Comprehensive Pharmacology: Drugs, Receptors, and Neurotransmission

Pharmacology

Drugs

Psychopharmacology

Drugs on behavior and psychological

Neuropharmacology

Drugs on brain function

Neuropsychopharmacology

Drugs on brain, behavior, and psychological

Psychoactive drugs

Alterations in perception, mood, or consciousness

Binge drinking

5 drinks for men; 4 drinks for women

Heavy drinking

5 binge days out of last 30 days

Current U.S. illicit drug use

In the last month, 13% of the U.S. population has used illicit drugs (mostly marijuana)

Daily marijuana use

Is on the rise among college students

Binge alcohol use

Is higher in college students than non-college peers

Marijuana/cannabis vaping

Is increasing among college students and non-college peers

Nicotine vaping

Is increasing among college students and non-college peers

Factors affecting U.S. drug use

Alcohol temperance movement, Prohibition, increased addictive potential of drugs, and medicalization of drug addiction

Addiction

Chronic, relapsing brain disease characterized by compulsive drug seeking and use, despite harmful consequences

Physical dependence

The body relies on the drug to prevent withdrawal

Addiction is NOT

Physical dependence and withdrawal

Addiction is

Craving and relapse

Illicit drug use in high school students

Has decreased from 2021-2024

War on Drugs

Launched by president Nixon in 1971, expanded incarceration and targeted anti-war left and Black people

Anti-Drug Abuse Act of 1986

Created sentencing disparity between crack and powder cocaine, fueling racial disparities in incarceration

Pharmacokinetics

Absorption, distribution, metabolism, and excretion of drugs.

Bioavailability

The amount of drug available to bind to target sites and elicit drug action.

ADME

Absorption, Distribution, Metabolism, Excretion.

Factors affecting absorption

Route of administration, blood circulation, surface area, digestive or metabolic transport across membranes.

Drug properties affecting absorption

Solubility and ionization.

Lipid soluble and non-ionized molecules

Molecules/drugs easily diffuse across membranes when they are lipid soluble and non-ionized.

Routes of administration

Different routes give different drug onset, peak concentration, and duration.

Slow routes of administration

Oral or transdermal routes lead to slow absorption.

Fast routes of administration

Intravenous (IV) injection or inhalation/smoking lead to fast onset.

Factors affecting distribution

Movement from blood to target site, affected by the blood-brain barrier (BBB) and depot binding.

Metabolism

Movement out of the system, usually by metabolism (biotransformation), particularly in the liver enzymes.

Phase I metabolism

Oxidation, reduction, or hydrolysis (nonsynthetic reactions).

Phase II metabolism

Addition of small molecules such as glucuronide, sulfate, or methyl groups (synthetic reactions).

Active metabolites

Metabolites that have biological activity of their own and still need further metabolism to become inactive metabolites.

Half-life

Time for plasma drug concentration to fall to half of peak level.

First-order kinetics

Exponential rate, half-life; this is the most common.

Zero-order kinetics

Constant rate (linear) because metabolism/excretion processes are saturated.

Ligand

A neurotransmitter or drug that fits a given receptor.

Receptor

The protein that a ligand interacts with to initiate its biological effects.

Drug-receptor interactions

The interaction between a drug and its receptor that leads to a drug effect.

Agonists

Ligands that bind to a receptor and initiate a cellular response.

Antagonists

Ligands that bind to a receptor and cause no cellular response; they block the action of an agonist or endogenous ligand.

Reversibility in drug-receptor interactions

The ability of a ligand to bind and unbind from a receptor.

Law of mass action

More drug molecules = increased receptor occupancy. Maximum drug effect = when all receptors are occupied. The cellular response is proportional to the degree of receptor occupancy.

ED100

Effective dose that gives maximum response when all receptors are occupied.

ED50

Dose that produces half the maximum effect.

TD50

Dose that produces a given toxic effect in 50% of subjects.

LD50

Dose that kills 50% of subjects (lethal dose).

Therapeutic Index (TI)

LD50 / ED50, also known as margin of safety.

Potency

Amount of drug needed to produce an effect.

Efficacy

Maximum effect that can be produced by a drug.

Binding affinity

Does not determine the maximum possible effect.

Competitive antagonists

Bind to the same receptor binding site as agonist; their effect can be overcome.

Non-competitive antagonists

Do not compete with agonist for receptor binding site; their effect cannot be overcome.

Partial agonists

Have lower efficacy than full agonists and higher than antagonists; can act as antagonists in presence of full agonists.

Inverse agonists

Bind to receptor and initiate cellular response opposite to agonist.

Allosteric modulators

Ligands/drugs that indirectly influence the effects of a primary ligand.

Positive allosteric modulators (PAMs)

Amplify primary ligand effects.

Negative allosteric modulators (NAMs)

Reduce primary ligand effects (also known as noncompetitive antagonists).

Withdrawal symptoms

Typically opposite to the acute effects of the drug.

Pharmacodynamics

Biochemical effects of drugs and their mechanism of action; how does a drug change the body?

Pharmacokinetic factors

Affect bioavailability and compete and work simultaneously.

Absorption

Factors affecting absorption include route of administration and drug solubility and ionization.

Oral (peroral, PO)

Absorption in gastrointestinal tract; slow, variable; first-pass metabolism in the liver (and GI system) before entering bloodstream.

Non-invasive routes of administration

These routes typically avoid first-pass metabolism.

Intranasal

Substance doesn't need to be dissolved; bypasses BBB

Inhalation

Quick brain access (large surface area & many capillaries)

Sublingual

Absorbed by mucous membranes in mouth

Rectal

Absorbed by blood vessels

Transdermal

Skin patch or gel

Drug ionization

Most drugs are weak acids or weak bases ionized (charged). Ionized drugs are not readily lipid soluble; different body fluids have different pH, which will affect drug ionization.

The blood-brain barrier (BBB)

BBB is selectively permeable (lipophilic)

Exceptions to BBB

Areas with weak barrier between blood and brain: Area postrema, Median eminence

Depot binding

Depot binding of drug can occur in albumin (plasma), fat, and muscle; inactive, protected from metabolism, affects peak and duration of drug concentration.

Example of depot binding

Depot binding of THC in fat leads to slow release, such that THC is detected in urine many days after a single dose.

Dependence and withdrawal

Withdrawal symptoms are typically opposite to the acute effects of the drug.

Drug experience: Tolerance and sensitization

Tolerance: More drug is required to get the same effect (dose-response curve shifts to right); Sensitization: Less drug is required to get the same effect (dose-response curve shifts to left).

Tolerance

Drug effect decreases with repeated administration.

Acute tolerance / tachyphylaxis

Drug effect decreases rapidly - within a single session, when blood alcohol level (BAC) is rising as compared to falling.

Cross-tolerance

Drug effect decreases due to repeated administration of another drug.

Sensitization

Drug effect increases with repeated administration.

Cross-sensitization

Drug effect increases due to repeated administration of another drug.

Mechanisms of tolerance/sensitization

1. Pharmacokinetic (metabolic): Changes in metabolism, such as enzyme induction. 2. Pharmacodynamic: Changes in receptors and their corresponding signaling pathways. 3. Behavioral: Changes due to learning factors.

Behavioral mechanisms of tolerance/sensitization

Pavlovian/classical conditioning; Conditioned stimuli (CS) can contribute to drug sensitization or tolerance.

Context-specific tolerance/sensitization

Tolerance/sensitization to certain drug effects may be context-specific -- Expressed only in the environment previously paired with drug.

Context-specific tolerance

Context-specific tolerance contributes to fatal heroin overdoses.

Triggers for ion channel opening

Ion channels may be opened by several triggers, including: A. Ligand binding (ligand-gated ion channel), B. Change in membrane potential (voltage-gated ion channel), C. Phosphorylation, G proteins (G protein-gated ion channel).

Inhibitory post-synaptic potential (IPSP)

Cl- or K+ ion channels open

Excitatory post-synaptic potential (EPSP)

Na+ ion channels open

Local potentials

(EPSPs & IPSPs)

Action potential

Electrical signals within a neuron

Action potentials

Down axon

Chemical signals between neurons

Neurotransmitters

Resting membrane potential

A resting neuron is polarized with a difference in electrical charge (ions) inside vs. outside the cell

Resting potential

The resting potential of a neuron is around -70 millivolts (mV)

Electrical pressure for potassium (K+)

To enter cell, but chemical pressure to leave cell

Electrical and chemical pressure for sodium (Na+) and calcium (Ca++)

To enter cell

Chemical pressure for chloride (Cl-)

To enter cell

Action Potential threshold

About -40 mV triggers a brief action potential (or spike)

Voltage-gated Na+ channels

Conduct the action potential down the axon