ADVERSE DRUG REACTIONS

GENDER AS A RISK FACTOR

Chief Editor

DR T R RAMANUJAM M.D., C.MI.Biol (Lond)

What is an Adverse Drug Reaction 

Gender Effects of Pharmacology

What  is  an  Adverse Drug  Reaction?

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ANY  NOXIOUS, UNINTENDED & UNDESIRED EFFECT OF A DRUG WHICH OCCURS AT A DOSE  USED  IN HUMANS FOR    PROPHYLACTIC,   DIAGNOSTIC  OR  THERAPEUTIC   PURPOSES.

FDA Definition- Any adverse event associated with the use of drugs in humans whether or not considered drug related including the following:

 ·an adverse event occurring in the course of  the use of drug in professional practice,
 ·     an adverse event  from drug overdose whether accidental or intentional,
 ·     an adverse event  occurring from drug abuse,
 ·     an adverse event  from drug withdrawal,
 ·     any significant failure of expected pharmacological action.

Probability

• Definitive
• Probable
• Possible
• Doubtful

Determination based on the presence of conclusive reports in literature, a negative dechallenge, positive rechallenge, alternate causes, a positive dose response relationship, a temporal relationship, and presence of toxic drug concentration.

Severity  

- Mild  -  symptomatic treatment, alter dose, no change of drug
  - Moderate  -  change in drug therapy
  - Severe  -  unexpected untoward leading to possible debility, or death.

Gender Effects  of  Pharmacology

Results of various animal studies illustrated the fact that significant SEX difference in drug metabolism and elimination did provide an impetus for sex based research in humans. 
Recent advances in the characterisation of specific isoenzymes of drug metabolism paved the way for preliminary identification of enzyme system affected by sex.  Limited current studies showed apparent CYT P₄₅₀ (CYP 3A4) activity higher in females than males while other enzymes are increased in males. Men and woman show different pharmacodynamic response to various drugs probably so with drugs having low therapeutic range.

In addition to sex gender differences in drug metabolism may play a role in increasing Adverse drug reactions in women.

Female specific issues such as pregnancy, menopause, menstruation may have profound drug effects in man.  A few clinically significant ones like increased elimination of anti-epileptics decreasing their efficacy in pregnancy, oral contraceptives interfering with metabolism of many drugs and conversely certain drugs can impair contraceptive efficacy.

In the past women were under represented in the participation of clinical studies.  Women were initially excluded for clinical studies during their child bearing potential period.  FDA extended them from Phase I to early Phase II.

The assumption that women and men metabolise and respond to drugs similarly is no longer tenable and it is also clear sex specificity occurrences like pregnancy, menopause, oral contraceptive etc., profoundly influence drug metabolism and therefore the response.  On getting back to animal studies now it is known that there are large sex gender differences in that female rats show differences in levels of CYP3A4 isoenzyme.  This and other observations should provide an impetus for gender  based research in human.

a. Qualitative and Quantitative Gender Differences:

Body compartment- Male have increase weight and differences in weight are due to body water space, muscle mass, organ blood flow and organ function which can alter pharmacokinetic profiles.  Females tend to have more percent of body fat; (V_d of lipophilic substance like trazodone, sufentanil).

In extreme obesity significant PCK drug alteration are observable V_d in females - Low V_d for ethanol, High V_d for diazepam.

Even after correction made for weight difference, lean body mass body surface area, significance sex difference to exist in drug metabolism which are attributable to factors like; Hepatic metabolism - Benzodiazepines - complex role of sex in drug metabolism and PCK.

Granblatt et al & Ochs et al observed in young females higher total and unbound hepatic clearance of diazepam than young males.  Higher Vd for diazepam. 

AGEING REDUCES TOTAL DIAZEPAM HEPATIC CLEARANCE IN men BUT not IN women.

The clearance can be influenced by factors like smoking and other drugs.  Similar clearance for Alprazolam in females are HIGHER than men.  In contract clearance of Oxazepam, Temazepam, Chlordiazepoxide increased in males.  Whereas NO SEX difference were observed with Nitrazepam, Bromazepam, Triazolam, and Lorazepm.

The above research findings have the following lacunae:

• There can be significant sex difference in systemic drug metabolism.
• Sex differences in drug absorption and first pass metabolism (because majority of studies are conducted with po administration).
• Change due to ageing can be gender specific
• Drugs of same pharmacological class (with similar structure) may show marked sex differences – as illustrated by:

i ) Temazepam and Oxazepam metabolised through conjugation – produces greater in males than females.

ii ) Nitrazepam is metabolized by nitro reduction group – No sex difference.

iii ) Other benzodiazepine metabolized primarily via oxidative metabolism with CYP isoenzymes which are greater in females than males. 

b) CYTOCHROME  P₄₅₀:

Metabolism of phenazone (antipyrine) shows significant sex difference.  In humans liver enzyme CYP3A4 is responsible for more than 50% of drugs including cyclosporine, quinine, niridazole, dapsone, erythromycin, lidocaine, troleandomycin and young females have 1-4 times.

Enzyme Specific by CYP3A4 mediate N-demethylation.

CYP3A4 is also involved in OH lation of steroid hormones and therefore rapid elimination of predisolone. (difference due to interhepatic hepatic clearance).

CYP3A4:  tirilzad, verapamil, diazepam 20% more in males Midazolam inactivation by CYP3A4 20-40% more faster in females Sex difference in steroid hormone levels.
Progresterone activates CYP3A4.  Steroid hormones activate CYP isoenzymes through gene expression.

CYP2D6 involved in the metabolism of propranolol, timolol, mexilitine, flecainide, codeine, dextromethorphan all of which show genetic polymorphism – but no sex differences OH lation of clomipramine is greater in males.
Ring oxidation is mediated by CYP2D6 and side chain cleaving by CYP1A, CYP2C.
Ondonsetron by CYP2D6 is faster in males and significant difference in propranolol is observed.

CYP2C19 with mephenytoin, mephobarbital, omeprazole, propranolol is greater or higher in males whereas with piroxicam is higher in females.

CYP1A2 is involved oxidation of Theophylline and women have low CYP1A2 and smoking induces this enzyme and therefore thiothixene is faster in males.

Therefore sex, smoking and age influence theophylline metabolism.  Because conflicting reports in CYP1A2, its implication in gender difference cannot be attributed at this stage.

c) Conjugation:

By CYP mediated hydroxylation step is rate limiting.  Temozapam, oxazepam cleared faster in males because of conjugation M:F clearance ration is 1.5:1.

Digoxin clearance is 12% less in females.

Males have high glucoronyl transferase activity and therefore clearance paracetamol is 22% greater in males.

Dihydrouracil dehydrogenase metabolism, flurourcil is reduced in females.

Renal elimination –

• Filtration – greater in males
• Ssecretion – greater in males
• Reabsorption – no diff.

d) Protein binding<

Less significant alpha 1 acid glycoprotein is reduced by estrogen and therefore females have low levels of protein binding e.g. warfarin.

e) Absorption

Sex influences gastric emptying time and intestinal transition time.  Stomach alc dehydrogenase is reduced in females per oral absorption of aspirin is more rapid and IM aspirin is slower in females.  Bio-availability is higher in females (aspirin) reduced Cu absorption in males.

f) Pulmonary route

Females show reduced pulmonary absorption of cromolyn na, and ribavirin Females show reduced pulmonary absorption of cromolyn na, and ribavirin

g) Pharmacodynamics

Antipsychotics – women greater impairment & increased ADR and therefore much lower doses are advocated.
Imipramine – men respond better.
Panic attacks - better with tricyclics in males
                   - MAO inhibitors in women.
Platelets of men have fewer receptors sites than females in binding paroxetine (5HT antagonist)
CVS drugs – Increased ADR in women and increased antithrombic effect.
Atracurium – increased response in omen.
Mehtyl prednisolone gender based differ, in PCK is offset by pharmacodynamic response because if increased sensitivity in females withmehtyl prednisolone.
Antiinflammatory activity with naproxen, piroxicam women show greater ADR.

h) Clinical significance

Drugs with wide T.I because of greater magnitude does not necessitate dose adjustment and only with narrow TI dose adjustment is necessary.

i) Sex specific disease

Menopause estrogen and/or progesterone therapy reduces risk of osteoporosis, reduce cardio-vascular disease and reduce risk of endometrial cancers.  Aging in women is significant than men.
Alfentanil clearance in female has inverse correlation (CYP3A4 is reduced menopause).  Reduced estrogen metabolism in old age and reduced prednisolone clearance in postmenopausal women.  Estrogen replacement in menopause does not reverse the enz status but affect PCK differently Ex: Prednisolone, anti-inflammatory steroids and reduced piroxicam clearance.  CA ABSORPTION IS IMPAIRED BY MENOPAUSAL STATE.

ii) Oral contraceptives can alter metabolism of other drugs

Drugs interfering with Oral Contraceptives :
1. Those increase hepatic metabolism
2. Decrease absorption from entero-hepatic circulation: Drugs interfering with Oral Contraceptives :
1. Those increase hepatic metabolism
2. Decrease absorption from entero-hepatic circulation: 

a) Rifampicin, phenobarbitorne, phenytoin
b)  Oral contraceptives steroids undergo extensive enterohepatic circulation after hydrolysis by gut flora and free hormones are released.  Antibiotics reduce gut flora and reduces oral contraceptives effectiveness – penicillin, tetracycline cephalosporins reduce oral contraceptives conc.

Oral contraceptives can influence metabolism
1.  Ethinyl content steroids in most Oral contraceptives are suicide inactivators of CYT P₄₅₀ CYP3A4 and other isoenzymes inactivated reduced hepatic metabolism of cyclosporin corticosteroids the ophylline (extent of 30% or more).
O.Cs increase glucoronyl transferase – Ex: paracetamol conjug 45% greater, oxazepam, temazepam and aspirin etc.

iii) Menstrual cycle

Methaqualone clearance is increased twice in mid cycle
Methyl prednisolone also similar effect
t½ of paracetamol shorter in mid cycle
Phenytoin clearance is increased at end of cycle.
Drug absorption is also influenced by cycle: Absorption  of alcohol, aspirin reduced in midcycle.

iv) Pregnancy

Antiepileptic – faster elimination – increased incidence of seizures.
Phenytoin, carbamazepine, phenobarbitone faster elimination
Betalactam antibiotics faster elimination
Caffeine t½ is increased by 200% clearance reduced by 705 because of reduction of xanthine oxidase and N acetyl transferase.
Alternation due to changes in steroids during pregnancy:
Increased progesterone inhibits CYP1A2 and increases CYP3A4.

Clinical Significance
In pregnancy, with oral contraceptives, menopause, and menstrual cycle phase there is alteration in both PCK and pharmacodynamic aspects of durg handling and therefore drugs with narrow therapeutic range dosage adjustment is necessary.  A sudden change in drug efficacy or toxicity should raise suspicion of gender phenomenon.
It is anticipated that gender difference in drug metabolism may become an important factor in deciding the dosage of drug with narrow therapeutic range probably involving an increase in incidence of ADR in man.