PCOL 1 - Introduction: The Nature of Drugs and Drug Development

Study of substances that interact with the living system through a chemical process

Pharmacology

Example of other branches in pharmacology

Medical Pharmacology and Toxicology

Science of substances used to prevent, diagnose, and treat disease

MEDICAL PHARMACOLOGY

Branch of pharmacology that deals with the undesirable effects of chemicals on living system

TOXICOLOGY

2 main branches of pharmacology

PHARMACODYNAMICS & PHARMACOKINETICS

• Action of the Drug on the Body

• Action of the Drug on the Katawan

PHARMACODYNAMICS

• Action of the Body on the Drug

• Action of the Katawan on the Drug

PHARMACOKINETICS

(Drug receptor interactions)

PHARMACODYNAMICS

(Absorption, Distribution, Metabolism, Excretion)

PHARMACOKINETICS

Any substance that brings a change in biologic function through its chemical process

DRUG

Component of cell or organism that interacts with drug leading to an effect

RECEPTORS

Specific region of the receptor molecule to which the drug binds

RECEPTOR SITE / BINDING SITE

Translate the drug receptor interaction into a change in cellular activity

EFFECTOR

Maximal effect drug can produce

EFFICACY

Amount/concentration of drug required to produce a specified effect

POTENCY

GENERAL PRINCIPLES?

NATURE OF DRUGS

PHARMACODYNAMIC PRINCIPLES

PHARMACOKINETIC PRINCIPLES

NATURE OF DRUGS (4)

Physical nature, drug size, drug-receptor bonds, shape

PHARMACODYNAMIC PRINCIPLES (3)

Types of drug receptor interactions, Mechanisms of drug interaction, Model of drug-receptor interactions

PHARMACOKINETIC PRINCIPLES (5)

Permeation, Absorption, Distribution, Metabolism,Elimination

DRUG SIZE: Very Small example

MW 7 = Li

DRUG SIZE: Most drugs have MW of? *sweet spot

MW 100-1000

DRUG SIZE: Very Large example

MW 50,000 = thrombolytics

DRUG SIZE: Rarely specific

<100

DRUG SIZE: do not diffuse between compartments of the body

> 1000

DRUG RECEPTOR BONDS: Strongest/ Very Strong/ Irreversible

COVALENT BONDS

DRUG RECEPTOR BONDS: covalent bond example

Aspirin (Acetylsalicylic acid)

DRUG RECEPTOR BONDS: Weaker than covalent bonds but stronger than hydrophobic

ELECTROSTATIC BONDS

DRUG RECEPTOR BONDS: Most of drugs

ELECTROSTATIC BONDS

DRUG RECEPTOR BONDS: Weak

HYDROPHOBIC BONDS

DRUG RECEPTOR BONDS:Highly lipid soluble drugs and lipids of cell membrane

HYDROPHOBIC BONDS

DRUG RECEPTOR BONDS: Hydrophobic bond example

corticosteroids

Concerned with receptors, effectors, dose-response curves, agonist, antagonist, signaling mechanisms, and receptor regulations

PHARMACODYNAMIC PRINCIPLES

TYPES OF DRUG-RECEPTOR INTERACTIONS(3)

AGONIST, ANTAGONIST, ALLOSTERIC ACTIVATORS & INHIBITORS

Drugs that binds to and activate the receptors

AGONIST

Affinity + Intrinsic activity

AGONIST

Affinity only

ANTAGONIST

Drugs that binds to and inhibits the receptors (receptor site)

ANTAGONIST

Action can be overcome by increasing the dosage of agonist

ANTAGONIST

Acts at different site on receptor molecule

ALLOSTERIC ACTIVATORS & INHIBITORS

Do not bind on the active site

ALLOSTERIC ACTIVATORS & INHIBITORS

MODEL OF DRUG-RECEPTOR INTERACTION: Receptors are postulated to exist partially in the _____ (Ri) and partially _____(Ra)

inactive, nonfunctional form; activated form

MODEL OF DRUG-RECEPTOR INTERACTION: Even in the absence of any agonist, some of the receptors pool must exist in Ra →________

may produce the same physiologic effect (Constitutive or Basal Activity)

MODEL OF DRUG-RECEPTOR

INTERACTION (4)

FULL AGONIST (Da), PARTIAL AGONIST,ANTAGONIST,INVERSE AGONIST

Ra >> Ri

FULL AGONIST

Stabilizes Ra configuration → maximal effect is produced

FULL AGONIST

Example of Full Agonists

Acetylcholine

Ra > Ri

PARTIAL AGONIST

Do not stabilize Ra configuration → significant receptors exist in the Ri-D pool

PARTIAL AGONIST

_____can also prevent access by full agonist on

receptor sites

PARTIAL AGONIST

Example of Partial Agonist

Pindolol

Ra = Ri → prevents binding of agonist

ANTAGONISTS

Ra < Ri → prevents conversion to Ra state → lowers constitutive activity

INVERSE AGONIST

To produce useful therapeutic effects, most drugs must be absorbed, distributed, and eliminated

PHARMACOKINETIC PRINCIPLES

Concerned with Absorption, Distribution, Metabolism, and Excretion

PHARMACOKINETIC PRINCIPLES

Movement of drug molecules into and within the biologic environment

PERMEATION

Under Permeation (3)

DIFFUSION,TRANSPORT BY SPECIAL CARRIERS, ENDOCYTOSIS

Movement of solutes from higher to lower concentration (downhill)

DIFFUSION

Do not use transport proteins and energy (passive)

DIFFUSION

Diffusion is governed by?

Fick’s Law

2 Types of Diffusion

AQUEOUS DIFFUSION and LIPID DIFFUSION

Across epithelial membrane tight junction and endothelial lining of blood vessel

AQUEOUS DIFFUSION

Passive movement across the lipid bilayer

LIPID DIFFUSION

Not governed by Fick's Law

TRANSPORT BY SPECIAL CARRIERS

Under TRANSPORT BY SPECIAL CARRIERS (2)?

FACILITATED DIFFUSION, ACTIVE TRANSPORT

Downhill, Passive

FACILITATED DIFFUSION

Use transport protein

FACILITATED DIFFUSION

Uphill, Active

ACTIVE TRANSPORT

transport for very large hydrophilic molecules

ENDOCYTOSIS

• CONCENTRATION - H → L

• TRANSPORT PROTEIN - x

• ATP USAGE - x

• SATURABILITY - x

SIMPLE DIFFUSION

• CONCENTRATION - H → L

• TRANSPORT PROTEIN - /

• ATP USAGE - x

• SATURABILITY - /

FACILITATED DIFFUSION

• CONCENTRATION - L→ H

• TRANSPORT PROTEIN - /

• ATP USAGE - /

• SATURABILITY - /

ACTIVE TRANSPORT

Predicts the rate of movement of molecules across a barrier

FICK'S LAW OF DIFFUSION

FICK'S LAW OF DIFFUSION: Concentration and Surface area are _____ proportional to rate of movement

directly

FICK'S LAW OF DIFFUSION: Thickness is ____ proportional to rate of movement

inversely