WHAT IS ADVERSE DRUG REACTION
GENDER EFFECTS OF PHARMACOLOGY
WHAT IS ADVERSE DRUG REACTION
:
ANY
NOXIOUS, UNINTENDED & UNDESIRED EFFECT OF A DRUG WHICH OCCURS AT A
DOSE USED IN HUMANS
FOR PROPHYLACTIC, DIAGNOSTIC OR
THERAPEUTIC PURPOSES.
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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.
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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; (Vd of
lipophilic substance like trazodone, sufentanil).
In extreme obesity significant PCK drug alteration are observable Vd
in females - Low Vd for ethanol, High Vd 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 �
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
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:
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
t� 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 t� 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.
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