Pharmacodynamics

Dr. Karun Kumar

JR –II

Dept. of Pharmacology

Definition

• Study of the detailed mechanism of action by which drugs produce their pharmacologic effect

• Provides a scientific basis for the selection & use of drugs

Nature of drug receptors

• Receptor [Recipere to receive, accept] 1. a molecular structure within a cell or on the cell surface and characterized by (1) selective binding of a specific substance and (2) a specific physiologic effect that accompanies the binding, e.g., membrane receptors for peptide hormones, neurotransmitters, antigens, complement fragments, and immunoglobulins, and nuclear receptors for steroid hormones. 2. a sensory nerve terminal that responds to stimuli of various kinds; classified in various ways including by the type of stimulus (see chemoreceptor, mechanoreceptor, photoreceptor, and thermoreceptor) and by the location in the body (see exteroceptor, interoceptor, and proprioceptor).

• Ligand (ligare to tie or bind) a molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. 2. a molecule that donates or accepts a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex.

Types of drug receptors

• GPCRs Largest family of receptors

• GPCRs 7 transmembrane domains

• Neurotransmitter transporter proteins 12 transmembrane domain proteins (SSRI/SNRI target them)

• Steroid hormone receptors Intracellular proteins that translocate to the nucleus

Steroid hormones diffuse through cell membrane

↓

Bind to steroid receptors in cytoplasm

↓

Dimerized steroid hormone-receptor complex is translocated to the nucleus

↓

Binds to specific sequences on the DNA of a gene

↓

↑ transcription of gene (↑ mRNA)

↓

↑ translation of proteins

Drug receptor interactions

• Bonds formed between receptor and drug

1. Strong bonds Covalent bonds

a) Anti-neoplastic drugs binding to DNA

b) Irreversible anti-chEs (Ops)

2. Weak bonds

a) Hydrogen bonds

b) Ionic bonds

c) Hydrophobic (van der Waals) bonds

• Binding exhibits stereospecificity (only 1 of the enantiomers will form a 3 point attachment with the receptor)

• Affinity • Tendency/ability of a drug to combine with a receptor

• Measure of the strength of the drug-receptor complex

Drug receptors (HE MAN)

• Hormone receptors

1. Insulin receptors Insulin

2. Opioid receptors Morphine & naltrexone

3. Steroid receptors Cortisol & Tamoxifen

• Enzyme receptors (ABCDE,X)

1. A nA,K+ ATPase Digoxin

2. A Amine oxidase (MAO) Phenlzine, Tranylcypromine, Moclobemide, Clorgyline

1. C Carbonic anhydrase Acetazolamide

2. C chE Donepezil & Physostigmine

3. C COX Aspirin & Celecoxib

4. D DNA polymerase Acyclovir & Zidovudine

5. D DNA topoisomerase Ciprofloxacin

6. H HIV protease Indinavir

7. X Xanthine oxidase Allopurinol

• Membrane transport proteins

1. Ligand GIC Diazepam & Ondansetron

2. Voltage GIC Lidocaine & Verapamil

3. Ion transporter Loop & thiazide diuretics

4. Neurotransmitter transporter Fluoxetine, Cocaine

• Among others

1. Membrane lipids Alcohol & Amphotericin B

2. Nucleic acids Anti-cancer drugs

• Neurotransmitter receptors

1. Adrenoceptors E & Ppnl

2. Histamine recep. Cimetidine, Diphenhydramine

3. 5-HT rec. LSD & Sumatriptan

4. Muscarinic receptors Atropine, Bethanechol