Pharmacology-1 PHL 313 Sixth Lecture By Abdelkader Ashour, Ph.D. Phone:

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 enzymes 3.Carrier Molecules, e.g. uptake proteins 4.Changing Physical Properties 5.Combining with Other Chemicals 6.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 Depolarization Repolarization

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: G s,G i and G q  Examples: mAChR, adrenoceptors, glutamate receptors, GABA B 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 GqGq