Pharmacodynamics

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 (Pd)- Biomolecule mediated drug action

1. Enzymes mediated
2. Intrinsic Ion channels mediated Non-receptor
mechanisms
3. Transporter proteins mediated
4. Receptors-
Type-I- Ligand Gated Ion Channels
Type-II- G-Protein Coupled Receptors (GPCR)
Type-III- Enzyme linked Receptors
Type-IV- Nuclear Receptors

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 Pharmacodynamics

• Dose-
• Aspirin-
AntiPlatelet dose- 100 mg
Analgesic dose- 300-600mg
Anti-inflammatory dose- 3 gm

- Cap Amoxycillin 500mg, oral, TDS X 5

days.
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 Combination drug Products

Fixed dose combination (FDC) –

-a single product containing two or more
drug ingredients; both components
contribute to product’s effectiveness
Co-packaged products –
- two or more products in their final dosage
form packaged together for ease of use
or distribution- eg., Combipacks
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 FDC
Carbidopa 50mg/ L-Dopa200mg

Carbidopa / LevoDopa

Combipack
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 Factors affecting drug response
1. Body weight (BW) / Surface Area (BSA)
-Dose  BW
-Drug dose calculations in children-
Young’s formula- Child dose= Age (Yrs) x Adult dose
Age + 12

Clark’s formula- Child dose= Child BW(Kg) x Adult dose

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Dubois Formula- Child dose= BSA (m2) x Adult dose
1.8
[BSA = BW 0.425(Kg) x Ht 0.725(cm) x 0.007184 ]

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 Factors affecting drug response
2. Age
A) Children-
Altered Pd-
 AntiHistaminics & Barbiturates- Hyperactive kids
 Glucocorticoids-  growth
 Tetracycline- stained teeth / poor Bone growth
  EPS with Phenothiazines

Altered Pk-
- Absorbtion- poor oral / Rectal adm.-
Diazepam/theophylline /  Skin absorb
- Distribution- poorly developed BBB- Kernicterus
- Metabolism-

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 Age &Metabolism

Glucuronidation
& other
Acetylation Conjugation

Gray Baby Syndrome- Chloroamphenicol

Rapid Metabolism after Neo Natal period
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Age & maturation of Kidney function

Glomerular Tubular
Filtration secretion
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 Factors affecting drug response- Age
Elderly
a) Pk changes-
- Absorbtion-  GI blood flow / motility
- Elimination- poor Renal fn,  CYP’s activity, poor
hepatic blood flow
b) Pd changes-
-  CNS depression with depressant drugs- opioids,
neuroleptics
- poor response to - Rec agonist & antagonist
-  orthostatic hypotension with anti-hypertensives
- Diuretics- electrolyte imbalance-
- Polypharmacy & serious ADRs

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 Factors affecting drug response- Gender
3. Gender differences in drug response
a) Females-
-smaller body size
-drug adjustments in pregnancy
• Fetotoxicity
•  GIT motility
•  E/c fluid volume /  body fat (Vd)
• PPB-  -acid Glycoprotein
•  Renal blood flow
• Induction of -somal enzymes

b) Males-
• Sexual dysfunction-
- Anti-hypertensives- Clonidine, -Blockers
- Fluoxetine, Ketoconazole
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 Factors affecting drug response-
3. Diet & Environmental factors

Grapefruit- Cyp inhibitor Drug Interactions-

• Grapefruit juice (inhibitor of CYP3A4)–
Terfenadine, Statins & antidepressants 12
 Factors affecting drug response-
3. Diet & Environmental factors

Milk retards the absorption of Tetracyclines

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 Drug-Food metabolic Interactions

Charbroiled meat-
Cytochrome P450 1A2
inducer

Brussels sprout( inducer)

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 Factors influencing drug Metabolism-
Environmental factors

Smoking induces Cyp1A2

& decreases the effects of
Dextropropoxyphene,
BZDs, Theophylline &
insulin.

•Pesticides / cigarette smoke- Inducer

•Alcohol- Chronic & Acute use 15
 4. Diseases affecting drug response-
Renal Impairment-
• Drugs elimination via renal route:
( Creatinine CL) - Aminoglycocides, Digoxin,
Norpethidine

↓ dose / ↑dose interval
Clinical Implications
• ↓ Maintainance dose
• ↑t ½ & ↑Css
• ↓ Albumin (↑ free acidic drugs)
• ↑ permeability of BBB
• Nephrotoxic drugs- Tetracycline, Vancomycin,
Aminoglycocides, Amphotericin-B, Cephalosporins. 16
 4. Diseases affecting drug response-

Hepatic impairment-
Clinical implications-
1. Oral Bioavail (↑)- eg., Morphine, Nifedipine,
Pethidine
2. ↓serum albumin- ↑ free acidic drugs (eg.,
Phenytoin)
3. Prodrugs- poor effect
4. Oral anticoagulants- ↑ response (risk of bleeding)
5. Avoid hepatotoxic drugs- eg., INH / Ethanol
(use alternatives- Lorazepam / Atenolol)

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 Factors affecting drug response-
4. Diseases affecting drug response-
Thyroid diseases-
• Hypothyroid- ↑ sensitive to CNS depressants
(eg., diazepam, opioids), digoxin

CHF (Congestive Heart Failure)

- ↓Absorb.- oral & parenteral
- Altered Vd-
- ↓ Elimination (↓ RBF / ↓ hepatic blood flow)-
toxicity of Propranolol / Lignocaine

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 Factors affecting drug response-
4. Diseases affecting drug response-
Other diseases-
- Antipyretics
- MI patients- Adrenaline / digitalis- arrythmias
- Mysthenia Gravis- d-Tubocurare
- BPH- Atropine- urinary retention
- AIDS- Cotrimoxazole / Thioacetazone- ↑ ADRs
- Burns / Malnutrition / sepsis- ↓↓ Albumin
- ↑ ICT / severe Pulmonary disease- Opioids / CNS
depressants use may result in Respiratory failure

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 Factors affecting drug response-
5. Drug interactions affecting drug
response-
A. Pk Drug interactions-
Absorbtion-
- Al 3+ or Fe 2+ - ↓ Tetracyclines
- Acid suppressants-↓ ketoconazole, ↓Iron
- ↑ GI motility- ↓ Digoxin

Distribution-(displacement Reactions)
1. Aspirin – Methotrexate
2. Sulfonamides – Bilirubin
3. Phenylbutazone - Warfarin

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5. Drug interactions affecting drug response-
Pk Drug interactions- Metabolism

Chloroamphenicol

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5. Drug interactions affecting drug response-
Pk Drug interactions- Metabolism

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 Factors affecting drug response-
5. Drug interactions affecting drug
response-
A. Pk Drug interactions-
Excretion-

Quinidine OCTP

OCTP= Organic Cation transporter protein 23

 Factors affecting drug response-
5. Drug interactions affecting drug
response-
B. Pd Drug interactions-
1. Diazepam / + Alcohol
Antihistaminics
1. Sildenafil + Nitrates
2. Warfarin + Aspirin
3. NSAIDS + Diuretics/ Anti-hypertensives
4. Digoxin + Diuretics
5. Propranolol + anti-diabetics
6. Phenothiazines + Levo-DOPA
& Metoclopramide

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Q. Inter-individual variations in drug response are
most marked if the drug is eliminated by-

a) Glomerular filtration
b) Tubular secretion
c) Hepatic metabolism

Ans: C)
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 Factors affecting drug response-
6. Genetically determined drug response
(Pharmacogenetics)-
A. Altered Pk - -Genetic polymorphisms /Inter-
individual variations in drug metabolizing
enzymes
Defect Population Drug Adverse
affected involved effect
Oxidation Poor metab- Debrisoquine Poor metab- -
(Cyp2D6 7% of Hypotension
polymor.) Caucasians,

Codeine  Poor/No effect

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 Genetic Polymorphisms in drug Metabolism
Defect Population Drug Adverse
affected involved effect
Oxidation Poor metab- Warfarin Bleeding
(Cyp2C9 1%
Caucasians

Oxidation Poor metab- Mephenytoin Ataxia /

(cyp2C19 Absent in 20- sedation
poly.) 30% of
Asians
Diazepam
Omeperazole
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 Genetic Polymorphisms in drug Metabolism
Defect Population Drug Adverse
affected effect
Acetylation Fast- INH Fast- Hepatic
(Acetylator Eskimos, impair.
polymorph. Japanese Poor metab-
Slow & Fast Peripheral
Acetylators Poor neuropathy in
metab- slow acteylators
60%Indians Other drugs-
Hydralazine
procainamide DLE

Dapsone Hemolysis
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 Genetic Polymorphisms in drug
Metabolism
Defect Population Drug Adverse
affected effect
Ester 1: 2500 Succinylcholine Prolonged
Hydrolysis Apnea
(Atypical
PseudoChe)

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 Factors affecting drug response-
6. Genetically determined drug response
(Pharmacogenetics)-
A. Altered Pk (Genetic polymorphisms)
-Acute Intermittent Porphyria
 ALA ↑↑↑Porphrins X Heme
ALA synthase Uroporphyrinogen I

 synthetase

Barbiturates / Steroids / alcohol / smoking

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 6.)- B) Genetically altered Pd drug responses

1. Malignant Hyperthermia-
Drugs- Halothane/ Enflurane/ Isoflurane/ Succinylcholine
Features-
Skeletal muscle rigidity
Hypercarbia,
Temperature elevation
Tachypnea , Tachycardia
Cardiac dysrhythmias
Acidosis
Hyperkalemia

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G6-PD deficiency Anaemia

Heinz body inclusions in red blood cells

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 6.)- B) Genetically altered Pd drug
responses
2. G6-PD deficiency Anaemia-
• X-linked disorder
• Africans, Blacks, Mediterraneans, Middle-East,
SE Asia
• Definite Risk- Primaquine, Dapsone,
Sulfonamides, Nalidixic Acid, Nitrofurantoin
• Possible Risk- Aspirin (>1gm) Chloroquine,
Quinine

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Altered Vit K Reductase – Resistance to Anti-coagulants

Inactive Bio-active
Clotting Clotting
Factors-II, VII, factors
IX, X Carboxylase

Vit K (Reduced) Vit K (Epoxide)

Reductase

X
Coumarins Anticoagulant- eg., Warfarin
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 Factors affecting drug response

1. Body Weight / BSA

2. Age
3. Gender
4. Diet & Environment
5. Diseases affecting drug response
6. Drug interactions
7. Genetically determined drug response
(Pharmacogenetics)
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 Factors affecting drug response

8. Drug dose Administration

9. Psychological factors
10. Racial differences
11. Drug Tolerance

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 Factors affecting drug response-
7. Drug dose Administration
- Dosage form-
- Time of drug Adm.- Glucocorticoids / Hypnotics
- Route of drug Adm.- (IV> oral)
-MgSO4-
-oral- Laxative
-Topical- Anti-inflammatory
-IV- CNS depress. / Anti-arrhythmic/
hypotension
-Oxytocin
- IV- induce Labour
- IM- PPH
- Intra-nasal- milk ejection
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 Factors affecting drug response-
8. Psychological factors
- Anxious Patients-  Hypnotic dose  GA dose
- Placebo (Latin- `I shall please’)
- Lactose / Glucose / water for injection
- Prescribed in-
-Psychogenic complaints
- Clinical trials

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 Factors affecting drug response-
9. Racial differences
- Thiacetazone
- -Blockers
- Chloroamphenicol
- 8- OH Quinolines-  SMON (Japanese population)
- Response to Mydriatics

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 Factors affecting drug response-
10. Drug Tolerance
Tolerance-decreased sensitivity to a drug
that develops as a result of exposure to it
- Need progressively greater amounts to
achieve the desired effect
- Eg., Morphine, Alcohol, Barbiturates, LSD,
Amphetamines
• Effect Specific- eg., Morphine, Phenobarbitone
• Cross Tolerance- eg., CNS depressants

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 Factors affecting drug response-
10. Drug Tolerance- Types of Tolerance
A. Natural (Innate) Tolerance
• Black Rabbits- Tol. to Atropine
• Black Americans- Tol. to - blockers, ACEI &
Ephedrine
B. Acquired Tolerance
• Pk tol.(Metabolic Tol.)- Eg., Carbamazepine, Barbiturates
• Pd tol.(Cellular Tol)- Eg., Down regulation of Receptors-
Morphine, 2 Agonists, Alcohol etc.
C. Tachyphylaxis
- depletion of Agonist or mediator (endogenous substance)
• Eg., Ephedrine, Tyramine, Nicotene
D. Drug Resistance- eg., Antibiotics
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Q. After daily administration of drug for 30 days at the
same dose the expected response to the dose of
the drug is decreased because the plasma drug
levels is less than the corresponding levels on day
1 of drug administration. This is an example of:

a) Cellular Tolerance
b) Tachyphylaxis
c) Metabolic Tolerance

Ans: c) Metabolic Tolerance or Pk

Tolerance
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Q. A Placebo is a substance that has all the following
features except:

a) Pharmacologically inert
b) Pleases the patient not requiring an active drug
c) Produces no effect in man
d) Used as control in the clinical trials of drugs

Ans: c)
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 Assignment- LQ
Q.1. Discuss the concept of Receptors.
Describe drug synergism & antagonism
with examples.

Q.2. Discuss Elimination kinetics & factors

affecting drug elimination.

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