Lecture 6II. Non-receptor Mechanisms

I- Ion Channels

DirectPhysical blocking

of channel local anesthetic & amiloride

ModulatorBind to the channel

protein itselfCa channel blockers

II- Enzymes

ChE inhibitors

α-Methyl dopa

II- Enzymes (cont.)

Drug acts as

Substrate leading to reversible OR irreversible inhibition of enzymereversible inhibition of cholinesterase by

neostigmine Irreversible inhibition of cyclo-oxygenase by aspirin

True/False substrateL-DOPA converted into dopamine α-methyldopa converted into α-

methylnorepinephrine (false transmitter)

III- Carrier Molecules What is carrier molecule? Carrier protein molecules function to transport ions & small

organic molecules (too polar to penetrate) across cell membranes.

III- Carrier Molecules

They possess a recognition site that confers specificity for a particular carried agent.

Such recognition sites can be targets for drugs where they block the transport system.

An example is the inhibition of cardiac Na+K+-ATPase by cardiac glycosides.

IV- Extracellular Sites of Drug Action Stomach: neutralize acid with base

(antacids) Blood: bind metals (chelation) like lead

with EDTA GI Tract: bind drugs (adsorption) with

Cholestyramine. GI Tract: increase water by osmotic

effects (laxatives) Kidney: increase water elimination

(osmotic diuretics)

V- Anti-metabolitesAn anti-metabolite is a chemical with a similar structure to a

substance (a metabolite) required for normal biochemical reactions, yet different enough to interfere with the normal functions of cells, including cell division

Examples: Anti-neoplastics e.g., 5-FU (5-fluorouracil) inhibits DNA and RNA

synthesis Antimicrobials such as sulfonamide drugs, which inhibit

dihydrofolate synthesis in bacteria by competing with para-aminobenzoic acid (PABA)

Allergy: antigen-antibody………unpredictable

Idiosyncrasy: genetic abnormality…….. Unpredictable

Side effects: unavoidable, undesirable, normal actions by therapeutic doses.

Over-dose: high dose of drugs

Supersenstivity: exaggerated response to normal dose due to upregulation of receptors.

Dependance: habituation and addiction.

Adverse effects of drugs

Desensitization and Tachyphylaxis

tachyphylaxis ◦ When it is developing in the course of few

minutes.

Tolerance ◦ To describe a more gradual loss of drug-induced

clinical effects that develops in the course of days or weeks.

Refractoriness ◦ Used to indicate the loss of therapeutic response.

Drug resistance ◦ Describes the loss of the effect of antitumor and

antimicrobial drugs

Mechanisms of Desensitization

Receptor phosphorylation◦ Usually by phosphorylating serine or threonine residues

in the C-terminal domain of GPCRs leading to reduce efficiency and alter their binding affinity.

Down-regulation of receptors

◦ Phosphorylation also signals the cell to internalize the membrane receptor leading to decrease the number of receptors on the cell membrane.

◦ In contrast, continuous or repeated exposure to antagonists initially can increase the response of the receptor (supersensitivity or up-regulation)

Mechanisms of Desensitization

Depletion of mediators◦ Drugs acting indirectly via transmitter release can cause

depletion of that transmitter and hence loss of action e.g. amphetamine or ephedrine act by releasing catecholamines from nerve terminals.

Pharmacokinetic desensitization◦ Drugs which stimulate hepatic metabolism may enhance

their own metabolism and hence a lower plasma concentration with repeated administration of the same dose e.g. barbiturates

Pumping of drugs out from intracellular site (chemotherapy)

Via p-glycoprotein

Schematic of P-glycoprotein