LMR PHARMACOLOGY

GENERAL PHARMACOLOGY PART-1

Movement of drugs across mucosal membranes

Acidic v/s Basic drugs:

Acidic drugs Basic drugs

Site of absorption – Stomach Site of absorption – Small intestine
Examples: Examples:
• Sulfonamides • Morphine
• Barbiturates • Amphetamines
• NSAIDs • Polymyxin B
• Vancomycin
• d-Tubocurarine and other
curiums
Excreted in alkaline urine Excreted in acidic urine

Bioavailability and oral route of drug administration

Bioavailability:
• Rate and extent of drug absorption
• Depends upon – Route of administration
• Maximum bioavailability – intravenous route (100%)

Enteric coating of drugs:

Purpose:
• Reduce degradation of drugs in acidic pH of stomach
• Allow drugs to pass unhindered into the small intestine
• Reduce gastric irritation of drugs
Examples:
• Erythromycin esteolate
• PPIs

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Routes of drug administration – non-oral

Drugs given by inhaled route – (Mnemonic: AB-RITZ-PLAN-SCAN)

A. Anticholinergics
B. Beta agonists
R. Ribavirin
I. Insulin (Affrezza)
T. Tobramycin
Z. Zanamivir
P. Prostacyclin analogue – Iloprost
L. Loxapine
A. Amyl nitrite
N. Nicotine
S. Steroids
C. Colistin
A. Anaesthetics (inhaled)
N. Nitric oxide

Z-track technique of intramuscular injection:

Advantages:
• Reduces local irritation due to the medication
• Less painful than traditional intramuscular injection
Used for –
• Iron injections
• Depot antipsychotics

Entry of drugs into systemic circulation

• Rate of drug absorption indicated by: Tmax and Cmax

• Extent of drug absorption indicated by: AUC

Drug distribution

Drugs amenable to be excreted by haemodialysis:

1. Carbamazepine 5. Phenobarbitone
2. Lithium 6. Salicylates
3. Ethylene glycol 7. Theophylline
4. Methanol 8. Valproate

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Examples of drug interactions due to displacement from plasma protein binding sites:

1. Sulfonamides displace bilirubin from albumin binding sites – increased risk of kernicterus
2. Loop diuretics and valproate displace warfarin from plasma protein binding sites –
increased risk of bleeding due to warfarin

Drug metabolism

• Shortest acting β-blocker – Esmolol

• Shortest acting CCB – Clevidipine
• Shortest acting opioid – Remifentanil

Drug excretion

First-order v/s Zero-order kinetics:

FIRST ORDER KINETICS ZERO ORDER KINETICS

1 Constant fraction of drug excreted in Constant amount of drug
unit time excreted in unit time
2 Rate of drug elimination increases Rate of drug elimination
proportionately with the plasma constant and independent of
concentration plasma concentration
3 t½ constant t½ increases with dose
4 Clearance constant Clearance decreases with dose
5 Exponential fall in plasma Linear fall in plasma
concentration concentration
6 Examples: Examples:
Rest all • Alcohol
• Phenytoin
• Theophylline
• Tolbutamide
• Warfarin

PK PARAMETER SIGNIFICANCE
1 Bioavailability Rate and extent of drug absorption
2 Volume of distribution Extent of tissue penetration of drug
3 Half life Rate of drug elimination >
Duration of drug action
4 Clearance Ability of the body to excrete the drug

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• Loading dose depends upon – Vd
• Maintenance dose depends upon – Clearance

GENERAL PHARMACOLOGY PART-2

Dose-response curves

• Shape of DRC: Rectangular hyperbola

• Shape of log DRC: Sigmoid

Advantages of log DRC over DRC:

1. Central portion is a straight line

2. Wider range of drug doses can be plotted
3. Easy comparison between agonists and antagonists

Therapeutic index (TI):

• ED50 / LD 50 ratio
• Best indicator of – drug safety
• Drug is considered safe if – TI > 2
• If TI < 2 – Unsafe (Narrow TI)

Examples of drugs with narrow TI: (Mnemonic – DAT-LAAT-MC)

• Digoxin
• Antiarrhythmics
• Theophylline
• Lithium
• Aminoglycosides
• Anti-epileptics
• TCAs
• Methotrexate
• Calcineurin inhibitors

Action of drugs on receptors

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Intrinsic activity of compounds of receptors:

COMPOUND INTRINSIC ACTIVITY

Agonist +1
Partial agonist 0 to +1
Antagonist 0
Inverse agonist 0 to -1

Competitive v/s Non-competitive antagonism:

COMPETITIVE ANTAGONISM NON-COMPETITIVE ANTAGONISM

1 Competition between agonist and No competition between agonist and
antagonist antagonist
2 Antagonist binds to same site as Antagonist binds to a different
agonist / endogenous ligand “allosteric” site
3 Increase in concentration of agonist Increase in concentration of agonist
can overcome the antagonism cannot overcome the antagonism
4 Also called ‘surmountable’ Also called ‘insurmountable’
5 Rightward shift of DRC Flattening of DRC
6 Km is increased Km is not affected
7 Vmax not affected Vmax reduced

Reversible v/s Irreversible antagonism:

REVERSIBLE ANTAGONISM IRRESVERSIBLE ANTAGONISM

1 Spontaneous dissociation of drug-
receptor complex
2 Binding generally with non-covalent
bonds
3 Usually does not require intervention
for termination of action
No spontaneous dissociation of drug-
receptor complex
Binding generally with covalent bonds
Requires intervention for termination
of action

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Clinical trials and other miscellaneous topics

Phases of clinical trials:

PHASE DONE ON TO DETERMINE

I Healthy volunteers Safety
Pharmacokinetics
Pharmacodynamics
II Small group of patients Efficacy
Safety
III Large group of patients Efficacy
Safety
IV Post-marketing Rare ADR
surveillance Chronic ADR
Effect of the drug on special populations

Orphan drugs:

• Drugs for rare diseases or for more common diseases (endemic in a resource poor setting)
• Cost of development and marketing cannot be recovered by sales
• No interest shown by pharma companies
• Incentives provided by Govt – tax benefits, discount for filing applications, market
exclusivity, etc.

Schedules of Drugs and Cosmetics Act, 1945:

Schedule Description
H Drugs to be sold only on the prescription by a RMP
H1 Antibiotics
X Narcotics and Psychotropic drugs
Records to be maintained by pharmacist when sold

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Fixed dose combinations (FDCs):

Advantages Disadvantages
1. Convenience of drug 1. Patient may not actually need all the drugs in
administration the combination – unnecessary exposure and
2. Better patient compliance possible adverse effects at additional cost
3. Certain combinations may be 2. Individualization of drug doses and dose
synergistic (e.g.: adjustment not possible
Sulfamethoxazole + 3. Time course of action of active ingredients may
Trimethoprim, Levodopa + be different – administering at same intervals
Carbidopa) may be inappropriate
4. Adverse effect of one active 4. Altered renal or hepatic function may affect
ingredient may be countered the pharmacokinetics of individual components
by the other (e.g.: differently
Spironolactone can prevent 5. Adverse effect may not be ascribed to one
hypokalemia due to thiazides) particular component
5. Better for conditions where 6. If adverse effect to any one component occurs,
combination therapy is whole FDC may have to be discontinued
required. E.g.: Tuberculosis, HIV- 7. Contraindication to one of the active
AIDS, etc. ingredients contraindicates the whole FDC

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