administered, a response
occurs, if a second drug is given and responseto 1st drug is altered ,a drug interaction is said tohave occurred
This may be Desired or beneficial
e.g. Multi drug treatment of T.B Naloone to treat Morphine overdose
!ndesired or hamful
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C%ini"a%%& imortant drug int!ra"tions
1. Drugs that have steep dose response curve and
small therapeutic inde, small change in
concentration at site will lead to substantial
changes in effect.
e.g. Digoin , "ithium
#. Drugs that are $nown en%yme inducers&inhibitors
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Distribution:
altered plasma protein binding ' binding of
penytoin in chronic renal failure decreases
Impaired blood brain barrier ' infilitration
of (enicillin in meningitis increases
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). Drugs that eibit saturable metabolism
e.g. (henytoin , Theophylline
*. Drugs used for prolong period and precise plasmaconcentration are re+uired
e.g. oral contraceptive ,lithium, antiepileptic drugs
. Different durgs used to treat same disease
e.g. Theophylline, -albutamol
. In patients with impaired $idney and liver function
/. In elderly who receive several drugs at the same time
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46ARMACODYNAMIC INTERACTIONS
1ot' drugs a"t at sam! targ!t sit! !+!rting s&n!rgismor antagonism
Drugs ma& a"t at sam! or diff!r!nt r!"!tors or ro"!ss)
!g a%"o'a% < #!ndia!in!s .s!dation
Mor'in! < Na%o+on! . to r!$!rs! ooid o$!rdos!
Rifami"in < IN6 . !ff!"ti$! anti T1 "om#ination)36
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P2A&3A456I'ETI4 I'TE&A4TI5'S
Drug a"t r!mot!%& from targ!t sit! to a%t!r %asma "on"!ntration
!)g) !n&m! indu"tion /in'i#ition
int!ra"tion ma& #! s&n!rgisti" or antagonisti")
Drug int!ra"tion "an o""ur at
8) out sid! t'! #od&
;) At sit! of a#sortion
>) During drug distri#ution
=) During drug m!ta#o%ism9) During drug !+"r!tion)
7) On r!"!tor or #od& s&st!m)
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Interaction out side the body
Drugs ar! add!d to r!s!r$oir or s&ring!s to ma-!
drugs so%u#%! t'!& ar! r!ar!d in sa%t forms, mi+ing
t'!s! drugs ma& %!ad to r!"iitation .in"omati#i%it&
Di%ution in r!s!r$oir ma& a%so %!ad to %oss of sta#i%it&)
4rotamin! in in" ma& #ind *it' so%u#%! insu%in andd!%a& its !ff!"ts.
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AT T2E SITE 5F ABS5&PTI5'
irect chemica! interactione.g. 0ntacids Tetracycline2s ,Iron form insoluble complees ,this can beprevented if drugs are administered at #hrs apart.
3ut motility4 drugs which reduce gastric emtying delay absorption of otherdrugs
e.g anti cholinergics , antidepressants
.
5ther than gut 4 "ocal anesthetics and adrenaline.
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(urgatives reduce time spent in smallintestine and reduce absorption.
0lteration in gut flora4 antimicrobialspotentiates ant coagulants by reducingbacterial synthesis of vit.6
5ther than gut 4 "ocal anesthetics andadrenaline.
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7&I'G IST&IB7TI5'
Dis%a"!m!nt from %asma rot!ins #inding
!)g) Sodium $a%roat! dis%a"!s 4'!n&toinSu%'onamid!s dis%a"!s #i%iru#in . in n!onat!s
Dis%a"!m!nt from tissu! #inding sit!s!)g) uinidin! dis%a"!s Digo+in)
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Interaction during metabolism Enzme induction: liver micsrosomal en%ymes are induced by a wide
variety of drugs and these affect the metabolism of otherdrugs reducing their concentration and hence effect.
e.g oral contraceptive metabolism is enhanced if(henytoin is co7administered ,leading to unplannedpregnancy
eg loss of anticougulant effect of 8arfarin leading todanger of thrombosis if barbiturates are administered.
chronic use of alcohal shows tolerance to generalanesthetics.
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En8yme inhibition
9ertain drugs inhibit the liver microsomal
en%ymes ,hence increase the activity of
drugs which are to be metaboli%ed bythese en%ymes.
:g. 9imetidine potenciates the effects of
propranolol ,theophylline, warfarin andothers
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Enzyme inducers.
(henobarbital
;ifampin
3risofulvin
(henytoin
:thanol
9arbama%epine
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Enzyme inhibitors
(henylbuta%one
Metronida%ole
9imetidine
5mpera%ole
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Int!ra"tion during !+"r!tion
this occurs in $idney
by latering binding and hence filtration
by inhibitin tubular secretion
eg probenecid and pencillins
by latering urine flow and or urine (<.
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<aemodynamic flow
variation in heaptic blood flow may
influence the rate of inactivation of drugs
as in reduced cardiac out put.
drugs which reduce cardiac out put li$e
(ropranolol may reduce the metabolismof other drugs.