Physicochemical Properties of Drugs in relation to Drug

Physicochemical Properties of Drugs in relation to Drug Action Roselyn Aperocho Naranjo, RPh, MPH USPF, College of Pharmacy rose_may 26@yahoo. com

Understanding the Modern Drug Design o o o o Modern chemical techniques Recent knowledge on disease mechanisms & receptor properties Transportation of drugs in the body Distribution of drug through different compartments Metabolism of drugs in the liver and other organs Structural characteristics of the receptor Acid-base chemistry Availability of the computer software that determines the three-dimensional shape of the receptor in order to design new molecules that will give optimum fit to the receptor

History: General Plant Source Specific Plants are selected Treatment for medical conditions Crude extracts

History: General Plant Source Structure of Natural products Specific Plants are selected Selective changes in the molecule Treatment for medical conditions Crude extracts

Selected molecules are changed due to: o o Reduction of undesirable pharmacologic response of the drug (side-effect) Obtain better drug response Alter drug’s metabolism Produce more cheaper and competitive supply of the product

Selected molecules are changed due to: Example: Addiction effect Morphine reduced Analgesic effect enhanced Cocaine Local Anesthetic Effect enhanced CNS effects reduced

Medicinal Chemistry in 1900’s o Phenothiazines – first synthesized as ANTIHISTAMINES - Careful investigation led to discover its TRANQUILIZING PROPERTY for the mentally ill patient. o Benzodiazepines – originated from an expected ring enlargement which resulted it to become a CNS RELAXANT

Overview drug receptor Drug-receptor complex Pharmacologic response

Overview

Drug Distribution o Oral Administration

Drug Distribution o Oral Administration n Solubility depends on: § Chemical Structure § Size of particles § § Surface area Nature of crystal form Type of tablet coating Type of tablet matrix

Drug Distribution o Oral Administration n Example: § CHLORAMPHENICOL PRODRUG- inactive form but are easily metabolized in the liver to become active §CHLORAMPHENICOL PALMITATE

Protein Binding

Protein Binding o o Can affect the drug’s effective solubility, biodistribution, half-life in the body and interaction with other drugs. Control access to certain body compartments Prolong the drug’s duration of action Limit the amount of drug available for biotransformation and interaction with specific receptor sites.

Tissue Depot o o Fats in the body which can be a storage for drugs The more Lipophilic the drug is, the more it will stay in the tissue o Example: § Thiopental

Drug Metabolism & Excretion

Statistical Prediction of Pharmacological Activity o Mathematical Model will explain many chemical processes Three goals in Drug Design • Predict biological activity in untested compounds • define the structural requirements required to fit to a specific receptor • design a test set of compounds

QSAR o o Proposed by Crum-Brown and Fraser in 1865 to 1870 Certain modification in the molecular structure of a poisonous compound produces an important differences in their action

QSAR

Topological Descriptors o Alternate method in describing molecular structure which is based on graph theory using the bonds that connects between atoms

Combinatorial Chemistry …to be continued Prepare ¼ sheet of paper for the quiz