Methotrexate
- targets S-phase - inhibits metabolism of folic acid (needed for de novo sythesis of nucleotide thymidine, required for DNA synthesis) - treatment of cancer, autoimmune diseases
5-flurouracil
- targets S-phase - irreversible inhibition of thymidylate synthase (required for DNA synthesis) - treatment of cancer
Hydroxyurea
= hydroxycarbamide - targets S-phase - inhibits ribonucleotide reductase (decreases production of deoxyribonucleotides) - antineoplastic, used in myeloproliferative disorders (polycythemia vera, sickle-cell disease)
Bleomycin
- targets G2-phase - induction of DNA strand breaks - used to treat cancer (Hodgkin's disease)
Paclitaxel
- targets M phase - interferes with microtubule breakdown during cell division - treatment against cancer
Vincristine
- targets M phase - binds to tubulin protein, stopping the cell from separating its chromosomes during metaphase - treatment for cancer (ALL, AML, Hodkin's disease)
Vinblastin
- targets M phase - disrupt microtubule synthesis - treatment for cancer (Hodgkin's lymphoma)
Quinolones
- inhibit DNA gyrase (prokaryotic topoisomerase II), preventing DNA replication and transcription - most active against aerobic gram-negative bacteria - Levofloxacin- Ciprofloxacin- Moxifloxacin - current uses: treatment of gonorrhea and upper and lower urinary tract infections in both sexes
Alport disease
- improper assembly of type IV collagen - glomerulonephritis (glomerular basement membrane with "basketweave" appearance) - hearing loss - blood in urine - proteinuria
Goodpasteure syndrome
- autoimmune disease in which antibodies attack the basement membrane (collagen type IV) in lungs and kidneys - blood in urine - proteinuria
Inhibition of protein synthesis by antibiotics
- Chloramphenicol binds to the 50S rRNA and inhibits formation of a peptide bond - Erythromycin binds to the 50S rRNA and prevents movement along the mRNA (translocation) - Aminoglycosides interfere with the initation of translation - Tetracyclin blocks the attachment of tRNA anticodon to the ribosome
Nitrogen Balance
Negative balance:- protein malnutrition (kwashiorkor)- dietary deficiency of even one essential amino acid- starvation- uncontrolled diabetes- infection Positive balance:- growth- pregnancy- convalescence (recovery phase of injury or surgery)
Cyanide
- deadly poison - binds irreversibly to cytochrom a/a3 - causes tissue hypoxia - source: burning pulyurethan, byproduct of nitroprussid - antidote: nitrites (convert hemoglobin to methemoglobin, which binds cyanide in the blood before reaching the tissues)
Carbon monoxide
- binds to cytochrom a/a3 and hemoglobin, displacing oxygen - headache, nausea, tachycardia, tachypnea - lips and cheeks turn a cherry-red color - source: gas grills, vehicle exhaust, house fires
Oligomycin
- poisonous - inhibitor of the ATP synthase - created by Streptomyces
Biosynthesis steps promoted by insulin
Conversion of glucose to acetyl CoA:- glucokinase- PFK-2 (dephosphorylation)- Pyruvate dehydrogenase (dephosphorylation) Fatty acid synthesis- Acetyl CoA carboxylase (dephosphorylation)- Fatty acid synthase
Medium Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency
- severe hypoglycemia - low to absent ketones (block in ß-oxidation) - lethargy, coma, death if untreated - C8-10 acyl carnitines in blood
Associations with ketoacidosis
- Polyuria, dehydration, and thirst - CNS depression and coma - K+ depletion - decreased plasma bicarbonate - breath with sweet or fruity odor, acetone
Drugs that disrupt pyrimidine synthesis
- Leflunomide: inhibits dihydroorotate dehydrogenase - Metrotrexate (MTX), trimethoprin (TMP), pyrimethamine: inhibit dihydrofolate reductase (↓dTMP from dUMP) - 5-fluorouracil (5-FU): forms 5-F-dUMP, which inhibits thymidylate synthase (↓dTMP)
Drugs that disrupt purine synthesis
- 6-mecaptopurine (6-MP) and its prodrug azathioprine. inhibit de novo purine synthesis - Mycophenolate and ribavirine: inhibit IMP dehydrogenase (↓GMP)
Drugs that disrupt purine and pyrimidine synthesis
Hydroxyurea: inhibits ribonucleotide reductase
Defects in DNA repair
Nucleotide excision repair --> Xeroderma pigmenosum Mismatch repair --> Lynch syndrome Nonhomologous end joining --> Ataxia telangiectasia, Fanconi anemia
Ethanol metabolism
↑ NADH/NAD+ ratio in liver causing:- Pyruvate --> lactate (lactic acidosis)- DHAP --> Glycerol 3-P (combines with fatty acids to make triglycerides --> hepatosteatosis) - disfavors TCA production of NADH --> ↑ utilization of acetyl-Coa for ketogenesis (--> ketoacidosis)
Glycogen storage diseases
1. Von Gierke disease (type I)- Glucose-6-phosphatase deficiency- severe fasting hypoglycemia- ↑ glycogen in liver, ↑ blood lactate, ↑ triglycerides, ↑ uric acid 2. Pompe disease (type II)- Lysosomal α-glucosidase deficiency- Cardiomegaly, exercise intolerance 3. Cori disease (type III)- Debranching enzyme (α-1-6-glucosidase) deficiency - mild form of von Gierke- gluconeogenesis is intact 4. McArdle disease (type V)- skeletal muscle glycogen phosphorylase deficiency- blood glucose levels unaffected- muscle cramps, myoglobinuria (red urine)- second-wind phenomenon due to ↑ muscular blood flow
