Pharmacology S1.6: Structural Modifications and Drug Effects

Pharmacology S1.6: Structural Modifications and Drug Effects

# 1. Structural Modification of Drugs

1.1. Structural Changes Influencing Pharmacokinetics (PK):

• Structural modification → alteration in physicochemical properties of the drug:

• Water/lipid solubility

• Drug-plasma protein binding

• Ionization

• Drug stability

1.2. Structural Changes Influencing Pharmacodynamics (PD):

• Drug-receptor binding, following the lock-and-key mechanism: minor structural changes can significantly alter drug effects.

• Development of new drugs aims to:

• Enhance therapeutic effects, minimize adverse effects (AEs)

• Modify pharmacological action

• Create optical or geometric isomers with distinct effects

Examples:

• Corticosteroids: addition of F at C9 and CH3 at C16 in Betamethasone increases anti-inflammatory potency 25-fold, without sodium retention, eliminating the need for salt restriction.

• Isoniazid: metabolized to Iproniazid, exhibiting antidepressant effects due to binding to a different receptor.

• PABA: bacterial nutrient. Sulfamides, with similar structures, competitively inhibit PABA, leading to bacterial inhibition (antagonistic effect).

• L-Quinine (anti-malarial) and D-Quinine (anti-arrhythmic): optical isomers resulting in distinct effects.

# 2. Drug Formulations

• Specialized presentation of drug substances for administration.

• Ensure optimal preservation, transportation, usage, and therapeutic efficacy.

# 3. Drug Composition

• Drug substance: the active ingredient responsible for pharmacological effects.

• Excipients: assist the drug substance, contributing to optimal drug efficacy.

# 4. Types of Excipients

• Fillers

• Binders

• Disintegrants

• Lubricants

# 5. Drug Substance State

• Finely dispersed drug substances facilitate absorption.

# 6. Objectives of Drug Formulation

• Maintaining drug potency

• Steady drug release

• Targeted drug delivery

• High drug bioavailability

# 7. Drug Dose Adjustments

• Renal impairment: adjusting dosage based on creatinine levels.

• Patients with coronary artery disease: avoiding drugs that increase cardiac function (adrenaline, levodopa).

# 8. Special Drug Effect States

• Adverse Drug Reactions (ADRs): unwanted reactions occurring during therapeutic drug use.

• Allergic reactions: triggered by drug hypersensitivity.

• Drug-induced adverse events due to genetic disorders: for example, deficiency in glucose-6-phosphate dehydrogenase (G-6-PD) enzyme can lead to hemolytic anemia when using primaquine, quinine, pamaquine, sulfonamides, nitrofurans.

• Drug tolerance: requiring higher doses for effectiveness.

• Drug dependence: for example, methadone used in opioid addiction treatment programs.

# 9. Drug Interactions

• Synergistic increase: combined drug effect is stronger than the sum of individual effects (A+B) > (A)+(B).

• Additive synergism: combined drug effect equals the sum of individual effects (A)+(B) = (A+B).

• Mutual synergism: one drug assists the other in enhancing its effects.

• Antagonism: one drug reduces the effects of another.

Examples:

• Penicillin and streptomycin: synergistic increase in antibacterial efficacy.

• Isoniazid and Streptomycin: additive synergism in tuberculosis treatment.

• Combination of 5 Sulfamethoxazole: 1 Trimethoprim (Cotrimoxazole): synergistic increase, acting as an antibiotic.

• Adrenaline: prolongs local anesthetic effect of Lidocaine, mutual synergism.

• Benzodiazepines (Diazepam): counteracts strychnine poisoning, antagonistic interaction.

# 10. Non-receptor Mediated Effects

• Effects based on physical or chemical properties of the drug:

• Examples: Al(OH)3 gel coats gastric ulcers, NaHCO3, Mg(OH)2 neutralize gastric acid.

# 11. Drug Side Effects

• Chlorpheniramine: antihistamine, causing drowsiness and dry mouth.

• Aspirin: analgesic, antipyretic, can induce gastric ulcers.

# 12. Selective Effects, Specific Effects, Local Effects, Systemic Effects

• Selective effects: strongest effect on a particular tissue or organ.

• Specific effects: strongest effect on a particular cause of disease.

• Local effects: localized effects at the site of application.

• Systemic effects: effects observed after drug absorption into the bloodstream.

Examples:

• Digitalis: selective effects on the heart muscle.

• Digoxin: strengthens, slows, and regulates heart rhythm, exhibiting selective effects.

• Quinine: specific effects on malarial parasites.

• Isoniazid: specific effects on Mycobacterium tuberculosis.

• Anti-fungal effects of ASA alcohol, topical anesthetics, inhaled medications: local effects.

• Morphine: systemic effects.

# 13. Drug Sequelae

• Tetracycline: enamel damage in children, irreversible effect.

• Gentamicin: can cause irreversible hearing loss in children.