Pharmacology: Drug Resistance, Desensitization, Adverse Effects, and Toxicity

Vocabulary flashcards covering drug resistance mechanisms, transport proteins, HIV pharmacogenomics, tolerance, dependence, desensitization, drug toxicity, adverse reactions, and medication errors.

Drug Resistance

The development of a reduced drug response, leading to insensitivity or reduced sensitivity to specific therapeutic agents in conditions such as cancer or microbial infections.

Primary Causes of Drug Resistance

The five main mechanisms by which cells develop reduced drug responsiveness: increased efflux, decreased uptake, drug inactivation, mutations in the drug target, and reversal of drug action.

MDR1 (ABCB1 / P-glycoprotein)

An ATP-dependent efflux transporter belonging to the ABC superfamily that actively extrudes a wide range of hydrophobic neutral or cationic compounds out of cells, contributing to multidrug resistance.

Membrane Topology of ABC-Transporters

Structural arrangements of ABC transport proteins including (a) 2 transmembrane domains and 2 NBDs (e.g., MDR1), (b) 3 transmembrane domains and 2 NBDs (e.g., MRP1, MRP2), and (c) 1 transmembrane domain and 1 NBD (e.g., BCRP).

Transporter Proteins

Complex membrane carrier proteins that transport molecules across cell membranes without damaging the membrane, operating at a flux rate of approximately $1 \times 10^6\,\text{molecules/second}$, which is significantly slower than ion channels.

Ion Channel Selective Filter

A narrow region of an ion channel lined with polar groups where only specific atomic ions of appropriate size and charge can pass, enabling passive transport rates up to approximately $1 \times 10^8\,\text{ions/second}$.

Nicotinic Receptor

A ligand-gated ion channel composed of subunits where binding of two acetylcholine (ACh) molecules—one on each $\alpha$ subunit—triggers a conformational change that opens the pore and allows $Na^+$ influx into skeletal muscle cells.

Solute Carrier OCT Family

Uptake transporters comprising OCT and OCTN families with 11–12 transmembrane domains that mediate organic cation uptake in organs such as the liver, kidneys, and brain.

Solute Carrier OAT/OATP Family

Uptake transporters with 8–12 transmembrane domains responsible for uptake of organic anions, bile acids, and conjugated metabolites in tissues including the liver, kidneys, and blood-brain barrier.

Blood-Brain Barrier Substrate Pathways

Four major trans-endothelial routes across the BBB for endogenous and exogenous molecules: (A) transcellular lipophilic pathway, (B) transport proteins, (C) receptor-mediated endocytosis, and (D) adsorptive endocytosis.

Enzymatic Hydrolysis Resistance

A drug inactivation mechanism wherein enzymes such as $\beta$-lactamase hydrolyze essential chemical structures (e.g., the $\beta$-lactam ring) to render antibiotics ineffective.

Glutathione Transferase

An antioxidant defense enzyme that detoxifies peroxides and reactive oxygen species, elevated levels of which can cause drug resistance by neutralizing oxidative drug damage.

CYP3A4 Tumor Oxidation

Overexpression of hepatic and extrahepatic cytochrome P450 3A4 in tumor cells, which inactivates chemotherapeutic drugs such as etoposide, ifosfamide, cyclophosphamide, and doxorubicin.

Cyclophosphamide Metabolic Pathway

The enzymatic biotransformation of cyclophosphamide (CPA) by CYP enzymes into active 4-hydroxy CPA and aldophosphamide (yielding phosphoramide mustard and acrolein), alongside competing inactivation pathways leading to N-dechloroethyl CPA, 4-keto CPA, and carboxy CPA.

BCR-ABL T315I Mutation

A point mutation in the gatekeeper residue threonine 315 of the BCR-ABL kinase domain that confers resistance in Chronic Myelogenous Leukemia (CML) to first-line kinase inhibitors such as imatinib, nilotinib, and dasatinib.

BCL-2 Family Proteins

A group of over 25 pro-apoptotic (e.g., BAX, BAK) and pro-survival (e.g., BCL-2, BCL-XL, MCL-1, BCL-W) regulators of programmed cell death whose balance determines cellular susceptibility to apoptosis.

BH3 Domain Mimetics

Therapeutic agents designed to neutralize anti-apoptotic BCL-2 family proteins by mimicking the BH3 domain of pro-apoptotic proteins, thereby overcoming apoptotic drug resistance.

MGMT ($O^6$-Alkyl Guanine DNA Alkyl Transferase)

A DNA repair protein that protects cells from alkylating agents by directly removing alkyl groups from the $O^6$ position of guanine; its depletion or inhibition can overcome cancer cell resistance to alkylating chemotherapy.

Bacterial Conjugation

A mechanism of genetic transfer in bacteria involving direct cell-to-cell contact through which drug resistance genes are transferred between bacterial cells.

HAART (Highly Active Anti-Retroviral Therapy)

An HIV treatment strategy combining two to three nucleoside analogs with one or two protease inhibitors or one reverse transcriptase inhibitor to suppress viral replication.

HIV Genome and Polyproteins

The genetic organization of HIV comprising 9 genes that code for 16 proteins, including structural core proteins from gag (p18, p24, p17), viral enzymes from pol (P10 protease, P66/51 reverse transcriptase/nuclease, P31 integrase), and envelope proteins from env (gp120, gp41).

Desensitization

The temporary, agonist-induced reduction in receptor responsiveness over time despite the continuous presence of the agonist, typically rapidly reversible upon removal of the ligand.

Vagal Escape

A compensatory physiological reduction in vagal bradycardia caused by muscarinic receptor desensitization in heart sinoatrial node cells following continuous exposure to acetylcholine or vagal stimulation.

Pharmacokinetic Tolerance

A type of drug tolerance caused by accelerated drug metabolism, disposition, absorption, or excretion, reducing the concentration of active drug at its target site over repeated administration.

Cross-Tolerance

A phenomenon in which tolerance developed to a specific drug confers an elevated tolerance to other drugs within the same or similar pharmacological classes.

Physical Dependence

An altered physiological state resulting from repeated drug exposure that necessitates the continued presence of the drug to maintain normal function and prevents a withdrawal syndrome.

Withdrawal Syndrome

An abstinence syndrome characterized by physiological disturbances that occur upon abrupt discontinuation or dose reduction of a drug to which physical dependence has developed.

Philadelphia Chromosome

A diagnostic genetic abnormality resulting from a reciprocal translocation between chromosomes 9 and 22 ($\text{t}(9;22)$), forming the $BCR\text{-}ABL$ fusion gene that drives Chronic Myelogenous Leukemia (CML).

Side Effect

A secondary response distinct from the primary intended therapeutic action of a drug, which may be beneficial, neutral, or harmful, and can share or differ in molecular mechanism from the main target.

Adverse Effect

A harmful, unintended, and undesirable consequence of a drug that occurs at normal therapeutic doses used for prophylaxis, diagnosis, or therapy.

Finasteride

An inhibitor of type II $5\alpha$-reductase that blocks the conversion of testosterone to dihydrotestosterone (DHT), marketed at lower doses for male-pattern baldness (Propecia) and higher doses for benign prostatic hyperplasia (Proscar).

Drug Idiosyncrasy

A quantitatively or qualitatively abnormal drug response that is genetically determined, non-immune mediated, specific, reproducible, and occurs at standard therapeutic doses.

Plasma Cholinesterase Deficiency

A genetically controlled polymorphism identified by Werner Kalow in 1956 that results in low substrate affinity for succinylcholine, leading to prolonged muscular paralysis during anesthesia.

Type I Hypersensitivity Drug Reaction

An IgE-mediated acute allergic response triggered by mast cell and basophil activation, which can manifest as urticaria, angioedema, or life-threatening anaphylaxis.

Type II Hypersensitivity Drug Reaction

An antibody-mediated drug reaction involving IgG or IgM binding to drug-modified host proteins, triggering complement-dependent lysis or antibody-dependent cellular cytotoxicity.

Teratogenesis

The induction of non-inheritable structural or developmental defects in a fetus resulting from maternal exposure to an exogenous agent during pregnancy.

Phocomelia

A severe congenital limb deformity characterized by missing or shortened limbs attached directly to the trunk, famously caused by maternal ingestion of thalidomide during the first trimester of pregnancy.

Pregnancy Category X

An FDA pregnancy risk classification indicating that studies in animals or humans have demonstrated fetal abnormalities, and the risk of using the drug in pregnant women clearly outweighs any possible benefit.

Connectivity Rule in Toxicology

The principle that agents exhibiting teratogenic potential frequently also possess mutagenic and carcinogenic properties ($\text{teratogenesis} = \text{mutagenesis} = \text{carcinogenesis}$).

Grapefruit Juice Interaction

A food-drug interaction caused by furanocoumarins in grapefruit pulp that inhibit intestinal and hepatic CYP3A4, significantly increasing systemic absorption and toxicity of drugs like felodipine and various chemotherapeutic agents.

NCC MERP Medication Error Index

A standardized categorization system ranking medication errors from Category A (circumstances with capacity to cause error) up through Category I (error resulting in patient death), classified by severity of harm and reach.