Basic Principles in Pharmacology

By

M.H.Farjoo M.D. , Ph.D.Shahid Beheshti University of Medical Science

Basic Principles in Pharmacology

Introduction

Drug Size

Drug-receptor Bonds

Drug Shape

Drug-Body Interactions

Drug-receptor Interactions

Duration of Drug Action

Weak Acids & Weak Bases

M.H.Farjoo

Introduction

Pharmacology: the study of substances that activate or inhibit normal body processes.

Medical pharmacology: the science of substances used to prevent, diagnose, and treat disease.

Toxicology: deals with the undesirable effects of chemicals on living systems.

M.H.Farjoo

Introduction (Cont,d)

Drug: a substance that changes biologic function through its chemical actions.

Prodrug: a chemical that is converted to the active drug inside the body.

A drug often interacts with a specific protein molecule, a receptor.

Orphan receptors: receptors for which no ligand has been discovered.

M.H.Farjoo

Introduction (Cont,d)

A receptor must be selective for drug; and it must change its function upon binding.

To interact with its receptor, a drug must have the appropriate size, electrical charge and atomic composition.

M.H.Farjoo

Introduction (Cont,d)

A drug must be capable of moving from its site of entry to its site of action.

A drug should be inactivated or excreted from the body at a reasonable rate.

Many drugs bind to albumin which is a nonregulatory protein and an inert binding site.

M.H.Farjoo

Introduction (Cont,d)

Poison: a drug that has almost exclusively harmful effects.

Toxin : a poison of biologic origin, synthesized by plants or animals.

All substances can under certain circumstances be toxic.

Dietary supplements and health-enhancing chemicals should prove their efficacy and safety.

M.H.Farjoo

Introduction (Cont,d)

Pharmacogenomics (or pharmacogenetics): the relation of the genetic makeup to response to drugs.

Gene therapy: insertion of a "healthy" gene into somatic cells.

Knocked out gene: the gene for the receptor has been mutated so that the receptor is absent or nonfunctional.

M.H.Farjoo

Introduction (Cont,d)

Homozygous knockout mice have complete suppression of the function.

Heterozygous knockout mice have partial suppression.

Knocked down genes: a gene with limited suppression of function.

Knockin mice: animals with overexpression of certain proteins of interest.

M.H.Farjoo

Introduction (Cont,d)

Big pharma: the multibillion-dollar companies in drug discovery and development.

These companies translate basic findings into commercially successful therapeutics.

Profit margins for big pharma have exceeded all other industries by a significant factor.

M.H.Farjoo

Drug Size

The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (alteplase MW 59,050).

Most drugs have molecular weights between 100 and 1000.

The lower limit is required for specificity and good "fit" to a receptor.

The upper limit is required for drug movement from site of administration to site of action.

M.H.Farjoo

Drug-receptor Bonds

Drugs interact with receptors by three types of chemical forces: covalent, electrostatic, and hydrophobic.

Because of covalent bond between aspirin and platelets, its effect is reversed by production of new platelets (7 days).

DNA-alkylating agents used in cancer chemotherapy also make covalent bonds .

M.H.Farjoo

Drug-receptor Bonds (Cont,d)

Electrostatic bonds are weaker but much more common than covalent bonds.

Electrostatic bonds consist of: Relatively strong ionic bonds

Weaker hydrogen bonds

Very weak van der waals forces.

M.H.Farjoo

Drug-receptor Bonds (Cont,d)

Hydrophobic bonds are important in the interactions of lipid-soluble drugs with the lipids of cell membranes.

Drugs that bind through weak bonds are more selective than drugs that bind by very strong bonds.

To design a highly selective short-acting drug for a receptor, we avoid molecules that form covalent bonds.

M.H.Farjoo

Drug Shape

More than half of all useful drugs are chiral molecules (stereoisomer), and exist as enantiomeric pairs.

Drugs with two asymmetric centers have four diastereomers.

In most cases, one of these enantiomers is much more potent than its mirror image.

M.H.Farjoo

Drug Shape (Cont,d)

One drug enantiomer is more susceptible to drug-metabolizing enzymes.

45% of the chiral drugs are marketed as the active isomer, the rest are racemic mixtures.

Many patients receive drug doses of which 50% or more is less active, inactive, or actively toxic.

M.H.Farjoo

Drug-Body Interactions

The interactions between a drug and the body are:

Pharmacodynamic processes: the actions of the drug on the body

Pharmacokinetic processes: the actions of the body on the drug

M.H.Farjoo

Drug-receptor Interactions

Agonist: drugs that bind to and activate the receptor.

Antagonist: drugs whose binding to a receptor, prevent binding of other molecules.

M.H.Farjoo

Drug-receptor Interactions (Cont,d)

Partial agonists produce a lower response, than do full agonists.

Partial agonists do not have decreased affinity for receptors.

Partial agonists competitively inhibit the responses produced by full agonists.

M.H.Farjoo

Duration of Drug Action

The effect may last as long as the drug occupies the receptor.

The action may persist after the drug has dissociated. (Some coupling molecule is still active).

In covalent binding, the effect persists until new receptors or enzymes are synthesized.

M.H.Farjoo

Weak Acids & Weak Bases

Weak acids and weak bases gain or lose protons depending on the pH.

Their movement between aqueous & lipid mediums varies with the pH.

Kidney filters drugs, by changing the urine pH the drug can be "trapped" in the urine (in overdose).

Weak acids are excreted faster in alkaline urine and vise versa.

M.H.Farjoo

Weak Acids & Weak Bases (Cont,d)

A large number of drugs are weak bases. Most of these bases are amine-containing molecules.

Primary, secondary, and tertiary amines undergo reversible protonation.

They vary their lipid solubility with pH.

Quaternary amines are always in the poorly lipid-soluble charged form.

M.H.Farjoo

Weak Acids & Weak Bases (Cont,d)

The protonated form of a weak acid is the neutral, more lipid-soluble form.

The unprotonated form of a weak base is the neutral form.

The uncharged form is more lipid-soluble.

A weak acid is more lipid-soluble at acid pH, and a basic drug is more lipid-soluble at alkaline pH.

Weak Acids & Weak Bases (Cont,d)

M.H.Farjoo

Body Fluid Range of pH

Total Fluid: Blood

Concentration Ratios for

Sulfadiazine (acid, pKa 6.5)

Total Fluid: Blood

Concentration Ratios for

Pyrimethamine (base, pKa 7.0)

Urine 5.0-8.0 0.12-4.65 72.24-0.79

Breast milk 6.4-7.6 0.2-1.77 3.56-0.89

Jejunum, ileum contents

7.5-8.0 1.23-3.54 0.94-0.79

Stomach contents 1.92-2.59 0.11 85,993-18,386

Prostatic secretions 6.45-7.4 0.21 3.25-1.0

Vaginal secretions 3.4-4.2 0.11 2848-452

SummaryIn English

Picture from earth as art website by NASA

40 Km.

Thank youAny question?