Analgesics and NSAIDs Flashcards

Question

Which of the following statements regarding Naloxone is false? A Naloxone has equal affinity for mu, kappa and delta receptors B Tolerance to naloxone does not develop C Naloxone is a pure antagonist D Intravenous administration reverses opioid effects in 1-2min

Answer 1

A Explanation Naloxone is a pure antagonist. It has a very high affinity for mu receptors and a lower affinity for the other receptor binding sites but can also reverse agonists at deltas and kappa sites. Naloxone has a half life of 1-2 hours when given by injection and 10 hours when taking via the oral route. Although naloxone is well absorbed via the oral route it undergoes rapid first pass metabolism. IVI administration reverses opioid toxicity in 1-3 minutes. There is no tolerance to the antagonistic action of these agents, nor does withdrawal of naloxone after chronic administration precipitate an abstinence syndrome Have a better explanation? Submit your own

Answer 2

A Explanation Peak blood concentration of acetaminophen following oral route is usually achieved in 30-60min. IVI route takes 15min, however the analgesic effect does not last as long via the IVI route

Answer 3

D Explanation The opioids are largely converted to polar metabolites (mostly glucuronides), which are then excreted by the kidney. 10% of morphine is metabolised to morphine 6 glucuronide, an active metabolite with 4-6x the potency of its parent compound. Note, these metabolites are not readily able to cross the blood brain barrier and do not contribute to the significant CNS effects that are seen with morphine. Nevertheless accumulation of these metabolites can produce unwanted side effects in patients with renal failure and when large doses of morphine are given over long periods. Although both heroin and remifentanil are metabolized by blood and non-specific tissue esterases, they do not result in the same metabolites. Heroin is ultimately metabolized to morphine (which then undergoes hepatic metabolism), whereas remifentanil is metabolized to a carboxylic acid derivative (remifentanil acid) which is excreted by the kidneys. Hepatic oxidation is the prime route of degradation for the phenylpiperidine opioids (remifentanyl, fentanyl, alfentanyl, and sufentanyl). This leaves only a small amount of parent drug for renal excretion. There are no active metabolites of fentanyl Codeine, oxycodone and hydrocodone undergo hepatic metabolism by the P450 system resulting in metabolites of grater potency.

Answer 4

A Explanation Ibuprofen in doses of 2.4g a day are anti-inflammatory. Doses less than this are analgesic and not anti-inflammatory. Indomethacin at normal doses cause the usual GIT side effects including pancreatitis. Naproxen’s incidence of GIT bleeding is double that of ibuprofen Ketoprofen is not superior to other NSAIDS in clinical effectiveness. GIT complications are common Aspirin causes about double the gastric ulcers as compared to ibuprofen at normal doses Extra: The relative risk of upper gastrointestinal complications for aceclofenac, celecoxib and ibuprofen is low (<2). Diclofenac, meloxicam and ketoprofen are intermediate (2–4) while naproxen, indomethacin and diflunisal have a higher relative risk (4–5). The highest pooled relative risk is associated with piroxicam (7.4) and ketorolac (11.5). Source: Peptic ulcer disease and non-steroidal antiinflammatory drugs. Dirini M et al

Answer 5

B Explanation Renal clearance of lithium is reduced by 25% with thiazide diuretics and the dose may need to be reduced by a similar amount. A similar reduction occurs with the newer NSAIDS. There is no issue with Aspirin however. Paracetamol is also safe. All neuroleptics with the possible exception of clozapine may produce more severe extrapyradimal side effects when combined with lithium NSAIDs. This includes every drug in the non-steroidal anti-inflammatory drug category except Aspirin and Sulindac. If you have a patient on Lithium who is taking significant ongoing doses of ibuprofen, indomethicin, naproxen, or even the new Cox-2 inhibitors such as Celebrex, more aggressive monitoring of Lithium levels is warrented. Lithium level can double. The mechanism is not entirely clear, but may relate to the inhibition of prostaglandins leading to interference with Lithium excretion. Extra: Textbook list Important drug interactions with lithium ACE inhibitors- decreased renal clearance (RC) Angiotensin II blockers - decreased RC Diuretics (thiazides)- decreased RC Haloperidol- occasional neurotoxicity Methyldopa- increased risk of neurotoxicity NSAIDS- decreased RC Theophylline- increased RC with reduced effect of Lithium

Answer 6

B Explanation Tramadol is a centrally acting analgesic whose main mechanism of action is blockade of serotonin reuptake. Because it is only partially reversed by Naloxone, it is believed to be a weak mu-receptor agonist. Toxicity includes an association with seizures. Another risk is the development of serotonin syndrome, especially if SSRI are being administered,

Answer 7

A Explanation Hepatic oxidative metabolism is the primary route of degradation of the phenylpiperidine opioids (fentanyl) and eventually leaves only small quantities of the parent compound unchanged for excretion. No active metabolite of fentanyl has been reported. Source: medscape Recommendations for Opioids in Renal Impairment Opioid Recommended Use Codeine - Not recommended due to accumulation Fentanyl - Appears safe, but renal dosage adjustment may be necessary Hydrocodone/oxycodone - Use cautiously; adjust dosage Hydromorphone - Use cautiously; adjust dosage Methadone - Appears safe; however, renal dosage adjustment may be necessary Meperidine - Not recommended due to metabolites Morphine - Not recommended due to metabolites Tramadol - Not recommended

Answer 8

A Explanation Celecoxib, meloxicam, ( rofecoxib, valdecoxib-removed from the market) Cox-2 inhibitors have analgesic, antipyretic and anti-inflammatory effects similar to those of the non-selective NSAIDS but with an approximate halving of the gastro-intestinal adverse effects. Cox 2 inhibitors at usual dose do no inhibit platelet aggregation; in contrast they do inhibit prostacyclin synthesis in vascular endothelium. As a result COX-2 inhibitors do not offer the same cardio protective of the traditional nonselective NSAIDs, which has resulted in some patients taking a low dose aspirin in combination with a COX-2 regimen to maintain this effect,

Answer 9

D Explanation According to oral:parenteral potency ratio Morphine: low Fentanyl: low Hydromorphone: low Hydrocodone: medium Oxycodone: medium Codeine: high Certain analgesics such ads codeine and oxycodone are effective orally because they have reduced first pass metabolism. Morphine is extensively metabolised visa the oral route, making the oral dose requirements much higher than the parenteral dose to elicit a therapeutic effect. Not a great question but based on a recall- so left as is other sources: A: Like codeine, oxycodone retained at least 1/2 of its analgesic activity when administered orally. We hypothesize that the high oral/parenteral relative potency ratios of codeine and oxycodone relative to morphine and its congeners are not due to more efficient absorption after oral administration, but rather that methylation at position 3 in codeine and oxycodone protects these drugs from rapid first-pass metabolism. Source J Pharmacol EXp Ther 1978 Oct;207(1):92-100. B: Analgesic studies of codeine and oxycodone in patients with cancer. I. Comparisons of oral with intramuscular codeine and of oral with intramuscular oxycodone. Codeine, in contrast to morphine, is two-thirds as effective orally as parenterally, both as an analgesic and as a respiratory depressant. It has therefore a highly oral-parenteral potency ratio (due to lower first-pass metabolism in the liver) (Goodman & Gilman, 1985). www.inchem.org

Answer 10

A Explanation Source: https://litfl.com/pharm-101-paracetamol/

Answer 11

A Explanation Source: https://litfl.com/pharm-101-morphine/

Answer 12

B Explanation Potency is defined as the dose required to produce 50% of the drug’s maximal effect. Fentanyl is usually given in the dose range 25-100mcg, compared to 2.5-10mg for morphine, 2.5-5mg for oxycodone, and buprenorphine 200-400mcg Source: https://litfl.com/pharm-101-fentanyl/

Answer 13

D Explanation Partial agonist: Produce a lower response when all receptors are occupied compared to full agonists. (out of TB: partial agonists produce a lower response , at full receptor occupancy , than do full agonists). Produce concentration-effect curves resembling those with a full agonist in presence of a non-competitive antagonist (i.e. reduced Emax). Competitively inhibit responses produced by full agonists e.g. buprenorphine and morphine can reduce analgesia and induce withdrawal symptoms if given to opioid-dependent patients.

Answer 14

C Explanation Tramadol, buprenorphine and methadone are opioid agonists. Naltrexone is a mu receptor antagonist.

Answer 15

A Explanation Aspirin toxicity causes “salicylism”, with features of hyperthermia, fever and vomiting accompanying headache, tinnitus, and dizziness. Source: https://litfl.com/pharm-101-aspirin/

Answer 16

B Explanation In overdose, glucuoronidation and sulphation pathways are saturated and paracetamol is broken down by phase I hydroxylation reaction which forms NAPQI (N-acetyl-pbenzoquinone imine). More NAPQI is formed, depleting glutathione stores and eventually causing accumulation of this toxic metabolite

Answer 17

D Explanation The preferred and standard of care therapy for gout during the period between acute episodes is allopurinol, which reduces total uric acid body burden by inhibiting xanthine oxidase.

Answer 18

A Explanation The incidence of upper GI bleeding in over-the-counter Naproxen use is low but still double that of over-the-counter ibuprofen (perhaps due to a dose effect). Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic Meloxicam inhibits COX-2 over COX-1. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen The provided text states that celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. It also indicates that meloxicam is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. However, a direct comparison of celecoxib and meloxicam in terms of GI upset is not explicitly provided. Source: Katzung pharmacology 15ed

Answer 19

A Explanation Aspirin is not a COX-2 inhibitor; it's a non-selective COX inhibitor. While it irreversibly inhibits COX enzymes, this action is not specific to COX-2; it affects both COX-1 and COX-

Answer 20

B Explanation All NSAIDs, including aspirin, are about equally efficacious with a few exceptions-Tolmetin seems not to be effective for gout, and aspirin is less effective thanother NSADIS for ankylosing spondylitis. Therefore, NSAIDS tend to be differentiated on the basis of toxicity and cost effectiveness. Some surveys suggest that indomethacin and tolmetin are the NSAIDs associated with the greatest toxicity, while aspirin and ibuprofen are least toxic. The selective COX2 inhibitors were not included in these surveys. For patients with renal insufficiency, nonacetylated salicylates may be best. Diclofenac and sulindac are associated with more liver function test abnormalities than other NSAIDs. The relatively expensive selective COX-2 Inhibitor celecoxib is probably safest for patients at high risk of GI bleeding but may have a higher risk of cardiovascular toxicity.: in this subpopulation of patients, they aremore cost effective despitetheirhighacquisition costs. The choice of NSAIDS thus require a balance of efficacy., cost effectiveness, safety and numerous personal factors (eg other drugs being used, concurrent illness, compliance) so that there is no best NSAID for all patients. There may be one or two best NSAIDS for a specific person Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. However, it also notes that the older NSAIDs (compared to celecoxib) have a correlation between the amount of enterohepatic circulation and the degree of GI irritation. The TB also mentions that newer NSAIDs, as a group, tend to cause less GI irritation than aspirin