1. Lecture 6 II. Non-receptor Mechanisms

2. Direct Physical blocking of channel local anesthetic & amiloride Modulator Bind to the channel protein itself Ca channel blockers

3. ChE inhibitors α-Methyl dopa

4.  Drug acts as Substrate leading to reversible OR irreversible inhibition of enzyme  reversible inhibition of cholinesterase by neostigmine  Irreversible inhibition of cyclo-oxygenase by aspirin True/False substrate  L-DOPA converted into dopamine  α-methyldopa converted into α- methylnorepinephrine (false transmitter)

5.  What is carrier molecule? Carrier protein molecules function to transport ions & small organic molecules (too polar to penetrate) across cell membranes.

6. 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.

7. 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)

8. V- Anti-metabolites  An 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)

9.  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.

10.  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

11.  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)

12.  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

13.  Pumping of drugs out from intracellular site (chemotherapy) Via p-glycoprotein