Factors modifying drug action
Dr Pradnya Rotithor
Definition
The drug response differs in different
individuals
And in the same individual at different times
Why it differs ?
Due to differences in—
Pharmacokinetics —ADME
Pharmacodynamics—Receptors - number and sensitivity
Neurotransmitters and hormone levels
Factors
Drug related
Patient related
Drug related factors
Route of administration
Time of administration
Cumulative effect
Tolerance
Tachyphylaxis
Dependence
Drug interactions
Patient related factors
Age
Body weight
Sex
Race and species
Genetic factors
Psychological- patient compliance - placebo nocebo
Clinical status
Body weight
Medium weight - standard dose
Obese : dose calculation formula
Dose = (wt in kg /70)x standard dose for adult
Body surface is more accurate but not convenient
Age
Children and elderly
Extremes of age group- modification needed
Infants : liver and kidney function not well developed
BBB not fully formed : more drugs may enter
Some drugs suppress growth ; androgens- premature closure of epiphysis - stunted height
Tetracyclines - dentition : discoloration and ill formed
Streptomycin : immature renal tubules: ototoxicity nephrotoxicity
FQ - growing cartilage affected
Chloramphenicol: gray baby syndrome
Formula for children
Young formula
(Age in years/age+12)x adult dose
Example: dose of amoxicillin for 3 yr old child
=(3/3+12)x 500mg
=1/5x500
= 100mg
Elderly age group
Decreased hepatic and renal function : delayed metabolism of drugs
Less GFR and decreased blood flow - cumulative effects
Reduced dose needed
Less patient compliance
FQ : withdrawn if patient c/o bone pain
Atropine : retention of urine if BHP
Sex
Hardly any difference if body weight is standard
In general females may need dose adjustment- smaller frame
Hormones : androgens xxx for females
Estrogen xxx for male
Some drugs cause gynaecomastia in males
Like : cimetidine metochlopramide chorpromazine
Pregnancy and lactation
Teratogenic drugs xxxx
Structural malformations in first trimester
Functional and other complications in second and third trimester
Thalidomide- phocomelia
Phenytoin- foetal hydantoin syndrome/ Alcohol-foetal alcohol syndrome
Warfarin- depressed nose
Sodium valproate - spinal bifida
ACE inhibitors - hypoplasia of organs , oral anti diabetics - hypoglycemia morphine ,morphine- resp
depression
Drugs secreted in milk : senna : purgative : diarrhea in breast fed infant
Species and race
Rabbits resist atropine
Mice resistance to digitalis
Indians tolerate thiacetazone better
Blacks need higher doses of mydriatics
Genetics
G6PD deficiency: haemolysis with primaquine chloroquine
Plasma pseudocholinesterase ; succynil choline apnea
Acetylation of INH slow or fast
Slow acetylation : neuropathy
Fast acetylation: hepatitis
Route of administration
Unique example of magnesium sulfate
Oral : purgative
Topical application : decreased swelling
Injectable: reduces blood pressure: life saving drug for Ecclampsia
Otherwise with most other drugs: speed with which drugs show response
Changes when given orally or otherwise
Food
Food interferes with absorption of drugs
Ampicillin, rifampicin
Fatty food increases absorption of grisofulvin
Tetracyclines with milk : unabsorbable complex
Iron shouldn’t be given with milk
Vit c increases absorption of iron
Time of administration
Hypnotics : before bedtime
Steroids : total dose as a single dose in the morning
Less suppression of HPA axis
Psychological factors
Anxious and apprehensive patients need higher dose of anaesthetic
medication
Placebo
Nocebo
Pathological status
Liver disorders - low protein: affects PPB
More free drug —- may cause more ADR
Examples : diclofenac warfarin
Low first pass metabolism: high plasma levels : may need dose
adjustment
Reduced metabolism of drugs : high and prolonged serum levels
Renal failure
Delayed excretion of drugs : high levels in blood 🩸: ADR
BBB isn’t tight in renal failure: more CNS action
Phenothiazines BZD
Cumulative effect
Tetracyclines - teeth discolouration
Chloroquine- retinal damage
Gentamicin-renal tubular damage
Emetine digoxin-myocardial suppression
Dapsone clofazimine - skin discolouration
Tolerance (SAQ)
More dose is required to produce same response
Natural or acquired
Natural:black race tolerant to mydriatics and need higher dose
Acquired tolerance
Cross tolerance: drugs belonging to a particular group: barbiturates
Develops due to repeated use of drug : opioids nitrates and barbiturates
Tolerance may be selective : patients develop tolerance to analgesic and euphoric
action of morphine but not to constipation and miotic action
Mechanism of tolerance
Pharmacodynamics : functional tolerance: Dow regulation of
receptors: salbutamol selective beta 2 agonist
Pharmacokinetics : change in ADME : dispositional tolerance
Tachyphylaxis MCQ
Rapid or acute development of tolerance
When given repeatedly at short intervals
Ephidrine amphetamine
Drug dependence
Drug abuse
Drug habituation
Dependence - physical or psychological or both
Psychological-nicotine caffeine amphetamine LSD cocaine
Physical and psychological-morphine alcohol barbiturates
Drug addiction- serious social problems
Drug interactions
At Pharmacokinetic level
At Pharmacodynamic level
How to select route of drug administration
Physical form- solid liquid and gas
Solid :disintegrate ▶ dissolve ▶ absorb
Liquid: mix with gastric juice ▶ absorbs
Gas : absorbs
Thus gas >liquids >solids
Solubility and pH
Water soluble : oral route
Lipids soluble: topical or other
——————————————-
pH
Alkaline or acidic
Urgency of desired action
Urgent action in emergency: intravenous or intramuscular
Sublingual
Oral
Site of desired action
Skin or mucus membrane: topical
Lungs : inhalation: drugs for bronchial asthma
CNS: intrathecal or inhalation ( general anaesthetic agents
Most other organs : oral
Bioavailability
% of the drug that reaches the systemic circulation in
unchanged form
Oral drug : git absorption and hepatic enzymes
Never 100%
IV : 100%
Other routes in between
First pass metabolism
Clinical status of patients
