Pharmacology-1 PHL 313

Sixth Lecture

By

Abdelkader Ashour, Ph.D. Phone: 4677212 Email: aeashour@ksu.edu.sa

Desensitization (Tachyphylaxis) and Tolerance

The loss of a drug’s effect, when it is given continuously or repeatedly On a short time-scale, such as a few minutes, this situation is called desensitization or

tachyphylaxis and on a longer time-scale, such as days or weeks, the term tolerance is preferred.

Receptor-mediated responses to drugs and hormonal agonists often desensitize with time, when they are given continuously or repeatedly

After reaching an initial high level, the response (e.g., cellular cAMP accumulation, Na+

influx, contractility, etc) gradually diminishes over seconds or minutes, even in the continued presence of the agonist

This is usually reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response

Example: chronic salbutamol (2 agonist) can cause internalisation of receptors → less receptors available for stimulation (down-regulation) → decreased bronchodilation

Why desensitization? Many receptor-effector systems incorporate desensitization mechanisms for preventing

excessive activation when agonist molecules continue to be present for long periods

Idiosyncrasy

A structural or behavioral characteristic peculiar to an individual or group

Idiosyncratic drug reaction is a qualitatively abnormal, and usually harmful, drug effect that occurs in a small proportion of individuals

In many cases, genetic materials are responsible

Example: Glucose-6-phosphate dehydrogenase (G6PD) is

an enzyme that maintains the content of reduced glutathione (GSH) in red blood cells, and thus prevent hemolysis

Individuals with G6PD deficiency cannot tolerate oxidant drugs e.g., primaquine, some sulfonamide drugs, .. (well tolerated in most individuals)

Those individuals will suffer from hemolysis leading to severe anemia

Primaquine and related substances reduce red cell GSH harmlessly in normal cells, but enough to cause hemolysis in G6PD-deficient cells

GSH

GSSG

Types of Targets for Drug Action

E. Others like structural proteins such as tubulin, which specifically binds colchicine

Other non-protein drug targets such as: DNA: antimicrobial and anti-tumor drugs

interact directly with DNA RNA: such as ribavirin against HCV

A. Receptors e.g., receptors targets for adrenaline

B. Ion Channels e.g., Na channel of excitable membranes target for local anesthetics

C. Enzymes e.g., cyclooxygenase target for NSAIDs (e.g., aspirin)

D. Carriers/transporters e.g., norepinephrine carrier target for

maprotiline

Drug Mechanisms (How Drugs Act?)

I. Receptor mechanisms: Most drugs exert their effects by binding to receptors This has the effect of either mimicking the body’s own

(endogenous) substances binding to receptors or preventing their binding or actions

II. Non-receptor mechanisms: These include:1. Changing Cell Membrane Permeability (Ion Channels)2. Actions on enzymes3. Carrier Molecules, e.g. uptake proteins4. Changing Physical Properties5. Combining with Other Chemicals6. Anti-metabolites

Receptors

Serve as recognition sites for specific endogenous compounds such as:1. Neurotransmitters, e.g. noradrenaline (NA)

2. Hormones, e.g. adrenaline (released from the adrenal medulla and acts on the heart)

3. Local Hormones /Autacoids (released and act upon the same/nearby tissue, e.g. prostaglandins)

Receptor-Effector Coupling

-When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacologic response.

-The transduction process between occupancy of receptors and drug response is often termed coupling.

Receptor Family Summary and Examples

Action Potential

Dep

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1- Ligand-gated Ion Channels They incorporate a ligand-binding (a receptor) site, usually in the

extracellular domain and they are activated by binding of a ligand (agonist) to the receptor on the channel molecule.

Binding of the agonist causes a conformational change in the receptor which leads to ion channel opening.

Involved in fast synaptic transmission They control the fastest synaptic events in the nervous system, in which

neurotransmitter acts on the postsynaptic membrane of a nerve or muscle cell and transiently increases its permeability to particular ions

Example: nACh receptor

2. G-protein-Coupled Receptors (GPCRs) The largest family: G-protein (guanine nucleotide binding regulatory

proteins) families: Gs ,Gi and Gq

Examples: mAChR, adrenoceptors, glutamate receptors, GABAB receptors

Actions: fast (seconds) Structure:

GPCR consists of seven transmembrane -helices G-protein consists of 3 subunits, , , . Guanine nucleotides bind to the -subunit which has enzymatic activity (GTP GDP) The and subunits remain together as , -complex

2. G-protein-Coupled Receptors

“The activation of the effector tends to be self-limiting”?? ------GTPase Amplification?

Mechanism: binding of the agonist to the GPCR activation of the GPCR G-protein activation (G-GDP G-GTP) : activation of enzyme with subsequent

generation of second messengers (e.g. cAMP, IP3) → biological effect or

opening or closing of an ion channel

(Inactive) (Active)

Opposite functional effects may be produced at the same cell type by GPCRs (e.g., mAChR and -adrenoceptors in cardiac cells)

2. G-protein-Coupled Receptors, Targets

PIP2: phosphatidylinositol-4,5-bisphosphate

IP3: inositol-1,4,5-trisphosphate

DAG: 1,2-diacylglycerol

PIP2

Gq