Pharmacovigilance

Pharmacovigilance AND ADVERSE DRUG REACTIONS.
MONITORING REPORTING ROLE OF PHARMACIST.
CLASSIFICATION OF ADR. MECHANISM OF ADR
ROLE OF PHARMACIST IN MANAGING ADR. AUGMENTED, BIZZARE, CONTINOUS, DELAYED, END OF TREATMENT, ABCD, ABCDE.

1. PHARMACOVIGILANCE AND ADVERSE DRUG REACTIONS AKHIL JOSEPH PHARM.D 5 TH YEAR

2. DEFINITION Pharmacovigilance (PV) also called as drug safety Pharmakon------- in greek ----drug Vigilare ----------- in latin ------to keep watch Pharmacovigilance is the science and activities relating to the detection, assessment, understanding and prevention of adverse effects or any other drug related problem.

3. history Fr o m th e e arlies t times , ph arma c eutical f o rmulations hav e be e n r e c o gnized a s being pot e ntiall y danger o us. Public an d pr o fessi o na l c o ncer n abou t these matter s first ar o se in t h e late 1 9 t h c e nt u r y . I n 19 2 2 , ther e wa s a n enqu i ry i n t o the JAUN D IC E asso c iate d wit h th e us e of SA LV ARSA N , a n o r gan i c a r senical use d i n the treatm e n t of Syphillis . I n 1 9 3 7 i n t h e USA , 1 7 peopl e die d f r om taki n g a n ELIX I R O F SU L F ANILAMID E t h at c o n t ai n e d t h e S O L VENT D I ETHYL E NE G L YC O L T h i s led t o t he est a bli s h me nt of t h e F O O D AN D D R U G ADMINIST R A TION (F D A), which wa s given t h e tas k of en q u iring i n t o the safety of n e w d r ugs befor e allowi n g t h e m to b e marketed. Ma j or mode r n cata s troph e t h a t ch a nged pr o fessional a n d p u bli c opinion t o w ards medici n e s wa s t h e THALIDOM I D E IN C I D EN T .

4. I n 1961, i t wa s r ep o rted i n W es t Germany tha t ther e wa s a n outb r ea k of P H OC O MEL I A ( hypoplastic and aplastic limb deformit i es ) i n th e ne w bor n babies. I t wa s s h o w n s u bseque n tl y th at thalidomid e, a no n barbiturat e hyp n oti c , was t o blame. The c r ucia l peri o d of pregnanc y duri n g which th alidomide i s TE R A T OGE N I C i s th e first three months. The TH A LI D OMID E INCID E N T led t o a public outc r y , t o t h e i nstitu tio n al l r o u n d th e w o rld of DRUG REGUL A T O R Y AUTHO R ITI E S , t o the dev e lopm e n t of a muc h mo r e soph isticated appr o ac h t o th e p r e c linical testin g and clinica l evaluatio n of drug s bef o re mar k eting , an d t o a greatly i n c r eased awa r eness of a dverse e ffect of d r ugs and method s of detecting the m .

5. D rug Y ear Adv e r se Re a ction O utcome Sul f an i lam i d e 1937 Live r d a m ag e d ue t o d i e thylene g l yc o l S o l v en t change d; FDA e s tabli s hed Thalid o m i d e 1961 Congen i tal Mal fo rmations W ithdra w n Chlo r a m p hen i c o l 1966 Bl oo d Dyscras i as Use s rest r icted Benoxapr o fan 1982 Live r da m age W ithdra w n A s p irin 1986 R ey e ’ s syn d r o me Use s rest r icted Flecai ni d e 1989 C ardiac A r r hythm i as Use s rest r icted No scapi ne 1991 G en e t o xici t y W ithdrawn T riaz o lam 1991 P s ychiatric d i s o rders W ithdra w n T e m afl o xacin 1992 V ariou s serious a d vers e e ffects W ithdra w n C o -t r i m o xaz o le 1995 Seri o u s allergic rea ct ions Use s rest r icted T er f en ad ine 1997 Interac t ions (e.g . with g r a p ef r ui t juice) W ithdra w n f r o m OTC sale S o tal o l 1997 C ardiac ar r hy t hm i as Use s rest r icted A stem iz o le 1998 Interac t ions W ithdra w n C i sapride 2000 C ardiac ar r hy t hm i as W ithdra w n C eri v a s ta t in 2001 Rhabd o m yl o sis W ithdra w n DRUGS THAT HAVE BEEN WITHDRAWN OR HAVE HAD THEIR USES RESTRICTED BECAUSE OF ADR

6. AIMS To improve patient care and safety in relation to the use of medicines, and all medical and paramedical interventions; To improve public health and safety in relation to the use of medicines; To contribute to the assessment of benefit, harm, effectiveness and risk of medicines, encouraging their safe, rational and more effective (including cost-effective) use; To promote understanding, education and clinical training in pharmacovigilance and its effective communication to health professionals and the public. To promote rational and safe use of medicines.

7. GOALS The ultimate goals of pharmacovigilance are: The rational and safe use of medical drugs. The assessment and communication of the risks and benefits of drugs on the market. Educating and informing of patients.

8. Why do we need pharmacovigilance ? 1. Humanitarian concern -Animal toxicology is often not a good predictor for human effects. -Evidence of safety from clinical trials is insufficient due to some limitations LIMITATIONS (phase 1-3): limited size , Narrow population (age &sex specific), Narrow indications (only specific disease), Short duration

9. 2. Safe use of medicines Medicines are supposed to save lives. Dying from a disease is sometimes unavoidable; dying from a medicine is unacceptable. It has been find that ADR’s may cause 5700 deaths per year in U.K. ADR’s were 4th-6th commonest cause of death in the us in 1994. 3. ADR’s ARE EXPENSIVE 6.5% of admissions are due to ADR’s Cost £446 million per annum in U.S. 4. Promoting rational use of medicines 5. Ensuring public confidence 6. To protect patients from unnecessary harm 6. Ethical concern To know of something that is harmful to another person who does not know, and not telling, is unethical.

10. ADVERSE DRUG REACTIONS 'A response to a drug which is noxious and unintended, and which occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function’ is called as an ADR . An  adverse event  ( ae ) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An adverse event (ae) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Serious adverse event or reaction is any untoward medical occurrence that at any dose; – results in death, life threatening, requires inpatient hospitalization or prolongation of existing hospitalization – results in persistent of significant disability or incapacity. Thus all adr are adverse events but all adverse events are not ADR.

11. PREDISPOSING FACTORS 1. RACE: Certain population in Africa and south east Asia have people who are deficient in glucose ‐ 6 ‐ phosphate dehydrogenase, such individuals are at substantial risk of developing haemolytic crises after the use of anti malarial drugs like primaquine. The rate at which drugs are acetylated varies considerably between ethnic groups. Rapid acetylators predominate among eskimos and slow acetylators among jews . Slow acetylators are likely to suffer from peripheral neuropathy due to INH. 2. GENDER: Women are likely to suffer from certain ADR than men. Agranulocytosis caused by phenylbutazone or chloramphenicol is 3 times more potent in women than in men. 3. AGE: The elderly over the age of 60 years are more susceptible for adr than the younger groups. It is well known that elderly are more sensitive to analgesics and become more confused with barbiturates. After a standard IV dose of pethidine, the plasma concentration is higher and half life is longer in older than in younger patients.

12. In younger patients , neonates when premature, some enzymes involved in drug metabolism and elimination are poorly developed and consequently the risk of ADR is high. HAZARDOUS DRUGS: chloramphenicol, sulphonamides, barbiturates. 4. ALLERGIC DISORDER: patients with allergic disorder and hyper sensitivity reaction are more likely to develop from ADR. 5. RENAL AND HEPATIC DISEASES: impaired renal and hepatic function predisposes ADR to those drugs that are wholly or mainly excreted unchanged in urine. 6. PLASMA PRITEIN BINDING : The pharmacological action and toxicity of certain drugs are influenced by degree to which they bind to plasma protein, mainly to albumin. A decrease in plasma albumin level due to age, malnutrition or disease and metabolism of drugs that are highly protein bound. Example : WARFARIN. 7. FORMULATION OFTHE DRUG: Epidemics of particular drug ADR occur because of toxic vehicles or change in formulation when pharmaceutical manufacturer change the excipients present in some capsules of phenytoin in the form of calcium sulphate dihydrate to lactose, many patients develop symptoms of phenytoin toxicity.

13. CLASSIFICATION Type A : ‘Augmented’:  on-target (too much of a good thing) - predictable. Type B : ‘ Bizzare ’:  idiosyncratic, vary from patient to patient - unpredictable. Type C : ‘Continuous’:  adverse effects which arise from long-term use of a drug. They may be perfectly safe and effective in the short term, but can become unfavourable with chronic use, die to physiological adaptations / accumulation of adverse effects. Type D : ‘Delayed’:  adverse drug effects long after the drug is gone.

14. Type A : ‘Augmented’: D O S E - RE LAT E D A D V E R S E DRU G RE AC T I O N S : PH A RMACEUTI C AL V A RIATION PH A RMAC O KINE T IC V A RIATION Pharmacoge n etic var i ation Hepati c d i sea s e Renal d i sea s e Ca r d i ac d i se a se Thy r oid d i sea s e Drug i n tera c tions C. PHARMACODYNAMIC VARIATION Hepa t i c di s ease Alte r ed flu i d and elect r olyte balance Drug i n tera c tions

15. Type B : ‘ Bizzare ’ : NO N - DOSE RE LA T E D A D V E R S E DRU G RE ACTI O NS IMMUN OLOGICA L R E ACTIONS PS E U D O ALLE RGI C R E ACTIONS PHARMACOGE N ETIC VARIATION Type C : ‘Continuous’: L on g- t e r m a d v e rs e dru g re a ctions ADAPTIVE CH A NG E S R E BOU N D PH E NOM E NA Type D : ‘Delayed’: De l a yed a d v e rs e dru g re actio n s CARCIN O GE N ESIS EFFECTS CONCERNED WITH REPRODUCT ION Im p ai r ed inferti l ity T eratogene s is Drugs i n b r east mi l k Type E : ‘End of treatment effect’ :

16. D o se r e lated adv e rse r e acti o n s hav e led to th e c o ncep t of th e TH E RAP E UTIC IND E X , or th e T OXIC:THERA P EUT I C R A TI O . This i n dicat e th e margi n betw e e n the therapeuti c dos e an d th e toxi c dose. The bigge r th e ratio, th e bett e r . Examples of drug s wit h a l o w T OXIC:THE R P E U T I C R A TI O : Anticoag ul a n t s ( w ar f arin, he p arin) Hypogly cemic drug s (ins u lin, sulfonylurea) A n tiarry t hmic drug s ( l ido c aine, amiodarone)

17. Cardiac g l yc o sides ( dig o xi n, digi t oxin) A m i no g l yc o side antib iotics (gentamicin , netilm i cin) Ora l c o ntracepti v es Cyt o to x i c and im m unosuppre ss i v e d r ugs ( c yc l osporine, methot r exate, azathiop r i ne) A n tihyper t ens i v e drugs ( bet a adreno c eptors antagonis t s , ACE i nhibitor s ) Dos e -r e lated adve r se r eacti o n s ca n o c c ur becaus e of va r iation s i n the P harmaceutical , P harmac o kinet i c , or P harma c od y nami c pr o pe r tie s o f a drug , o f ten du e t o P harmac o genetic charact e ristic of a patie n t.

18. Adverse dru g r eactio n s oc c ur beca u se of alteration s i n t h e systemic availabilit y of a fo r m u lation EXAMPLE: Phe n ytoin In toxicatio n , b y a ch ange i n one of th e excipien t s i n th e p h eny toin caps u les f r om c a lcium s u lfate to lact o s e , which i n cr e as e t h e sy s temi c avail a bili t y of p h e n ytoi n . Adverse r e actio n ca n o c cu r becau se of t h e prese n c e of a cont a mi n a n t EXAMPLE: Pyroge n s or eve n Bacter i a i n in t ravenous f o rmulation s .

19. Out of dat e f o rmulations ca n som e time s cause adve r se r e actions , becaus e of degradation pr o ducts EXAM P LE: ou t - date d Te t ra c yc l i ne ca n caus e Fa n c o n i ’s Syndrom e .

20. T h er e i s m u c h variation amo n g no r mal i n divi d u al s i n t h e rate of elimi n at ion of dru g s. T h i s variation i s mos t marke d for dru g s t h at ar e clea r e d b y h epati c metabolism. I t i s de t ermine d b y several facto r s, which ma y b e GENET I C , ENV I RONME N T AL, or HE P A TIC.

21. Ace t ylatio n Oxi d a t ion Succi n ylcholine hydr olysis Ace t ylatio n: Acetylation s h o w s genetic variabili t y . T h er e ar e Fast a n d Slow acetyl a tors. Seve r a l dru g s ar e a cetyla t e d b y N- ACETYL T R ANS F ERAS E . Fa s t Acetylat io n i s a u tosoma l domi n a n t a n d Slow Acetylat io n i s a u tosoma l re c ess i ve.

22. Drug s whos e Ac e tylatio n i s genetically dete r mine d are: Is o n i azid Hydra l azine P r o cainamide Dapsone S o m e sulfonamides Incr e ase d i n cidenc e of PE R IPHE R AL N E URO P A THY i s obse r ved i n sl o w acetylato rs of Is o niazid

23. Oxi d ation: Oxidati o n als o sho w s g e neti c va r iabilit y . There ar e i n divid u al s wit h impaire d oxidation an d wit h norma l oxidation. Impair e d oxidation ones a r e c alle d a s PO O R METBOLIZ ERS an d th e ones w it h norma l are calle d EXTE N S I V E ME T ABOLIZ E R S . Debrisoquine type: CYP2D 6 i s a cyt o chr o m e P450 enzym e a n d ca r ries out Deb r isoqui n e hy d r o xylation. Impair e d hy d r o xylation of Debrisoqu i n e i s an A U T OS O MA L REC E S S I V E DEFEC T o f t h is cyt o chr o me.

24. Drug s th at ar e aff e cte d beside s Debris o qu i ne are: Captop r il Metop r ol o l P he n f o rmin P e r hexiti n e N o rt r ypti n e P o o r h ydr o xilators ar e mo r e likely t o show dose relat e d adverse effect of thes e drugs. I n cas e of tox i c metabolit e s risk w o ul d be great e r i n extensiv e hy d r o xilators.

25. Suc c inylcho l ine Hydrolysi s : S u ccinylc h ol i n e i s hydr o lyzed by P S EU D O CHO L I NEST R AS E . I n some indivi d ual s pse u d o ch o linestr as e is ab n ormal an d d o e s no t metab o lize succinylch o line rapi d l y . I n such case s dr u g persis t i n bl o od a n d c o nt i n u e t o pr o duc e neur o muscula r bl o ckad e for several ho urs. This result i n respiratory paralysi s called SCOL I N E APNOE A . T h er e ar e thre e type s of ab n orm a lities of pse u d o ch o linestrase eac h inherite d i n an A U T OSOMAL R E CESSIV E F ASHIO N. Dibucain e resistant type Flu o ride resista n t type Silent gene type

26. Adve r se dru g r e actio n du e t o impaired hepati c me t abolis m ar e n ot so c o mm o n. Hepatoc el l ula r dysfunctio n , a s i n seve r al hepat i ti s o r advance d c ir r hosis , ca n r e duce th e cl e aranc e of drug s like phenytoin, t h eop h y l line and w a rf a ri n . A r eductio n i n hepa t i c bloo d f l o w , a s i n h eart failure, ca n r e duc e th e hepat i c cl e aranc e of drug s th at hav e a n hi g h extra c tio n ratio f o r e.g . pr o pr a nolo l , morp h in e an d pet h idin e . R educe d pr o ductio n of pl a s m a proteins (for e.g . alb u min ) b y th e liver i n cir r hosi s can lead t o reduced pr o tei n bi n di n g of drugs.

27. I f a dru g o r activ e metabolit e i s exc r ete d by glom e rular filtrati o n or tu b ula r sec r etion , it wil l ac c um u late i n r ena l i nsufficiency and toxi c it y wil l o c cu r . Cardia c failure, particularl y c o nge s tive ca r dia c failur e , ca n alte r the pharma c o k ineti c pr o pe r tie s o f drug s by sev e ral me c ha n isms: 1) Impair e d absorption , du e t o i n testi n al mucosa l edem a an d a p o or splan chn i c ci r culation , ca n alte r th e ef f icac y of some o r a l diuretic , such a s FUROSEM I D E ;

28. 2) Hepati c c o ngest i on an d r e duce d liver bl o od fl o w ma y impai r th e metabolis m of some drug s (e.g . Lidocain e ). P o o r renal pe r fusion ma y r e sult i n r educed r e na l eliminat i on (e.g . Pro c ainamide ). R eductio n i n th e apparen t v o lumes of distrib u t i on of some ca r di o activ e drugs , by me c ha n ism s th at ar e no t u n derst o od cause r e duce d loading dos e r e qu i r e ment s (e.g. Pr o cainamid e , Lidocain e , Quinid i n e )

29. Hepati c diseas e ca n alter pharmac o dynamic respo nses t o drug s i n several way s; 1 . Redu c ed Bloo d Clo t ting: I n cirrh o sis an d acu t e he p ati t is , pr o d u cti o n of clot t in g factor i s impaire d an d pa t ient s bleed mor e rea d il y . D rug s tha t impai r bl o od clot t in g , tha t impair home o stasis, or tha t predis pose t o bleedi ng by causin g gas tric ulceratio n sho u ld b e avoide d or use d wit h ca r e for e. g . A n tico a gulants and NSAID S .

30. 2. He p atic Encep h alopathy: I n patient s with , or on th e bo r de r line o f , hepat i c encephalopat h y , th e brai n i s mo r e sensi tiv e t o t h e e ff e ct s of drug s wit h sedative actions . I f such drug s ar e used , c o m a can r e sult. I t i s theref o re wis e t o avoi d Opioid s & other Nar c otic A n al g esics an d Barbiturate s . 3. S o diu m and Water Rete n tion: I n hepati c ci r rhosis, sodium an d water r e tentio n ca n b e e xace r bate d b y c e rtain drugs . Drug s tha t should b e av o ide d o r used wit h ca r e includ e NSAIDS , Corti c osteroid s , Carbamazep i n e an d f o rmulations c o nt a i n i ng large amoun t of sodium.

31. The ph arma c odynamic e ff e ct s o f some drugs ar e alter e d b y cha nges i n fluid and ele c tr o lyte bala n c e . Example: The toxi c ef f e c t o f ca r dia c gly c osides are potentiate d b y bot h Hypokal aemia and Hyper c a l c a emia . The Class 1 of Anti arrhyt h mi c drug s such as Qui n idin e , Pro c aina m id e an d Di s opyram i de ar e mo r e arrhyt h mog e n ic i f t h e r e is hypo k alae m ia.

32. Include IM M U N OL O GICAL and PHARM AC O GENETIC mechanism s of adverse reacti o ns. There i s n o relatio n ship t o th e usual p h armac o lo g ica l effec t s of th e dr u g; There i s often a d e lay be t wee n th e fir st exp o sure t o th e dru g an d th e occurrence of the subs e qu e n t advers e reaction; T h er e i s n o formal d o se - response curve; The illnes s i s of t e n recog n izabl e a s a form o f immun olo g ica l reaction like rash, serum sickness, urticari a etc.

33. Fact o rs i nv o lved i n dru g alle r gy c onc e rn the Dru g an d P atient s : THE DRUG: Macr o mo l e c ule s su c h a s PRO T EI N S ( vaccines an d en z ymes such a s strept o kinase), PO L YPEPTIDE S ( i nsulin an d dext r an s ) can themsel v e s b e immunog e nic. THE PATIENT S : There ar e genetic fact o rs tha t mak e some patie n t s mo r e likely t o devel o p alle r gic r e acti o n s tha n othe r s: A histor y of allergi c disord e rs HL A status(ant i g e n s on h u ma n lympho c ytes)

34. Class i f i e d ac c . t o t h e c lassification of hy p e r sensi tiv i t y r e actions , i.e . i n t o f o ur types , TYPES I - I V . T y pe 1 Reactions (a n ap h ylaxi s ; immedi a t e hy p e r sensi tivity ) : The dru g or metabolit e i n tera c t s wit h IgE mole c ules fixed t o c ells , particularl y tiss u e mas t c e lls an d basophile s leuk o cytes. This trigger s a pr o c e ss tha t lead t o t h e r e lease of pha r maco l ogi c al mediators like histami n e , 5 - H T , k ini n s , an d ara c hidoni c acid deri v atives , whic h caus e allergi c r e sponse.

35. Manifes t a s Ur t icaria , R h initis , Bronchial A s thm a , Angi o - oede m a an d Anap hylact i c S h oc k . D rug s likely t o caus e typ e 1 are Penic illi n s, Streptomycin , Loc a l Anaesthetics etc. Type II Reaction s (Cytotoxic Reactions): A circulatin g anti b o d y of th e IgG , IgM, or Ig A class interac t w it h a n anti g e n formed b y ha p ten. Complemen t i s the n activate d an d cel l lysis o c curs. Exam p le: Thrombocytopenia, Haemolyti c Anaemia

36. Type III Reactions (Immun e Co m plex Reactions): Anti bod y (IgG ) c o mbi n e s w it h an t ige n i.e . the ha p te n - pr o tei n c o mple x i n c ir c ulat i on Comple x th u s f o rm e d i s deposite d i n the tiss u es , c ompl e men t i s activated , an d damage t o capillar y endotheli u m r e sults. S e ru m s i ckness i s th e typica l dru g r e action of thi s type. Penicillin s , Sulfo n amides & A n tith y roi d drug s ma y b e r esponsible.

37. Type I V reactions (Cel l Media t ed): T-lymphocytes ar e sensi tize d b y a h apte n - pr o tei n an t igeni c c o mplex. Inflammato r y r espons e ens u e s when lymphocytes c o m e i n c o nt a c t wit h th e ant i gen. E.g. Dermatitis cause d b y lo c a l anest h etic c r eams , topica l an t ibiotic s an d antif u ng a l c r eams. Pseudo All e rgi c Reactions: T e r m applie d t o r e acti o n s tha t r e semb l e allergi c r e action s c lin icall y bu t f o r whic h no immu n ol o gical basi s ca n b e f ound. A s thm a an d Ski n Rashe s cause d b y aspiri n are th e exampl e s.

38. Me c ha n isti c appr o ac h d o e s not fit i n the clinica l pres e nt a tio n so a clinica l approa c h. Fever: Dru g fe v e r a s a n isolate d phe n om e no n can o c cu r wit h penicillin , phe n ytoin , hy d ralazine an d qu i n i di n e. Rashes: Dif f e r en t type s of rashes ar e sho w n i n the tabl e given.

39. T y p e of r ash D e s c rip t ion Examp l es of dru g s cau s i ng it E r ythe ma m ul t if o rm T arge t like lesi o n s o n the extenso r sur f ac e o f th e limbs. P en i cilla m ine P en i cillin Sulphonam i d es E r yt he ma n o dosum T en d e r red n o dules , s om e t i m es w i t h bruisi n g o n th e extensor sur f ac e o f th e l i m bs. P hen o b arbita l s Sulphonam i d es Oral c o nt r ace p ti v es E x f o liative d erm a ti t is R e d , scal y , E x f o liative lesi o ns sometim e s inv o l v in g extens i v e area s o f sk in C arba m aze p ine G o ld sal t s P hen ylbutaz o ne P e m p higus W i d e spread blistering P en i cilla m ine Ri f a m p icin U r ticaria R e d raised lesi o n s surr o un d ed b y o e d e m a o f te n c o nf l uent Cod i ene Dext r ans P en i cillin

40. BLOO D DISORDE R S: T h r o mbocytope n ia , Neu tr o pe n ia , Hemolytic A n aemi a , a n d Apl a stic A n aemi a ca n al l o ccur a s advers e dru g r eactio n s. R E SPI R ATOR Y D I SO R DE R S: Asth m a oc c ur r i n g a s a p s e u d o allergic r e actio n t o Aspiri n , other NSA I D S a n d T artarzi n e i s a n e.g . advers e dru g r eactio n .

41. Re d cell enzyme defects Po r phy r ia Mali g na n t hypert h er m ia RED CELL EN Z YM E DEFEC T S: Unus u a l dr u g reacti o n o c cu r i n in d ivi d ual s wh o se er y throcyte s ar e deficien t i n an y one of three differen t bu t func t io n all y related enzymes. Glu c os e - 6 - p h osph a t e dehydro g enase Gl u tathion e re d u c tase Meth a emoglo b i n red u c t ase

42. M ethaemo g l o b i n r e d uc t ase G 6 PD G l uta t hion e redu c t a se

43. G l ucos e- 6 - phosphate dehydroge n ase deficie n cy: G 6PD deficien t e r yt h r o cyte s w he n exposed t o o xi d izi n g age n t s un dergoe s Ha e moly s is . T h e prevalenc e of t h i s defec t varies with race. There ar e tw o varieties of d efi c iency: Black variety Med i terranea n variety Blacks h a ve norma l G 6PD pr o d u ctio n bu t its degra d at ion i s accelerated. Med i terranea n h av e ab n o r ma l G 6 PD produc t ion.

44. Glutathione reductas e deficiency Defi c ienc y i s autosoma l domina n t. Defi c ienc y of enzym e dir e ctl y cause defi c ienc y of r e duce d glutath ione. Methaem o globin reductase deficiency I f Methaemoglobi n i s no t r e duce d to Haem o globin c o nt i nousl y ac c um u lation of Methaem o gl o bi n tak e s pla c e r e sulting in impairmen t of O 2 delive r y t o tis s ues , causi n g HY P OXA E MIA . In h e r ita n c e of def e c t i s autosoma l r e c e ssive.

45. Porp h yri a : P o r ph yrias c o ns t it u t e a gr o u p of disord e rs o f hae m - biosynt h e s i s . Dif f e r en t type s of po r phyria s ar e the r e: Acute i n ter m itten t po r ph yrias V ariegat e po r ph yria P o r ph yria c ut a ne a tarda E r ythr o poi e ti c P o r phyria Ea c h typ e o f P o r ph yria is associate d wit h a diffe r en t ab no r malit y o f a n enzym e i n hae m - biosynt h eti c pat h wa y . Drug s t o b e av o ide d i n po r phyri a : Barbiturates , Dapso n e, Ch l oramphenico l , Diclo f enac et c .

46. Malignant h y per thermia: I t i s a n autos o ma l do m ina n t g e neri c diso r der of sk e letal muscle s tha t o c cur s i n susceptible i n divid u al s u n derg o i ng Gener a l A n esthesia wit h i n hale d agent s ( h alogena t ed ) and muscl e r e laxan t s like Su c cinyl c ho l i n e . This ra r e conditio n of unc o ntrol l ed release of ca l cium b y sar c oplasmic r e ticul u m of sk e letal muscl e s leads t o muscl e s spasm, hy p e r thermi a an d autonomi c liabilit y . Dantrolen e i s in d icate d i n life threateni n g situ ations.

47. Exampl e s includ e de v el o pmen t of to l e r ance t o an d ph ysical dependenc e on the NARC O TIC ANALGES I CS an d th e o c cur r ence of T ARD I VE DYSKINES I A i n s o m e patie n ts r e c e ivin g long te r m neurol e pti c dru g therapy f o r schizophr e n i a. Durin g l o n g te r m therap y sudden withdra w al of th e dru g c a n result i n r eb o u n d r e actions.

48. Exampl e s : T ypica l Syndr o me s o c cur r i ng aft e r su d den withdrawa l of narc o ti c analgesi c or of alc o hol (deliriu m tre m ens ) . Sudden withdra w a l of B arbiturat e s r e sult in restless n ess , me n ta l c o nfu s io n and c o n v ulsions . Sudden withdrawa l of β - adreno c epto r s an t agonist s r e sult i n rebou n d ta c hy c ardia whic h ca n pre c ipita te myo c ardia l ischemia. Sudden withdrawa l of c o rtic o ster o id s results i n syndr o m e o f a d rena l in s uffi c ienc y .

49. There ar e thre e majo r me c ha n ism s of ca r cinogenesis: i. Hormonal: Incidenc e of V AGINAL ADE N OCARCI N OMA is i n c r ease d i n daug h ter s of w o me n wh o have take n ST I LBOESTR OL duri n g pregnanc y f o r th e treatm e n t of threatene d abortions. Incr e ase d risk of BREA S T CANCE R S i s about 50 % an d w oman t akin g HORMO N E R E PLACEM E N T TH E RA P Y (H R T) f o r m o re t h an five years.

50. i i . G e n e T o xicity: O c cur s w he n c e r tai n mo l e c ule s bi n d to n u cl e a r DN A an d pr o duc e cha nges i n gene expressi o ns. Examples: BLADDER CANCE R i n patien t takin g long te r m CY C LOPHOS PHAMIDE Car c inoma s of R E N A L P E L V I S asso c iate d with PHE N ACETIN ab use. N o n lymphocytic LEUKEMI A i n patients r e c e ivin g ALKYL A TI N G AGENTS such as melphala n , chlo r ambuci l etc.

51. ii i . Suppressio n o f immune re s ponse s : P atient s ta k i ng immu nosuppre s s i ve drugs such a s AZ A THI O PR I N E with CO R TICO S TE R OIDS hav e incr e ase d risk of dev e loping L YMPHOMA S .

52. Impaire d Fertility T e ratogenesis Impaire d Fe r tility: Cytot o xic drug s ca n caus e fe m al e infe r tility throug h o v aria n failure wit h amenor rhea. Mal e fe r tilit y ca n b e r educe d b y impairm e nt of spe r matoz o a l pr o ductio n or fun cti o n a n d ca n b e e it h e r r e ve r sible o r irr e ve r sible:

53. RE V ER S IBL E IM P AIRM E N T ca n b e c au s e d by sulfasal a z i ne , n i t r o furantoin, MA O i n h i bitors an d an t imalaria l drugs; I R R E V E R S IBL E IM P AI R ME N T , du e t o azospe r mia, ca n b e c au s e d b y c ytot o xic drugs , such as alkylatin g agent s cy c lophosphamide and chlo r ambucil.

54. Teratogen e sis: T e r atogenesi s o c cur s whe n a dru g tak e n durin g ea r ly stag e s of pregnanc y c ause s a dev e lopm e nt al ab no r malit y i n a fetus. Drug s ca n aff e c t fetus a t 3 stages: 1) FE R TILI Z A TION AN D IMPL A N T A TION: Conc e ptio n t o 17 days Failure of pregnanc y whic h o f te n go e s u n noticed. 2) O R GAN O GENE S IS: 18 t o 55 day s o f gestati o n Mos t vuln e r abl e peri o d , def o rmities are pr o duced

55. 3) G R OW T H AN D D E VELOPMEN T : 5 5 day s onwa r ds de v el o pmen t an d functional abnormalities ca n o c cur ACE i n h i bitor s ca n caus e HYPOPLASI A of o r gans N S AIDs ma y ind u c e PR E M A TURE CLO S UR E OF DUCT U S A R TE R IO S US Diff e r e n t terat o genic drug s are: Thalido m ide , Methot r exate , W ar f arin, P he n ytoin , P he n oba r biton e, V alproate S o d. , Lit h i u m , etc.

56. CAUSALITY ASSESSMENT WHO-UMC CAUSALITY ASSESSMENT SCALE

57. NARANJO’S CAUSALITY ASSESSMENT CRITERIA

58. Role of Pharmacist in the Management of ADRs A pharmacist plays a pivotal role in the identification, detection, prevention, and management of drug-drug interactions, drug-food interactions and adrs . Pharmacist can carry out such activities in inpatient setting, while taking part in viewing charts during ward rounds, and during medication management while dealing with prescriptions. Since pharmacists have a vast knowledge on drugs and therapeutics, their ability to discover and deal with adrs is quite important. Keeping in view the reporting of adrs , a pharmacist’s participation enhances reporting rate with higher calibre.

59. The intervention of pharmacists by organising lectures and group discussions thus providing information about the importance, seriousness, preventability and necessity of reporting shows heightened improvement of knowledge, attitude and perception about adrs . All health professionals play their respective roles in balancing between benefits and risks of medication when it is introduced in the market. However, the expertise of a pharmacist about a drug, especially if newly marketed, play a more important role in adrs reporting to the authorities which helps in either withdrawing the product from the market or cause labelling changes. Pharmacists working in community pharmacy have an added advantage of detecting and reporting adrs while dealing with on the counter prescriptions and herbal products. In a community pharmacy, a pharmacist may not have direct and definite patient list but the patients coming to the same pharmacy to refill their prescription gives the pharmacist an opportunity to detect a possible adr that the patient might be experiencing and can help in the management and the reporting of the said adr .