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FACTORS MODIFYING DRUG ACTION, Created by Dr.Yamuna Venkatraman - Coggle…
FACTORS MODIFYING DRUG ACTION
3.SEX
FEMALES
Smaller body size →
require lower doses
Subjective effects of drugs may differ because of their mental makeup
Maintenance treatment of CHF with digoxin → associated with higher mortality
PREGNANCY
A -
↓Gastrointestinal motility → delayed absorption of oral drugs
D
- Plasma and extracellular fluid volume expands — ↑Vd; Plasma albumin level falls, that of α1 acid glycoprotein increases—the unbound fraction of acidic drugs ↑ but that of basic drugs↓
M
- Hepatic microsomal enzymes undergo induction— many drugs are metabolized faster
E
- ↑Renal blood flow—polar drugs are eliminated faster
MALES
Antihypertensives (clonidine, methyldopa, β-blockers, diuretics) - interfere with sexual function
Gynaecomastia
→ ketoconazole, metoclopramide, chlorpromazine, digitalis
Ketoconazole → loss of libido only in males
4.SPECIES & RACE
SPECIES
Rabbits - resistant to
atropine
Rats, Mice - resistant to
digitalis
Rats - more sensitive to
curare
than cats
RACE
Blacks require higher and Mongols require lower concentrations of
atropine and ephedrine
to dilate their pupil
Afro-Caribbeans -
β-blockers
are less effective as antihypertensive
Hong Kong –Few cases of
Chloramphenicol induced aplastic anaemia
Japan - ↑
Quiniodochlor related cases of subacute myelooptic neuropathy (SMON)
1. BODY SIZE
It influences the concentration of the drug attained at the site of action. The average adult dose refers to individuals of medium built.
Individual Dose = Body Weight (Kg) /70 X Average Adult Dose
Individual Dose = BSA (m^2) /1.7 X Average Adult Dose
Dubois formula:
BSA (m2) = BW (kg)0.425 × Height (cm)0.725 × 0.007184
BSA provides a more accurate basis for dose calculation -TBW, ECF volume and metabolic activity are better paralleled by BSA; but available only for anticancer and a handful of other drugs
2.AGE
CHILDREN
Child dose - calculated more accurately on BW basis.
A
- In Infants,lower gastric acidity and slower intestinal transit. Transdermal absorption – faster because infant skin is thin and more permeable. Rectal absorption is fast and more predictable (Rectal Diazepam – Febrile seizures)
D
- In Newborns, BBB more permeable—drugs attain higher concentration in the CNS (easy entry of unconjugated bilirubin in brain causes kernicterus).
M
- In Newborns, hepatic drug metabolizing system is inadequate - chloramphenicol can produce gray baby syndrome. After the first year of life, drug metabolism is faster than in adults - t½ of theophylline, phenytoin, carbamazepine -
shorter in children
E
- In Newborns there is low g.f.r, immature tubular transport; t½ of drugs excreted by glomerular filtration (gentamicin) and tubular secretion (penicillin) is prolonged by 3 to 5 times. Glomerular filtration reaches adult rates by 5 months of age and tubular secretion takes about 7 months
Solid dosage forms and metered dose inhalers are
difficult to administer
Children are susceptible to
special adverse effects of drugs:
Corticosteroids - Suppression of growth Androgens - early fusion of epiphysis - stunting of stature Tetracyclines – discoloured / deformed teeth Phenothiazines - dystonic reactions
ELDERLY
A
- slower absorption due to reduced gut motility and blood flow to intestines,
D
-lesser plasma protein binding due to lower plasma albumin, increased or decreased volume of distribution of lipophilic and hydrophilic drugs respectively
M
-reduction in the hepatic microsomal drug metabolizing activity and liver blood flow: oral BA of drugs with high hepatic extraction is increased
E
- Renal function progressively declines g.f.r. is ~ 75% at 50 years and ~ 50% at 75 years. Drug doses have to be reduced, e.g. Streptomycin dose - 0.75 g after 50 years; 0.5 g after 70 years of age compared to 1 g for young adults
Due to lower renal as well as metabolic clearance -
cumulative toxicity
on prolonged medication
Reduced responsiveness of β adrenergic receptors
Due to prostatism in elderly males, even mild anticholinergic activity of the drug can accentuate bladder voiding difficulty
Patients on multiple drug therapy for HT,DM etc -
increased DDIs
Higher incidence of ADRs
5.GENETICS
PHARMACOGENETICS
- The study of genetic basis for variability in drug response
PHARMACOGENOMICS
- use of genetic information to guide the choice of drug and dose on an individual basis
SPECIFIC GENE DEFECTS
Atypical pseudocholinesterase
→ prolonged succinylcholine apnoea
G-6PD deficiency
→ haemolysis with primaquine and other oxidizing drugs
Thiopurine methyl transferase (TPMT) deficiency
→ increases risk of severe bone marrow toxicity of 6-mercaptopurine and azathioprine
UGT1A1 *28 allele of glucuronyl transferase
→ Irinotecan induced neutropenia and diarrhoea
Dihydropyrimidine dehydrogenase (DPD) deficiency
→ Severe 5-fluoouracil toxicity
Over expression of P-gp
→ tumour resistance to many cancer chemotherapeutic drugs→ it pumps out the drug from the tumour cells
Polymorphism of N-acetyl transferase 2 (NAT2)
gene → Slow acetylation - Isoniazid neuropathy, procainamide and hydralazine induced lupus
Abnormal Ca2+ release channel
(Ryanodine receptor)
in the sarcoplasmic reticulum of skeletal muscles→ Malignant hyperthermia after halothane
8.PSYCHOLOGICAL FACTOR
PLACEBO
Placebo
- inert substance which is given in the garb of a medicine.
Used in two situations:
1.As a control device in clinical trial of drugs (dummy medication) 2.To treat a patient who, in the opinion of the physician, does not require an active drug.
Substances commonly used as placebo are
lactose tablets/capsules and distilled water injection
Nocebo
- converse of placebo, and refers to negative psychodynamic effect evoked by the pessimistic attitude of the patient, or by loss of faith in the medication and/or the physician
Efficacy of a drug can be affected by the
patient’s beliefs, attitudes and expectations.
This is particularly applicable to centrally acting drugs, e.g. a nervous and anxious patient requires more general anaesthetic;
11.TOLERANCE
Requirement of higher dose of a drug to produce a given response. Loss of therapeutic efficacy after prolonged/intensive use of a drug (e.g. sulfonylureas in type 2 diabetes, β2 agonists in bronchial asthma)→
REFRACTORINESS.
Natural
-inherently less sensitive to the drug, e.g. rabbits are tolerant to atropine; black races are tolerant to mydriatics.
Acquired
tolerance occurs by repeated use of a drug; Tolerance
need not develop equally to all actions of a drug
e.g. Tolerance develops to the sedative action of chlorpromazine but not to its antipsychotic action. Tolerance occurs to analgesic and euphoric action of morphine, but not as much to its constipating and miotic actions.
Cross tolerance
- development of tolerance to
pharmacologically related drugs,
e.g. alcoholics are relatively tolerant to barbiturates and general anaesthetics.
Closer the two drugs are, more complete is the cross tolerance
between them, e.g.— There is partial cross tolerance between morphine and barbiturates but complete cross tolerance between morphine and pethidine.
Pharmacokinetic/drug disposition tolerance
— the effective concentration of the drug at the site of action is decreased, mostly due to
enhancement of drug elimination
on chronic use, e.g.barbiturates and carbamazepine induce their own metabolism, while renal excretion of amphetamine is accelerated after regular intake.
Pharmacodynamic/cellular tolerance
—drug action is lessened; cells of the target organ become less responsive, e.g. morphine, barbiturates, nitrates. This may be due to
desensitization/ down regulation of receptors
or weakening of response effectuation.
Tachyphylaxis
- rapid development of tolerance when
doses of a drug repeated in quick succession;
result in marked reduction in response. This is usually seen with indirectly acting drugs, ephedrine, tyramine, nicotine (synthesis is unable to matchthe rate of release)
Drug resistance
It refers to tolerance of microorganisms to inhibitory action of antimicrobials, e.g. Staphylococci to penicillin.
10.CUMULATION
Slowly eliminated drugs
are particularly liable to cause cumulative toxicity, e.g. prolonged use of
chloroquine
causes retinal damage. Full loading dose of
digoxin
should not be given if patient has received it within the past week. A course of
emetine
should not be repeated within 6 weeks.
7.ROUTE OF ADMINISTRATION
Parenteral administration -
more rapid, more pronounced and more predictable
drug action
Drug may have entirely
different uses through different routes,
e.g. MgSO4→ orally causes purgation, applied on sprained joints it decreases swelling, given i.v produces CNS depression and hypotension.
6.ENVIRONMENTAL FACTORS & TIME OF ADMINISTRATION
Exposure to
insecticides, carcinogens, tobacco smoke and consumption of charcoal broiled meat
→ induce drug metabolism
Type of diet and temporal relation
between drug ingestion and meals can alter drug absorption, e.g. food interferes with absorption of ampicillin, fatty meal enhances absorption of Griseofulvin and Lumefantrine
Subjective effects of a drug may be markedly influenced by the
setup in which it is taken
. e.g. Hypnotics taken at night and in quiet, familiar surroundings may work more easily. Statins cause greater inhibition of cholesterol synthesis when taken in the late evening. Corticosteroids taken as a single morning dose cause less pituitary-adrenal suppression.
12.PATHOLOGICAL STATES
RENAL DISEASE
Drugs that are primarily
excreted unchanged
(aminoglycosides, digoxin, phenobarbitone) - clearance is reduced parallel to decrease in creatinine clearance -
maintenance doses should be reduced
or dose interval prolonged proportionately.
Drugs only
partly excreted unchanged
in urine - dose rate needs reduction, but to lesser extents.
↓ plasma albumin
- binding of acidic drugs is reduced
↑Permeability of BBB
(opiates, barbiturates, benzodiazepines produce more CNS depression)
Pethidine should be avoided
- metabolite nor-pethidine can accumulate on repeated dosing and cause seizures.
↑Target organ sensitivity
- Antihypertensive drugs produce greater postural hypotension
Certain
drugs worsen the existing clinical condition
in renal failure, e.g. Tetracyclines have an anti-anabolic effect and accentuate uraemia. NSAIDs cause more fluid retention.
Nephrotoxic drugs should be avoided
e.g. aminoglycosides, tetracyclines (except doxycycline), sulfonamides (crystalluria), vancomycin, nitrofurantoin, cyclosporine, amphotericin B should be avoided.
LIVER DISEASES
PK
A
- BA of drugs having high FPM is increased due to loss of hepatocellular function and portocaval shunting.
D
- Serum albumin↓— ↓protein binding of acidic drugs (diclofenac, warfarin, etc.) and ↑unbound drug
M & E
of some drugs (morphine, lidocaine, propranolol) is decreased—their dose should be reduced. Alternative drugs that do not depend on hepatic metabolism for elimination and/or have shorter t½ should be preferred, e.g. oxazepam or lorazepam in place of diazepam; atenolol as β-blocker. Prodrugs needing hepatic metabolism for activation, e.g. bacampicillin should be avoided
PD
↑sensitivity of brain to depressant action of
morphine and barbiturates
—normal doses can produce coma.
Oral anticoagulants
can markedly prolong PT, because clotting factors are already low.
Hepatotoxic drugs should be avoided
in liver disease.(Methotrexate, Flutamide, Vildagliptin, Carbamazepine, INH, Pyrazinamide,Tacrine)
CHF
A
-
↓absorption
from g.i.t. due to mucosal edema and splanchnic vasoconstriction. E.g. Procainamide, hydrochlorothiazide
D
- Altered volume of distribution -
↑Vd
due to expansion of ECF volume or
Vd ↓
due to decreased tissue perfusion. LD of lidocaine and procainamide should be lowered.
E
-
reduced
due to decreased perfusion and congestion of liver, ↓GFR and increased tubular reabsorption; dosing rate may need reduction - lidocaine, procainamide, theophylline.
G.I DISEASES
can alter absorption of orally administered drugs. E.g. Coeliac disease - ↓absorption of amoxicillin, ↑absorption of cephalexin and cotrimoxazole. Migrane – gastric stasis ↓absorption. Achlorhydria ↓aspirin absorption by favouring its ionization. NSAIDs can aggravate peptic ulcer disease.
THYROID DISEASE
Hypothyroid
patients are more sensitive to digoxin, morphine and CNS Depressants
Hyperthyroid
patients are relatively resistant to inotropic action of digoxin, but more prone to its arrhythmogenic action
9.OTHER DRUGS
Drugs can modify the response to each other by
pharmacokinetic or pharmacodynamic interaction
between them.
Created by
Dr.Yamuna Venkatraman