Definitions of physical dependence and withdrawal after repeated exposure; distinct from addiction.

Sections II, V and VIII: pharmacokinetic modelling, parameters, covariates and terminology. Mathematical examples in concept articles are illustrative derivations.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Institutional or regulatory source. Cited for drug class and mechanism, not as a patient-specific treatment or dosing recommendation.

Drug tolerance is a reduced response to a specified exposure after repeated exposure. Comparison requires defining the endpoint and concentration: a smaller response at the same administered amount can also arise because drug metabolism has increased and target exposure has fallen. Cellular adaptation at unchanged exposure is a different mechanism. ^[ref]

In a concentration–response experiment, tolerance may appear as a shift toward higher concentrations, a lower maximum response or both. Different effects of one drug can adapt at different rates. This is why preserved response on one endpoint does not prove absence of tolerance on another, and why drug tolerance does not itself establish addiction or a withdrawal syndrome.

Drug withdrawal is a physiological or behavioural response to reducing or stopping exposure after adaptation to a drug. It differs from simple elimination of the substance: its manifestations reflect the adapted system functioning under changed exposure. It also differs from recurrence of the original condition, although both can occur together. ^[ref]

For example, a system that has compensated for a persistent inhibitory influence may show excessive activity when that influence is removed. The timescale of adaptation can differ from the drug elimination timescale, so a response can continue after concentrations have fallen. Physical dependence, drug tolerance and compulsive use describe different phenomena; the presence of one alone does not establish all the others.

Physostigmine is a carbamate alkaloid that inhibits acetylcholinesterase. Normally this enzyme hydrolyses acetylcholine; inhibition prolongs the availability of acetylcholine at cholinergic signalling sites. Physostigmine is therefore an indirect enhancer of cholinergic signalling, rather than simply a substitute ligand for every acetylcholine receptor. ^[ref]

A mechanistic distinction matters: increasing transmitter persistence can affect both muscarinic and nicotinic signalling wherever transmitter release and susceptible receptors occur. The outcome therefore depends on location, receptor type and baseline activity. This example separates an enzyme-directed drug action from the eventual physiological response, without assuming one universal effect in every tissue.

Pharmacodynamics describes how a drug changes a biological system as a function of exposure. It connects target binding to a measured response, whereas pharmacokinetics describes the time course of exposure. A simple illustrative model iswhere $E_{max}$ is the maximum increment above baseline and $E{C}_{50}$ is the concentration producing half that increment. Doubling $C$ does not generally double the response. ^[ref]

Potency and maximal effect differ: two drugs can have different $E{C}_{50}$ values but the same $E_{max}$, or the same $E{C}_{50}$ but different maximal effects. Moreover, $E{C}_{50}$ need not equal a binding dissociation constant, because downstream amplification and measurement time also shape the response.