Pharmacology - Stepensky Flashcards
What is the halflife and bioavailability of aspirin?
How is it absorbed and excreted?
How can the products of aspirin be eliminated more quickly (in the case of toxicity)?
tmax = 15-20 min
Hydrolized into salicylic acid, halflife = 3-4h, converted in the GI, blood or tissues
For >4g halflife is 15-30h (becomes zero order- can cause toxicity)
F=50%
Absorbed through the GI through passive diffusion, 80-90% bound to plasma proteins, mostly albumin
Salicylic acid is renallly excreted (10%)
Conjugated into Salicyl CoA has halflife of <3-4h, metabolized into salicyluric acid
Salicyluric acid is the major excreted form, through the kidneys
Salicylate can be eliminated faster by urinary alkalinazation with NaCo2 so pH goes from 5 to 8
What are the signs and symptoms of aspirin toxicity/ salicylism?
What is the treatment?
• headache - tinnitus - dizziness –
• hearing impairment – dim vision
• confusion and drowsiness
• sweating and hyperventilation
• nausea, vomiting
• marked acid-base disturbances
• hyperpyrexia (extremely high fever)
• dehydration
• cardiovascular and respiratory collapse,
coma convulsions and death
Treatment:
• decrease absorption - activated charcoal,
emetics, gastric lavage
• enhance excretion - alkalinize urine,
forced diuresis, hemodialysis
• supportive measures - fluids, decrease
temperature, bicarbonate, electrolytes,
glucose, etc…
What are the effects of selective COX2 inhibitors
What is its halflife?
Antiinflammatory (block COX2 and production of prostaglandins, prostacylcin, thromboxane)
Prevent CRC and maybe other cancers and Alzheimer’s disease
t1/2 = 11h
~2 fold lower incidence of GI adverse effects vs nonselective NSAIDs
Potential kidney and platelet toxicities, Rofecoxib has a higher risk of thrombotic events
What is the mechanism of acetaminophen?
What are its uses?
What is its dose and halflife?
How is it metabolized?
Mechanism: COX-1 and COX-2 inhibitor in peripheral tissues, and COX-3 inhibitor in the CNS
• Mechanism of analgesia action is unknown
• Antipyretic actions due to PGs inhibition in the hypothalamus
• Does not have significant anti-inflammatory effect is not considered a true NSAID
Indication: mild pain
• Effective as NSAIDs for pain relief in RA patients
• Combined with NSAIDs can reduce the dose in RA with out loss of overall analgesic efficacy while reduce GI toxicity
• Dose - every 6 hrs, with 4 g max daily dose
• tmax= 30-60 min, t1/2= 2-3 h
How is acetaminophen metabolized and what are its toxicities?
Major pathway is through glucuronidation(40-60%), sulfation (20-40%) and N-hydroxylation to NAPQI and GSH conjugation to glutathione, cysteine, mercapturic acid conjugates(~4%m through CYP2D6 which is a free radical toxic compound and CYP1A2 which are high in smokers)
• delayed toxicity due to gradual formation of NAPQI & depletion of glutathione stores (4-6 hr asymptomatic, max toxicity at 48-96 hr)
NAPQI production is increased in:
• CYP2D6 extensive and ultrarapid metabolizers
• intake of excessive doses of paracetamol
• chronic intake of ethanol (depletion of glutathione stores & induction of CYP2E1)
• NAPQI interacts with nucleophilic sites of proteins & nucleic acids leading to liver necrosis
• N-acetylcysteine (Parvolex®, Mucomyst®) is used as antidote for paracetamol poisoning (up to 3-4 days)
What classification of drug is methotrexate?
What is the method of action?
How is it metabolized?
What are its indications/contraindications?
What is its proposed mechanism, especially in Rheumatoid Arthritis?
Antimetabolite Disease-Modifying Antirheumatic Drug (DMARD)
- plasma protein binding ~50-60%. Possible interaction with NSAIDS and aspirin (not at low MTX doses used in RA)
- uptake through folate transport system
- higher affinity for DHFR than does FH2
- depletion of FH4 in cell → depletion dTMP → “thymine-less death” → inhibits DNA & RNA synthesis
- intracellular MTX metabolites (polyglutamate derivatives) are formed and retained for weeks → long duration of action
- low lipid solubility → does not readily cross the BBB
Indications (at low doses)
• rheumatoid arthritis (1st choice- remission in 30%)
• psoriatic arthritis
• juvenile rheumatoid arthritis
• Crohn’s disease
• psoriasis
• systemic lupus erythematosus
Indications (at high doses)
• cancer
• immunosuppressive agent in allogeneic bone
marrow and organ transplantation
• in combination with PGs: induces abortion
Contraindications:
• pregnancy
• nursing
• renal failure or renal infections
• chronic liver disease
• immunodeficiency
• inhibition of T cell proliferation via suppressed purine and pyrimidine metabolism
• inhibition of transmethylation reactions required for the T cell cytotoxicity
• interference with glutathione metabolism leading to alterations in recruitment of monocytes and other cells to the inflamed joint
• promotion of the release of the endogenous adenosine
– anti-inflammatory mediator, a potent inhibitor of stimulated neutrophil function
– inhibits the production of proinflammatory cytokines such as TNF-alpha, IL-6 and IL-8
MTX in RA:
• favorable efficacy and toxicity profile (safe at low doses)
• rapid onset and offset of action
• immunosuppressive and anti-inflammatory properties.
• superior to: gold, penicillamine, azathioprine, and cyclosporine
How often is methotrexate administered? How?
What is the halflife of methotrexate?
How is it excreted? How is this excretion inhibited?
What are adverse effects of methotrexate?
What is an antidote to methotrexate and how does it work?
How is methotrexate monitored?
- Once a week 7.5-20 mg
- PO (F = 40-100%), IM, or SC (self-injections in some countries)
- plasma protein binding ~50-60%. Possible interaction with NSAIDS and aspirin (not at low MTX doses used in RA)
- t1/2= 6 hr
- Substrate of hepatic aldehyde oxidase to form 7-hydroxymethotrexate
- MTX and its metabolites are excreted by kidney by glomerular filtration and proximal tubular secretion
- MTX renal clearance can be inhibited by organic acids, sulfonamides, salicylates
- Low-dose MTX: Modest decline in renal GFR and tubular function
- High-dose: in chemotherapy, MTX precipitates in renal tubules and may cause renal failure
- Low-dose MTX: HSV, Nocardia, Pneumocystis carinii, fungal infections, Cryptococcus have been reported-acquisition or latent resurgence
- Patients treated with MTX should receive vaccinations, including influenza and pneumococcal vaccines
- Transient but reversible oligospermia
- Reversible impotence
- Teratogenicity (but not carcinogenicity): discontinue MTX before conception: women - 30 days, men - 90 days
Leucovorin, (folinic acid, not a chemotherapy drug)- does not require DHFR for its bioconversion
Uses:
• an antidote to methotrexate to rescue
bone marrow and gastrointestinal mucosa cells from the drug in high doses
• supplemental folic acid, 1 mg/day, 24 hrs after MTX dose reduces toxicity without affecting efficacy of the treatment
Before treatment:
• Blood count Chest radiology
• Hepatitis B and C serology in high risk patients, general infection background
• Transaminase enzymes (ALT, AST, AP)
• Renal function, urea, creatinine
During treatment:
Complete blood count, AST (inflammation), albumin and creatinine should be tested every 4-8 weeks of treatment, kidney and liver monitoring
Caution with diuretics administration (renal function)
Trimethoprim-sulfamethaxozole should be avoided because of possible increase risk of hematologic toxicity with MTX
What are the biological DMARDs (Disease-Modifying Antirheumatic Drugs)?
What diseases are they used in?
What are possible limitations?
TNF antagonists (on separate flashcard)
IL inhibitors:
- Leflunomide (Arava®): antimetabolite, inhibits IL-2 stimulated T-cells, given p.o., daily
- Anakinra (Kineret®): IL-1 receptor antagonist, s.c., daily
- Toclizumab: Anti IL-6, binds to membranous and soluble receptors of IL-6, given q1mo. via IV, prevents fatigue and anemia, but immune modulatory activity may increase chance of infection, induce leukopenia and alter LFTs
Depletion of B lymphocytes:
• Rituximab (Rituxan®): monoclonal Ab against CD20, antineoplastic agent, signals B-cell apoptosis, IV infusion once yearly or 6 months depending on disease activity.
Immune synapse inhibitors:
• abatacept binds to CD80/86 on DC and inhibits T-cell costimulation, blockes second connection betwen T-cells and macrophages via CD28, more effective for RA with MTX, used after one failure of TNFi
• efalizumab blocks CD11a (LFA-1) from binding to ICAM-1, inhibiting T-cell adhesion, migration, and activation
• alefacept inhibits activation of T cells by blocking the interaction of LFA-3 & CD2
• ipilimumab - can lead to T-cell activation by blocking CTLA-4
Cyclosporine (and Tacrolimus):
What is their drug classification?
What is their mechanism of action?
How are they administered?
What is their halflife?
What conditions are they used in?
What are frequent side effects?
What drugs does it interact with?
What parameters should be monitored?
DMARDs (Disease-Modifying Antirheumatic Drugs ): calcineurin inhibitors (thus inhibiting NFATc - nuclear factors of activating T cells and cytokine transcription)
Administered orally, substrate to CYP3A4 and Pgp so large first-pass effect and variability, needs to be titrated, inhibited by grapefruit juice
t1/2 = 5-18h in adults, steady state 2-3 days after dose change
Only 25% reaches T-cells
- binds to cyclophillin which binds to calcineurin → inhibit NFATc activation→ block T cells signaling → suppress IL-2 release
- also inhibits: IL-1 & IL-2 receptor production, macrophage-T cell interaction, T cell responsiveness, T cell-dependent B cell function
- is used in solid organ transplantation (kidney, heart, etc.) and in graft-versus host syndrome in bone marrow transplants
- in severe cases of: psoriasis, RA, and related diseases
- side effects are frequent: nephrotoxicity, hepatoxicity, hirsutism, gingival hyperplasia, hyperlipidemia
Drug interactions:
• Rifampin, phenytoin, carbamazepine, …→ induction of CYP3A4 → decrease in CsA
• erythromycin, clarithromycin, verapamil, … → inhibit CYP3A4 → increase in CsA
Monitoring parameters:
• cyclosporine trough blood levels but after 4 days so levels off
• serum electrolytes
• renal function
• hepatic function
• blood pressure
• serum cholesterol
What is the treatment of gout?
(Distinguish between prevention and acute attacks)
What is the method of administration of each drug?
What is the drug of choice long term? What is its halflife? What is its mechanism of action?
What is the only drug which treats both preventatively and in acute attacks? What is its mechanism? What is its halflife? How is it excreted? Who is this different for? What are its adverse effects?
Antiinflammatory – used in acute attack:
• colchicine – inhibits mobility of granulocytes and
decreases the inflammatory response
• NSAIDs - symptomatic relief, some are uricosuric
• corticosteroids (prednisone), PO or injected into
joint for enhanced effect (short-term use for 10-14
days is not likely to cause major problems).
Uric acid-lowering therapy - chronic:
• Uricosuric drugs: probenecid, sulfinpyrazone
• Inhibition of uric acid synthesis: allopurinol,
febuxostat
Probenecid:
- Increases elimination in the nephron
- Can’t be used in renal failure, increases renal stones
Allopurinol:
• drug of choice in long- term treatment of gout, but not of acute attack
• analogue of hypoxanthine → competitive inhibitor of xanthine oxidase →reduced synthesis of uric acid
• also, xanthine oxidase converts allopurinol to oxypurinol, which is a noncompetitive inhibitor of the enzyme
• good PO absorption, t1/2= 2-3 hr; oxypurinol t1/2= 18-30 hr
• most of the action of allopurinol is due to oxypurinol
• can be used in renal failure
• probenecid can reduce renal tubular reabsorption of oxypurinol; still probenecid-allopurinol coadministration is beneficial
Colchicine:
-oral (absorbed both before and after the GI tract) or IV administration
-binds to tubulin and interferes with the function of the mitotic spindles & microtubules in granulocytes and other motile cells → inhibits:
• neutrophils motility and migration of granulocytes into the inflamed area
• release of chemotactic factors, metabolic & phagocytic activity of granulocytes
also:
• inhibits the release of histamine-containing granules from mast cells
• inhibits secretion of insulin from beta cells of pancreatic islets (so can’t be used in metabolically instable patients)
• lowers body temperature
• colchicine does not influence the synthesis or renal excretion of uric acid or its concentration in blood
• rapidly absorbed after oral administration; t1/2
= 10 hr
• 10% to 20% is excreted in the urine; most of the drug is excreted in the feces
• dosage should be lowered in renal and hepatic impairment
• the elderly are more sensitive to the drug
• Inhibits proliferation of epithelial cells in the GI tract: nausea, vomiting, diarrhea, and abdominal pain are the most common and dose-limiting (diarrhea, in 50 80% of patients); can be avoided by IV administration
• In acute poisoning: GI hemorrhagic, extensive vascular damage, nephrotoxicity, muscular depression, paralysis of the CNS
• Long-term use: risk of agranulocytosis, aplastic anemia, myopathy, and alopecia and reversible azoospermia
Whatdo TNF antagonists do?
What are they and where do they act?
Inhibit TNF production
Etanercept (Enbrel), Infliximab (Remicade),
Adalimumab (Humira)
Retard radiographic progression of joint damage
Regulate also IL- 1 and IL- 6 production
Anti-TNFα agents:
• Adalimumab (Humira®); human mAb, SC q 2 weeks
-Low immunogenicity, ~5% of patient develop neutralizing Ab
-Used in rheumatoid arthritis (combined with MTX), psoriasis, psoriatic arthritis, Crohn’s disease, other autoimmune
-Must be used for life, and high cose. May incrase risk for opportunistic infections
• Infliximab (Remicade®); chimeric mAb, IV q 2 months
• Etanercept (Enbrel®); soluble receptor fusion protein (TNF receptor Fc domain of IgG-dimer), SCx2/week, doesn’t reactivate TB as much
