Prescribing in physiological and pathological conditions

1. PRESCRIBING IN
PHYSIOLOGICAL AND
PATHOLOGICAL CONDITIONS
DR SAHIL KUMAR
3RD
YEAR POST-GRADUATE STUDENT
DEPARTMENT OF PHARMACOLOGY
MAULANA AZAD MEDICAL COLLEGE, DELHI

2. FACTORS MODIFYING
DRUG ACTION
(1) Individuals differ in pharmacokinetic hand­ling of drugs: attain varying
plasma/target site concentration of the drug.
•This is more marked for drugs disposed by metabolism (e.g. propranolol)
than for drugs excreted unchanged (e.g. atenolol).
(2) Variations in number or state of receptors, coupling proteins or other
components of response effectuation
(3) Variations in neurogenic/hormonal tone or concentrations of specific
constituents, e.g. atropine tachycardia depends on vagal tone, propranolol
bradycardia depends on sympathetic tone, captopril hypotension depends on
body Na+ status.

3. • A multitude of host and external factors influence drug response
• Genetic and non genetic including all environmental, circumstantial and
personal variables
• Their understanding can guide the choice of appropriate drug and dose for
an individual patient
• Final adjustments have to be made by observing the response in a given
patient on a given occasion

4. FACTORS MODIFYING DRUG
ACTION
1. Quantitatively --The plasma concentration and/ or the action of
the drug is increased or decreased. Most of the factors
introduce this type of change and can be dealt with by
adjustment of drug dosage
2. Qualitatively- The type of response is altered, e.g. drug allergy or
idiosyncrasy. This is less common but often precludes further
use of that drug in the affected patient.

5. PRESCRIBING IN
PHYSIOLOGICAL STATES

7. BODY SIZE

8. • Influences the concentration of the drug attained at the site of action
• The average adult dose refers to individuals of medium built
• For exceptionally obese or lean individuals and for children dose may be
calculated on body weight (BW) basis:
• Individual dose =BW (kg)/70 x average adult dose
• Body surface area (BSA) provides a more accurate basis for dose calculation,
because total body water, extracellular fluid volume and metabolic activity are
better paralleled by BSA
• Individual dose = BSA (m2 )/1.7 x average adult dose

10. AGE

11. PRESCRIBING IN PEDIATRICS
• Prescriber should know the form in which
the drug will be dispensed and provide
proper instruction to pharmacist and
parent
• Many drugs prepared for children are in
the form of elixirs and suspensions
• Doses should always be given after
calculating using body weight/ age of the
child.

12. KEEP IN MIND
• Infants and children are not small adults [Physiologically different]
• Newborn has low G.F.R and tubular transport is immature
• Drugs excreted by glomerular filtration(gentamicin) and tubular secretion (penicillin) is
prolonged by 3 to 5 times
• Hepatic drug metabolizing system is inadequate in newborns –Chloramphenicol(gray
baby syndrome)
• Blood-brain barrier is more permeable-drugs attain higher concen­tration in the CNS
(accumulation of unconjugated bilirubin causes kernicterus)

13. • Lower gastric acidity and slower intestinal transit -Drug absorption is altered
in infants
• Transdermal absorption however, is faster because their skin is thin and more
permeable
• Solid dosage forms and aerosol inhalations are difficult to administer to young
children
• After the first year of life, drug metabolism is often faster than in adults, e.g.
theophylline, phenytoin, carbamazepine t 1/2 is shorter in children

14. • Children are growing and are susceptible to special adverse effects of drugs,
e.g.
Suppression of growth can occur with corticosteroids
Androgens may promote early fusion of epiphysis(stunting)
Tetracyclines deposited in growing teeth and discolour/ deform them
Dystonic reactions to phenothiazine are more common in children
Infant doses must be learned as such and not derived

17. ELDERLY

18. THINGS TO
NOTE..
• Age-related physiologic changes make the elderly susceptible to adverse effects
• Understanding the influence these changes have on the pharmacokinetics and
pharmacodynamics of the elderly is essential to prevent harm
• Renal function progressively declines (intact nephron loss) - 25% at 50 years and
- 50% at 75 year compared to young adults
• Elderly are also likely to be on multiple drug therapy for HTN, DM, Arthritis,
etc which increases many fold the chances of drug interactions

19. PHYSIOLOGIC CHANGES OF AGIN
AFFECTING ABSORPTION
• Physiologic change
– Decreased gastric acidity
– Decreased gastrointestinal blood flow
– Delayed gastric emptying
– Slowed intestinal transit time
• General clinical effect
– None on passive diffusion or bioavailability for most drugs
– Decreased active transport: Decreased bioavailability
– Decreased first-pass effect: Increased bioavailability
• Special considerations
– Antacids decrease absorption of acidic drugs: digitalis, phenytoin, tetracycline
– Anticholinergics: Slow GI motility and absorption rate

20. PHYSIOLOGIC
CHANGES OF AGING
AFFECTING
DISTRIBUTION
• Decreased Total body water
– Decreased Volume Distribution
– Increased Plasma Conc. of water soluble drugs
– Lower doses are required: Lithium, digoxin, ethanol, etc
• Decreased Lean body mass and Increased body fat
– Increased Volume Distribution, Longer (t½) of water soluble drugs
– Accumulation into fat of lipid soluble drugs: Bzd, etc
• Decreased Serum Albumin
– Increased unbound fraction of highly protein bound drugs
– Binds acidic drugs: warfarin, phenytoin, digitalis, etc
• Decreased Alpha 1 Acid glycoprotein
– Increased unbound fraction of highly protein bound drugs

21. EFFECTS OF AGING ON VOLUME OF DISTRIBUTION
Aging EffectAging Effect Vd EffectVd Effect ExamplesExamples
⇓⇓ body waterbody water ⇓⇓ Vd for hydrophilicVd for hydrophilic
drugsdrugs
ethanol, lithium
⇓⇓ lean body masslean body mass ⇓⇓ Vd for for drugs thatVd for for drugs that
bind to musclebind to muscle
digoxin
⇑⇑ fat storesfat stores ⇑⇑ Vd for lipophilic drugsVd for lipophilic drugs diazepam, trazodone
⇓⇓ plasma protein (albumin)plasma protein (albumin) ⇑⇑ % of unbound or free% of unbound or free
drug (active)drug (active)
diazepam, valproic acid,
phenytoin, warfarin
⇑⇑ plasma proteinplasma protein
((αα11-acid glycoprotein)-acid glycoprotein)
⇓⇓ % of unbound or free% of unbound or free
drug (active)drug (active)
quinidine, propranolol,
erythromycin, amitriptyline

22. METABOLISM
• Determined primarily by hepatic function and blood flow
• Capacity of the liver to metabolize drugs does not appear to decline consistently with
age for all drugs
• For drugs with extensive first-pass metabolism, bioavailability may increase because less
drug is extracted by the liver
– Decreased liver mass
– Decreased liver blood flow
• Examples: morphine, meperidine, metoprolol, propranolol, verapamil, amitryptyline,
nortriptyline

23. ELIMINATION
• Determined
– Primarily by renal function
– Declines with age and is worsened by co-morbidities
– Decline is not reflected in an equivalent rise in serum creatinine since creatinine production
is reduced due to lower muscle mass
• Physiologic change
– Decreased GFR
– Decreased renal blood flow
– Decreased renal mass
• General clinical effect
– Decreased clearance, Increased (t½) of renally eliminated drugs

24. • Renal blood flow, GFR, tubular secretion decrease with age above 55 years.
• Creatinine clearance (CrCl) is used to estimate GFR
• Serum creatinine alone not accurate in the elderly
– ⇓ lean body mass ⇒ lower creatinine production
– ⇓ glomerular filtration rate
• Serum creatinine stays in normal range, masking change in creatinine clearance
• Creatinine clearance = (140-age) x wt (kg)
72 x S. Cr in mg/dl
For female it should be multiplied with 0.85

25. PHARMACODYNAMICS
• Pharmacodynamic changes in the elderly have been less extensively studied
• Evidence of enhanced end-organ responsiveness or “sensitivity” to medications with
aging
• Enhanced “sensitivity” may be due
– Changes in receptor affinity
– Changes in receptor number
– Post-receptor alteration
– Age-related impairment of homeostatic mechanisms Example: decreased
baroreceptor reflexes

26. BE VIGILANT..• Drugs that act on the CNS appear to produce an exaggerated response than that
expected from their plasma concentration
• Old people are more sensitive to the respiratory effect of opioid analgesic because of
age related respiratory changes
• Baroreceptor sensitivity reduced– more risk of orthostatic hypotension with
antihypertensive drugs
• Response to β adrenoreceptor agonist and antagonist reduced because of smaller
number of receptor and reduced affinity for adrenoreceptors
• Prostatism in elderly males, even mild anticholinergic activity of the drug can accentuate
bladder voiding difficulty

27. MAJOR DRUG GROUPS REQUIRING MONITORING
• CNS drugs
– Sedative-hypnotics: Benzodiazepines and barbiturates
– Analgesics: Opioids
– Antipsychotic, antidepressants: Haloperidol, lithium, TCAs
• Cardiovascular drugs
– Antihypertensives: Thiazides, beta-blockers
• Antiarrhythmic drugs
– Quinidine and procainamide: ↓ clearance and ↑ (t½)
• Antimicrobial drugs
– Beta-lactams and aminoglycosides: ↓ clearance
• Anti-inflammatory drugs
– NSAIDs: GI bleed and irritation

28. MAJOR REASONS FOR ADVERSE DRUG REACTIONS IN THE
ELDERLY
• Positive relationship between number of drugs taken and incidence of ADR
• Overall incidence is estimated to be at least twice that in the younger population
• Prescribing errors
– Polypharmacy
– Drug interactions with other prescriptions
– Unawareness of age related physiologic changes
• Drug usage errors
– “Hidden ingredients”: OTCs

29. COMPLIANCE
• There are several practical obstacles to compliance that the prescriber must recognize
– Forgetfulness
– Prior experience
– Physical disabilities
• Recommendations to improve compliance
– Take careful drug history
– Prescribe only for a specific and rational indication
– Define goal of drug therapy
– High index of suspicion regarding drug reactions and interactions
– Simplify drug regimen

30. SEX

31. SEX
•Body size varies with sex.
•Drugs may interfere with sexual function.
•Gynecomastia (only in males).

32. PREGNANCY
•↓GI motility.
•VD↑.
•Albumin ↓; α-acid glycoprotein ↑.
•RBF ↑ markedly.
•Hepatic microsomal enzyme
induction.

33. PREGNANCY

36. LACTATION

37. LACTATION
•Certain non-electrolytes and small
molecular weight electrolytes can pass
through filtration.
•Certain acidic drugs (though less secreted)
are better avoided. Eg Sulfonamides.
•Neonates usually deficient in G-6-PD
enzyme.

38. RACE
•Atropine, Ephedrine – more dose in Blacks.
•Beta blockers less effective in Blacks.
•Chloramphenicol better tolerated by
Indians than Caucasians.

39. GENETICS
• Pharmacogenetics vs Pharmacogenomics.
• Goal: Personalized medicine on large scale.
• Atypical pseudocholinesterase
• G-6-PD deficiency
• Low activity CYP2C9 variant
• TPMT deficiency – Mercaptopurine, Azathioprine
• UGT1A1*28 allele – Irinotecan
• DPD deficiency – Fluorouracil
• P-gp Overexpression
• Acetylation – Slow and Fast
• CYP2D6 abnormality
• Malignant Hyperthermia
• Routine application is limited.

40. PSYCHOLOGICAL FACTORS
•Efficacy can be affected by patient’s belief,
attitude and expectations.
•“Placebo reactors”.
•Placebo used as dummy medication in
CT.
•Lactose, Distilled Water (DW) injection.
•Nocebo – Negative psychodynamic
effect.

41. PRESCRIBING IN
PATHOLOGICAL STATES

43. GASTROINTESTINAL DISEASE
•Malabsorption.
•Gastric stasis.
•Achlohydria (eg in gastrectomy).

44. LIVER DISEASE
•↑BA.
•↓Albumin.
•M, E of some drugs ↓.
•Prodrugs.
•No simple test like CLCR can exactly be
used for dose titration.
•Avoid hepatotoxic agents.

45. KIDNEY DISEASE
•↓ Albumin.
•BBB permeability in Renal Failure.↑
•Some drugs worsen RF.
•Thiazides, Potassium Sparing Diuretics.
•Urinary Antiseptics.

46. CONGESTIVE HEART FAILURE
•↓ Absorption.
•Alteration in Volume of Distribution.
•Drug elimination affected.
THYROID DISEASE
•Hypothyroidism.
•Hyperthyroidism.

47. OTHER PATHOLOGICAL
STATES
•Fever.
•Edematous patients.
•MI patients.
•Schizophrenics.
•Head Injury.
•Benign Prostatic Hyperplasia.

48. THANK YOU