Phases of Drug Action PDF

Phases of Drug Action Dr. Ahmed Elkerdawy Senior Lecturer in Pharmaceutical Chemistry [email protected] JBL2W25 Learning Objectives To understand the different phases of drug action (Pharmaceutical, Pharmacokinetic, and Pharmacodynamic). To appreciate the different factors influencing...

Phases of Drug Action Dr. Ahmed Elkerdawy Senior Lecturer in Pharmaceutical Chemistry [email protected] JBL2W25 Learning Objectives To understand the different phases of drug action (Pharmaceutical, Pharmacokinetic, and Pharmacodynamic). To appreciate the different factors influencing the drug behaviour in the different phases of drug action. To appreciate the different drugs physicochemical properties influencing its behaviour in the different phases of action. Drug action  Successful Drug Successful Drug = Activity + ADME + Safety (T) ADME/T Absorption Distribution Metabolism Excretion (Elimination) Toxicity Drug Journey Portal Membrane Vein Liver Solid Dissolution Drug in Transfer Absorbed Extraction Systemic Drug Solution Drug Circulation Solubility Absorption Metabolism Excretion Distribution (Elimination) Body Outside Tissues Body The Three Phases of Drug Action Pharmaceutical phase For an orally administered drug, this includes the disintegration of a pill in the GIT, the release of the drug, and its dissolution. Pharmacokinetic phase Absorption, Distribution, Metabolism, and Excretion (ADME) Pharmacodynamic phase Involves the mechanism by which a drug interacts with its biomolecular target and the resulting pharmacological effect.  The Three Phases of Drug Action The compound with the best binding interactions for a target is not necessarily the best drug to use in medicine. This is because a drug must reach its target in the first place to be effective. So, it is important to study pharmacokinetics alongside pharmacodynamics.  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmaceutical Phase property Drug Dissolution Ionization Depends on the pH of the medium, Lipophilicity Such that weakly acidic drug are (Lipid solubility) better dissolved in the alkaline (and its balance regions of the GIT and vice versa. with hydrophilicity)  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 1. Absorption Drug passage through GIT membrane to circulation.  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 1. Absorption Passive diffusion Physicochemical Properties and Phases of Drug Action Physicochemical Properties and Phases of Drug Action  Absorption:  Para- and transcellular are passive process (Passive diffusion) and they are the major processes of drug absorption (~ 90%).  Transcellular: intramembrane or through cytoplasm, fast and may occur along the whole GIT wall. Lipid‐soluble unionized drugs dissolve in the membrane, and are driven through by a concentration gradient across the membrane  Paracelluar: via aqueous pores between cells, slower and only in small intestine (Polar, small molecules).  Carrier‐mediated facilitated transport occurs usually for some polar drugs, particularly those which are analogs of endogenous compounds for which there already exist specific membrane carrier systems. e.g. For example, methotrexate, an anticancer drug which is structurally similar to folic acid, is actively transported by the folate membrane transport system.  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 1. Absorption Ionization For the absorption to take place the drug should be unionized and Lipophilicity lipophilic to be able to dissolve in (Lipid solubility) the lipophilic cell membrane and passes to the other side of the Size and shape membrane.  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 2. Distribution Once in the blood, drugs are simultaneously distributed throughout the body.  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 2. Distribution Ionization Plasma protein binding: Depends on the ionization and the Lipophilicity lipophilicity of the drug (Lipid solubility) Blood-Brain Barrier (BBB): Drug with sufficiently high lipophilicity Size and shape can pass through the BBB to the brain. Adipose tissue: Highly lipophilic drugs distributed rapidly to the adipose tissue.  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 2. Distribution Site of action: Desired distribution site  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 3. Metabolism Lipophilicity --------------------------- (Lipid solubility)  Physicochemical Properties and Phases of Drug Action Physicochemical Process Pharmacokinetic Phase property 4. Excretion Ionization ✓ Compounds with suitable size pass the glomerular membranes Lipophilicity and that are soluble in water at (Lipid solubility) the urine pH are expected to be excreted in the urine. Size and shape ✓ Lipophilic compounds usually excreted in bile.  Physicochemical Properties and Phases of Drug Action Physicochemical Pharmacodynamic Phase Process property Drug-binding site interaction Ionization Through the different type of (Electrostatic , ionic binding interactions. and H-Bond interactions) Lipophilicity (Hydrophobic interactions) Size and shape (VdW and repulsive interaction) Physicochemical Properties and Phases of Drug Action Physicochemical properties play an important role in the different phases of the drug action, mainly:  Hydrophobicity (Lipophilicity)  Ionization (Electronic properties)  Size and shape (Steric properties) They are dependent on the chemical structure of the drug and any change in the structure will lead to a change in this physicochemical properties and subsequently on the behavior of the drug in the different phases of drug action and so its biological activity. Hydrophobicity The hydrophobic character of a drug is crucial to how easily it crosses cell membranes and may also be important in receptor interactions. Changing substituents on a drug may have significant effects on its hydrophobic character and, hence, its biological activity. Therefore, it is important to have a means of predicting this quantitatively. Hydrophobicity ❑The partition coefficient (P): ❑It is the parameter used to measure (quantify) hydrophobicity of a drug. Hydrophobicity ❑The partition coefficient (P): ❑It is the parameter used to measure (quantify) hydrophobicity of a drug. Concentration of drug in octanol phase 𝑃= Concentration of drug in aqueous phase ❑Hydrophobic compounds have a high P value, whereas hydrophilic compounds have a low P value. ❑Varying substituents on the lead compound will produce a series of analogues having different hydrophobicities (different P values) and mostly different biological activity.  Hydrophobicity ❑Hydrophobicity is expressed as (log P) Hydrophobic compounds have a high logP value, whereas hydrophilic compounds have a low logP value. Hydrophobicity ❑Correlation between hydrophobicity and biological activity: Parabolic correlation Biological activity Hydrophobicity ❑Correlation between hydrophobicity and biological activity: You might think that increasing log P should increase the biological activity forever (ad infinitum). In fact, this does not happen. There are several reasons for this. For example, 1. The drug may become so hydrophobic that it is poorly soluble in the aqueous phase. 2. It may be ‘trapped’ in fat depots and never reach the intended site. 3. Hydrophobic drugs are often more susceptible to metabolism and subsequent rapid elimination. Hydrophobicity ❑Correlation between hydrophobicity and biological activity: The biological activity increases as log P increases until a maximum value is obtained. The value of log P at the maximum biological activity (log P0) represents the optimum partition coefficient for biological activity. Beyond that point, any increase in log P results in a decrease in biological activity. Hydrophobicity ❑Correlation between hydrophobicity and biological activity: There are relatively few drugs where activity is related to the logP factor alone. (e.g. General anesthetics). (activity depends on BBB permeability) Drugs which are to be targeted for the CNS should have a log P value of approximately 2. Drugs which are designed to act elsewhere in the body should have log P values significantly different from 2 in order to avoid possible CNS side effects. Hydrophobicity ❑Correlation between hydrophobicity and biological activity: There are examples of drugs for which hydrophobicity has only a slight contribution in their biological activity. Ex. Antimalarial drugs. Ionization (electronic properties) Dissociation constant Ka (measures the extent of ionization at a certain pH) Weak acid: (Low pKa) (the lower the stronger) Weak base: (High pKa) (the higher the stronger) Ionization (electronic properties) Weak acids exist in stomach (pH= 1-2) mostly in unionized form (absorbable form). Weak bases exist in the small intestine (pH= 6-8) mostly in unionized form (absorbable form). Size and shape (Steric properties) Molecular volume: (measures the steric extent) It determines transport characteristics of molecules, such as intestinal absorption or blood-brain barrier penetration. Size and shape (Steric properties) Molar refractivity (MR) : It is a measure of the volume occupied by an atom or a group of atoms. Where n is the refractive index, MW is the molecular weight, and d is the density. Reading list Victoria F. Roche, S. William Zito, Thomas L. Lemke, David A. Williams., Foye’s Principles of Medicinal Chemistry (8ed) (2020) ProQuest (Firm), Textbook of drug design and discovery (5ed) (2017) Graham L. Patrick, An introduction to medicinal chemistry (7ed) (2023)