factors modifying drug effects.ppt

7/21/2019 FACTORS MODIFYING DRUG EFFECTS.ppt

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FACTORS MODIFYING

DRUG EFFECTS/DRUGVARIATIONS

1



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

2



Physiological factors

AGE:

Pregnancy Sex/gender

Body weight

Food

Timings

3



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

4



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

5



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)

6



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.

7



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



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

9



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"

10



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"

11



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

12



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)

13



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

14



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

15



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

16



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)

.

17



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



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)

19



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)

20



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

21



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

22



$olerance *it' som! drugs int!nsit& of r!sons! to gi$!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



#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

24



$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!

25



%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)

26



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

27



$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%)

28



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

30



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

31



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

32



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

33



Distribution:

altered plasma protein binding ' binding of

penytoin in chronic renal failure decreases

Impaired blood brain barrier ' infilitration

of (enicillin in meningitis increases

34



). 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

35



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



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)

37



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.

38



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.

39



(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.

40



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)

41



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.

42



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

43



Enzyme inducers.

(henobarbital

;ifampin

3risofulvin

(henytoin

:thanol

9arbama%epine

44



Enzyme inhibitors

(henylbuta%one

Metronida%ole

9imetidine

5mpera%ole

45



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 (<.

46



<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.

factors modifying drug effects.ppt

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