cram :( exam 2 pda i

At what stage is an IND filed?

After preclinical testing and before human clinical trials (before Phase I)

Major methods for discovering new drug leads

High-throughput screening, rational drug design, natural products, combinatorial chemistry, serendipity

Phase I trials characteristics

Small group of healthy volunteers; assesses safety, dosage, pharmacokinetics

Phase II trials characteristics

Moderate number of patients; evaluates efficacy and side effects

Phase III trials characteristics

Large patient population; confirms efficacy, monitors adverse reactions, compares to standard therapy

Effect of urine pH on weakly basic drug absorption

Alkaline urine increases reabsorption (more non-ionized);

acidic urine increases excretion (more ionized)

Paracellular drug transport

Movement between cells through tight junctions; most relevant in intestinal epithelium

Glomerular filtration principles

Depends on molecular size,

charge,

protein binding;

only free drug is filtered

Factors influencing transdermal absorption

Lipophilicity, molecular size, skin hydration, temperature, formulation

Protein binding effects on drugs

Decreases elimination, decreases free drug, lowers clearance,

increases apparent volume of distribution Vd

Enterohepatic recirculation

Drug is excreted in bile, reabsorbed in intestine; prolongs drug action

First-pass metabolism

Drug metabolized in liver before reaching systemic circulation; reduces bioavailability

Disadvantages of rectal administration

Variable absorption,

irritation,

inconvenience,

partial first-pass metabolism

Multidrug Resistance Protein (MDR)

Efflux transporter that pumps drugs out of cells, reducing drug efficacy

Orthosteric vs allosteric sites

Orthosteric = active site; allosteric = different site that modulates activity

Sulfonamide mechanism of action

Inhibits dihydropteroate synthase (folate synthesis)

Effect of increased PABA on sulfonamides

Decreases drug effectiveness due to competitive inhibition

Transition state analogs

Mimic high-energy transition state; bind very tightly to enzymes

Penicillin inhibition type

Irreversible (suicide inhibitor of transpeptidase)

Clavulanic acid inhibition type

Irreversible beta-lactamase inhibitor (suicide inhibitor)

Purine N atoms targeted by DNA alkylators

Typically N7 of guanine

Effect of competitive inhibition on Vmax

Vmax unchanged, Km increases

Non-competitive inhibition characteristics

Vmax decreases, Km unchanged; inhibitor binds allosteric site

Polypharmacy vs polypharmacology

Polypharmacy = multiple drugs; polypharmacology = one drug affects multiple targets

Mechanism of resistance to penicillins

Beta-lactamase production, altered PBPs, decreased permeability, efflux pumps

Antifungal class with large lactone rings

Macrolides (polyenes like amphotericin B)

Drugs targeting squalene epoxidase

Allylamines (e.g., terbinafine)

Common resistance mechanisms

Target modification, drug modification, efflux pumps

Drugs commonly showing enzymatic modification resistance

Macrolides and aminoglycosides

Vancomycin mechanism of action

Binds D-Ala-D-Ala, inhibits cell wall synthesis

Daptomycin mechanism of action

Inserts into membrane, causes depolarization and cell death

Ionized vs non-ionized drug concept

Non-ionized = more lipid soluble, better absorbed; ionized = more water soluble, less absorbed