Pharmacokinetics

Psychopharmacology

• Psychopharmacology is the study of the effects of drugs on the nervous system and on behavior

• The term drug has many meanings:– Medication to treat a disease– A chemical that is likely to be abused– An “exogenous” chemical that significantly alters the

function of certain bodily cells when taken in relatively low doses (chemical is not required for normal cellular functioning)

Drug Effects

All drugs produce harmful as well as beneficial effects.

• Main effects are related to desired therapeutic effect.

• Side effects are unrelated to the desired effect.• Placebo Effects are based upon an inert

substance's ability to elicit a significant therapeutic response, independent of any chemical property.

Drug Effectiveness• Dose-response (DR) curve:

Depicts the relation between drug dose and magnitude of drug effect

• Drugs can have more than one effect

• Drugs vary in effectiveness– Different sites of action– Different affinities for receptors

• The effectiveness of a drug is considered relative to its safety (therapeutic index)

Dose-Effect Curves

Therapeutic Index

This is a figure of two different dose response curves. You can obtain a different dose response curve for any system that the drug effects. When you vary the drug, this is the Independent variable, what you are measuring is the % of individuals responding to the drug. Here we see the drugs effects on hypnosis and death. Notice that the effective dose for 50 % of the people is 100 mg and if you double the dose to 200 mg then 1 % of your subjects die. Thus, if you want to use this drug to hypnotize 99 % of your subjects, in the process you will kill 2-3 % of your subjects.

This is a figure of two different dose response curves. You can obtain a different dose response curve for any system that the drug effects. When you vary the drug, this is the Independent variable, what you are measuring is the % of individuals responding to the drug. Here we see the drugs effects on hypnosis and death. Notice that the effective dose for 50 % of the people is 100 mg and if you double the dose to 200 mg then 1 % of your subjects die. Thus, if you want to use this drug to hypnotize 99 % of your subjects, in the process you will kill 2-3 % of your subjects.

Drug Safety and Effectiveness• Not all people respond to a similar dose of a drug

in the exact same manner, this variability is based upon individual differences and is associated with toxicity. This variability is thought to be caused by: – Pharmacokinetic factors contribute to differing

concentrations of the drug at the target area. – Pharmacodynamic factors contribute to differing

physiological responses to the same drug concentration. – Unusual, idiosyncratic, genetically determined or

allergic, immunologically sensitized responses.

Pharmacokinetics• Drug molecules interact with target sites to effect the

nervous system– The drug must be absorbed into the bloodstream and then

carried to the target site(s)

• Pharmacokinetics is the study of drug absorption, distribution within body, and drug elimination– Absorption depends on the route of administration– Drug distribution depends on how soluble the drug molecule is

in fat (to pass through membranes) and on the extent to which the drug binds to blood proteins (albumin)

– Drug elimination is accomplished by excretion into urine and/or by inactivation by enzymes in the liver

Overview

Pharmacokinetics

Routes of Administration

• Routes of Administration:Orally: • Rectally: • Inhalation: Absorption through mucous

membranes: • Topical: • Parenterally:

– Intravenous: – Intramuscular: – Subcutaneous:

Routes of Administration

Drug Delivery Systems

• Tablets • Injections (Syringe) • Cigarettes • Beverages • Patches • Suppositories

• Candy • Gum • Implants • Gas • Creams• Others?

– Stamps

– Bandana

Membranes

• Types of Membranes:• Cell Membranes: This barrier is permeable to many drug molecules but not

to others, depending on their lipid solubility. Small pores, 8 angstroms, permit small molecules such as alcohol and water to pass through.

• Walls of Capillaries: Pores between the cells are larger than most drug molecules, allowing them to pass freely, without lipid solubility being a factor.

• Blood/Brain Barrier: This barrier provides a protective environment for the brain. Speed of transport across this barrier is limited by the lipid solubility of the psychoactive molecule.

• Placental Barrier: This barrier separates two distinct human beings but is very permeable to lipid soluble drugs.

Drug Distribution• Dependent upon its route of administration and target area, every drug has to

be absorbed, by diffusion, through a variety of bodily tissue. • Tissue is composed of cells which are encompassed within membranes,

consisting of 3 layers, 2 layers of water-soluble complex lipid molecules (phospholipid) and a layer of liquid lipid, sandwiched within these layers. Suspended within the layers are large proteins, with some, such as receptors, transversing all 3 layers.

• The permeability of a cell membrane, for a specific drug, depends on a ratio of its water to lipid solubility. Within the body, drugs may exist as a mixture of two interchangeable forms, either water (ionized-charged) or lipid (non-ionized) soluble. The concentration of two forms depends on characteristics of the drug molecule (pKa, pH at which 50% of the drug is ionized) and the pH of fluid in which it is dissolved.

• In water soluble form, drugs cannot pass through lipid membranes, but to reach their target area, they must permeate a variety of types of membranes.

Acute vs Steady State

Drug Half-Life

Liver P450 systems• Liver enzymes inactivate some drug molecules

– First pass effect (induces enzyme activity)

• P450 activity is genetically determined:– Some persons lack such activity leads to higher drug

plasma levels (adverse actions)

– Some persons have high levels leads to lower plasma levels (and reduced drug action)

• Other drugs can interact with the P450 systems– Either induce activity (apparent tolerance)

– Inactivate an enzyme system

Drug Metabolism and PK

P450 Interactions

• Substrate: Is the drug metabolized via a specific hepatic isoenzyme?

• Inhibitor: does a specific drug inhibit a specific hepatic isoenzyme?– Would expect this to interfere with drug inactivation

• Inducer: does a specific drug enhance a specific hepatic isoenzyme?– Would expect this to speed up drug inactivation

–http://www.georgetown.edu/departments/pharmacology/clinlist.html

Drug-Hepatic InteractionsEnzyme Substrate Inhibitor Inducer

–1A2 Clozapine, haloperidol Cimetidine Tobacco smoke

–2B6 Bupropion Thiotepa Phenobarbital

–2C19 Citalopram Fluoxetine Prednisone

–2C9 Fluoxetine Paroxetine Secobarbital

–2D6 Most ADs, APs CPZ, ranitidine Dexamethasone

–2E1 Gas anesthetics Disulfiram Ethanol

– 3A4,5,7 Alprazolam Grapefruit juice Glucocorticoid

–http://www.georgetown.edu/departments/pharmacology/clinlist.html

Drug Enantioners• A drug molecule may be organized in such a way that

the same atoms are mirror images– Enantioners represent drug molecules that are structurally

different (spatial configutation)• Different physical properties

– Light rotation (levo = left; dextro = right)– Melting points

• Different biological activities (typically: dextro > levo)

– Fenfluramine = racemic mix of• dextro-fenfluramine• levo-fenfluramine

• Enantiomers often have different affinity for receptors

Supra-additive:The Case of Fen-Phen

DAYS

1 3 5 7 9 11 13 15 17 19 21

BO

DY

WE

IGH

T (

g)

0

40

320

360

400

440DEX 0 - 0 PHEN DEX 0 - 5 PHENDEX 1 - 0 PHEN DEX 1 - 5 PHEN RESIDUAL

Wellman et al., 2003