Mechanisms of Drug Acition, Dose, Response Curves

Pharmacology

Scientific study of the effects of drugs and chemicals on living organisms where a drug can be broadly defined as any chemical substance, natural or synthetic, which affects a biologic system

Pharmacodynamics

Study of a drug’s molecular, biochemical, cellular, and physiologic effects or actions.

“Pharmakon”: drug

“Dynamikos”: power

Pharmacokinetics

Study of how the body interacts with administered medication for the entire duration of exposure

Absorption
Distribution
Metabolism
Excretion

Molecular target (drug target)

macromolecule or cellular or tissue structures that a drug interacts with (binds to) resulting in a change in their function that elicit a desired pharmacological effect. The vast majority of targets are proteins with some drugs targeting DNA, lipids and carbohydrates.

Receptors (Pharmacologic)

Target molecule for an endogenous or exogenous ligand.

With few exceptions, drug actions are mediated through the effects of drug ligand molecules on drug receptors in the body.

Most receptors are large regulatory molecules that influence important biochemical processes (eg, enzymes involved in glucose metabolism) or physiologic processes (eg, ion channel receptors, neurotransmitter reuptake transporters, and ion transporters).

Receptors (biochemical)

Proteins that bind to external messengers to create a series of downstream effects that mediate a specific response in the cell

Have a ligand-binding domain that recognizes the specific ligand and the effector domain that undergoes conformational changes to produce a downstream event.

Antacids

Combination of various compounds with various salts of calcium, magnesium, and aluminum as active ingredients.

Act by neutralizing the acid in the stomach and by inhibiting pepsin, which is a proteolytic enzyme

Chelating agents

Used to reduce blood and tissue levels of injurious heavy metals

Classified based upon target heavy metal (iron, copper, mercury, and lead)

Some have high degree of specificity for target metal, while others chelate multiple agents

Mannitol

Increases osmolality of blood plasma

Used to lower pressure in head and increased pressure in eye

Can treat brain swelling

2-Mercaptoethane sulfonate (Mesna)

Sulfhydryl compound used to reduce incidence of hemorrhagic cystitis (inflammation of bladder) associated with certain chemo agents

converted to free thiol compound in kidney —> binds and inactivates acrolein + other urotixic metabolites of ifosfamide and cyclophosphamide —> reducing toxic effects on urinary effects on urinary tract during excretion

Bile acid sequestrants (Cholestyramine)

Bile acids, metabolites of cholesterol, normally reabsorbed in jejunum + ileum

Excretion increased tenfold when given —> enhanced conversion of cholesterol to bile acids in the liver via 7α-hydroxylation normally controlled by negative feedback by bile acids

Lowers cholesterol by excretion —> body is forced to create instead of recycle

What are receptors responsible for?

Molecular size, shape, and electrical charge

Agonist

Drug/substance that binds to a receptor inside a cell or on its surface —> causes same action as the substance that normally binds to the receptor

Antagonist

Drug/substance that reduces the action or effect of another substance (can also block)

Receptors

Protein inside/surface of cell that binds to a specific substance (ligand)—> causes specific effect in the cell

Main classes: GPCR, tyrosine kinase, ion channel receptors, hormone receptors

Enzymes

Biologic catalyst and is almost always a protein

Speeds up rate of a specific chemical reaction in the cell

Not destroyed during the reaction (recycled)

Transport proteins

Transfers polar solutes across cell membranes

Occur in many forms and in all types of biologic membranes

Each protein transports a particular class of molecule and often only certain molecular species of the class

Structural Proteins

Maintain cell shape

Compose structural elements within cells/connective tissue

E.g. tubulin

Non-covalent forces governing ligand-receptor interactions

Ionic Interactions

H-bonds

Van der Waals Forces

Hydrophobic Interactions

Small molecule/micromolecule

Low molecular weight (< 1000 daltons) organic compound that may regulate biological process

Size on the order of 1 nm

Dalton

A unit of mass for expressing masses of atoms, molecules, or nuclear particles equal to ¹/₁₂ of the atomic mass of the most abundant carbon isotope C-12: atomic mass unit

Biologics

Pharmaceutical compounds synthesized/extracted from a biologic source

Highly complex structures

Divided into: monoclonal antibodies, receptor modulators, replacement/modulators of enzymes

Manufacturing process of biologics

Involves living systems and complex processes

Level of constitutive activity of a receptor for cells is dependent on

Allosteric transition state (L)

Receptor density

Effector concentration and activity

Receptor-effector coupling efficiency

Type of conformation that the receptor adopt in the absence of ligand

Effector

Small molecule that selectively binds to a protein to regulate its biological activity

Act as ligands that can increase/decrease enzyme activity, gene expression, influence cell signaling, other protein functions

Cellular response to a specified concentration of a drug is composed of:

Drug dependent properties (affinity and intrinsic efficacy)

System-dependent properties (target density and efficiency of target-effector coupling)

Magnitude of response that a drug produces is determined by the:

Affinity and intrinsic efficacy of drug

Fraction of the target population occupied by the drug (defined by concentration of drug and drug’s affinity value)

Total target density

Efficiency with which the drug causes active conformation (multiple may exist) and converts activated targets into a response (coupling efficiency)

Effector(s) concentration and activity

EC₅₀

Dose or concentration at which effect is half-maximal

Relation between drug dose or concentration (X-axis) and drug effect (Y-axis)

Dose axis linear —> hyperbolic curve

Logarithmic dose axis

The dose or concentration at which effect is half-maximal is denoted EC₅₀, whereas the maximal effect is E_max

If the percentage of receptors that bind drug is plotted against drug concentration, a similar curve is obtained like in B

Concentration at which 50% of the receptors are bound is denoted K_d, and the maximal number of receptors bound is termed B_max

Potency

Amount of a drug that is needed to produce a given effect

E.g. EC50 (or ED50) is the concentration or dose of drug that causes 50% of maximum effect

Efficacy

Maximum effect that a drug can produce regardless of dose (Emax)

If you have two drugs and drug A has a higher potency than drug B, does that mean that drug A will also have a higher efficacy?

No, not really