PSYC 3822: Drugs & Behaviour (Chapter 4)

Pharmacokinetics

Refers to how drugs pass through and are eliminated from the body. The 4 steps are:

Absorption, Distribution, Metabolism (biotransformation) and Elimination

Absorption

Refers to passage of a drug into the bloodstream.

- In most cases, drug must pass through cell membrane(s)

- Depends on route of administration

- e.g., intravenous goes into blood directly, oral must pass through mucous membranes in mouth or wall of intestines

Common Routes of Administration (Absorption)

- Inhalation

-Intramuscular

- Intravenous

- Oral

- Nasal and mucosal membrane

- Subcutaneous and Sublingual

- Transdermal

Route of Administration affects

1. how much drug reaches blood stream

2. speed of absorption (may contribute to abuse)

Inhalation

-Form: Inhaled into lungs

-Absorption amount & time: High rate of absorption and Rapid time

-Other: Convenient for patients and common for many drugs of abuse

Intramuscular

-Form: Injection into skeletal muscle

-Absorption amount & time: More stable than oral adminstration and quick time, but not as rapid as intravenous injections

-Other: Not convenient/common for drug abusers

Intravenous

-Form: Injection into vein

-Absorption amount & time: 100% absorption and immediate time

-Other: Unlikely for patients to administer themselves

Oral

-Form: Pill

-Absorption amount & time: Variable, affected by food in stomach & digestive rates. Several minutes in time to work

-Other: Convenient and common. Most preferred by patients

Nasal and mucosal membrane

-Form: Absorbed through membranes in nasal passage or mouth

-Absorption amount & time: More stable and quicker than oral in time, but not as rapid as intravenous injection

-Other: Convenient and common for drug abuse

Subcutaneous

-Form: Injection under skin

-Absorption amount & time: More stable and quicker than oral in time, but not as rapid as intravenous injection

-Other: Individuals can administer themselves, not convenient to so

Sublingual

-Form: Dissolved under tongue

-Absorption amount & time: More stable and quicker than oral in time, but not as rapid as intravenous injection

-Other: Can be used for those who may not want to take a medication or patients with schizophrenia

Transdermal

-Form: Absorbed through skin by skin patch

-Absorption amount & time: More stable and quicker than oral in time, but not as rapid as intravenous injection

-Other: Convenient, providing an even, sustain release of drug into blood stream

Henderson-Hasselbalch equation

The closer the pKa and pH, the more non-ionized particles (better diffusion into blood stream)

- e.g., pKa = 3, better absorbed in stomach (pH = 1) than intestine(pH = 7).

Liberation

The process of drug molecules separating from the pill or solution it was delivered in.

- Many orally administered drugs are designed to be liberated in small intestines (drug must be protected from stomach acid)

- Generally, most drug absorption occurs in the small intestine (may take 15-30 min)

- Slow release capsules designed to release drug over longer period of time (to prolong drug levels in bloodstream)

Distribution

After absorption (into blood stream), passage of drug from bloodstream to intended body sites (e.g. brain)

Bioavailability

Ability of a drug to reach its intended target (site of action).

Blood-Brain Barrier

Protective layer of cells surrounding blood capillaries in brain that prevent many substances in blood from entering brain.

- Comprised of tightly fitted endothelial cells

- Nutrients and some molecules can penetrate BBB

- Either through Passive Diffusion or Active Transport

Passive Diffusion

Drugs (chemical) that have the following properties may diffuse across the blood brain barrier (and reach brain targets):

1. Lipid (or fat) soluble

2. Neutral charge

3. Small in size

Active Transport

Consists of membrane channels or transporters that facilitate passage of chemicals through cell membranes.

- Examples: Glucose transporter & Large amino-acid transporters

Non-specific binding

Drugs sometimes bind to other (unintended targets) which reduces amount delivered to intended targets

Protein Binding

Drug may bind to proteins in bloodstream (not free to cross blood-brain barrier)

Depot Binding

Drug may bind to other tissues which reduces amount in blood available to intended target (e.g., THC in fatty tissues).

Metabolism (Biotransformation)

Process of converting a drug unto one or more metabolites

Metabolites

Products resulting from transformation of a drug via enzymes.

- mostly smaller molecules

- water soluble (increases excretion)

- may be active or inactive

- Metabolism occurs mostly in liver

Phase I biotransformation

Metabolites are small, water soluble (easily excreted, e.g. urine).

- often occurs in liver (CYP cytochrome p450 enzymes)

- may produce active metabolites (e.g., heroin -> morphine)

Phase II biotransformation

Metabolites from Phase I may be modified via conjugation (attachment of another molecule) to produce a larger metabolite.

- usually results in less diffusion through BBB

- more likely to be excreted (usually more water soluble)

- May produce active metabolites (e.g., L-Dopa is changed to Dopamine)

Rapid Metabolizers

Decreases amount of drug (have to use higher dose or use different class of drugs).

- More metabolic enzymes

Poor Metabolizers

Prolongs drug life-span (stronger effects)

- Fewer metabolic enzymes

Personalized medicine

Prescribe treatments based onpatient's unique biological make-up

Elimination

Process by which drug leaves the body (final stage of pharmacokinetics). Several channels:

- Urine, Sweat , Breath (e.g. alcohol)

Elimination Rate

The amount of drug eliminated from the body over time.

Half-life

Amount of time required to eliminate half of the amount of a drug (used if drugs follows first-order kinetics).

- amount eliminated (in a given time) is proportional to the amount of drug.

- amount eliminated per unit time varies (e.g., 50 mg in first hour, 25 in next hour etc)

- can vary considerably

- determines dosing frequency

Zero-order kinetics

The drug is eliminated at a fixed amount per unit time.

- Alcohol is eliminated at about 10-14 mg per hour

Pharmacodynamics

Mechanisms of action for drug which accounts for its (psychological) effects.

Binding affinity

The drug's strength of binding to a receptor

Receptor efficacy

The drug's ability to activate a receptor

Agonist

Binds to a receptor and exerts actions similar to the neurotransmitter

Partial Agonist

Binds to the same receptor that the neurotransmitterbinds to but has a weaker effect than the neurotransmitter (so functionally reduces the action of the neurotransmitter)

Antagonist

Binds to a receptor and blocks the action of a neurotransmitter

Competitive antagonist

Binds to the same receptor that the neurotransmitter binds to and blocks the action of the NT (direct competition for receptor)

Non-competitive antagonist

Binds to a different receptor than the NT (usually on a complex) and blocks action of NT

Allosteric regulators

Bind to a receptor other than neurotransmitter and affects action of NT.

- usually receptor for drug is part of a larger receptor complex

Positive modulator

Drug enhances the action of the NT

Negative modulator

Drug decreases the action of the NT

Repeated, usually daily, use of a drug may lead to either...

1. Sensitization: Increased effects of drug

- lower dose necessary for a given level of effect

- dose-response curve shifted to the “left”

2. Tolerance: Decreased effect of a drug

- larger dose necessary for a given level of effect

- dose-response curve shifted to the “right"

Pharmacokinetic tolerance (drug dispositional tolerance)

Reduction in the amount of drug reaching target

- e.g., increased production of metabolic enzymes (as in alcohol dehydrogenase)

Pharmacodynamic tolerance

Changes in the number of neurotransmitter receptors

Behavioural tolerance

Decreased behavioural response (learn to perform tasks better under effects of drug

Conditioned (or contingent) tolerance

Tolerance due to conditioned physiological responses that counteract the drug effects.

- Stimuli associated with drug use may active a pharmacokinetic response that reduces drug's effect

- In presence of CS, drug effect decreases

- However, in absence of CS, drug effect is much stronger (may overdose)

Cross tolerance

Tolerance to one drug may result in tolerance to another drug.

- Someone with high tolerance to heroin may be tolerant to methadone (require higher dose)

Withdrawal syndrome

Collection of responses that occur when a drugis no longer administered.

Physical effects

Severity depends on length and/or amount of use(usually opposite to drug's effects).

- Alcohol withdrawal can lead to seizures (even death)

- Heroin withdrawal often involves intense stomach cramps

Psychological effects

Commonly include drug cravings or mood changes.

- Usually diminish with time (but may re-appear in some contexts)