Analgesics

Question 1

Paracetamol / Acetaminophen

Answer 1

• non-opioid analgesic, kein NSAID
• non-acidic, mild analgic, stark antipyretic, NOT antiphlogistic (insoluable in inflamed tissues)
• MOA: unklar, hypotheses:
  + inhibition of COX biosynthesis in CNS
  + modulation of TRPV1 / endocannabinoid system
  ► IND: mild/moderate pain, fever
  + 1st line medication in pregnancy (does not affect closure of fetal DA)
  ► CI: hepatic insufficiency, regular alcohol consumption
  ► ADR: not relevant in therapeutic doses (esp: NOT ulcerogenic!) but: dose-dependent hepatotoxicity!

Question 2

Acetyl Salicylic Acid (ASA)

Answer 2

NSAID (analgic, antipyretic, antiphlogistic)
► MOA: non-selective & irreversible COX-1 + 2 inhibition, in low doses only COX-1
► IND: - mild/moderate pain, fever
- antiplatelet therapy (platelet aggregation inhibition): 75-100 mg/d
(eventuell prevention of colorectal cancer, if taken > 10 years, but higher bleeding risk)
► CI:
- active gastric/duodenal ulcers
- children < 16 yrs (risk for Reyes Syndrome)
- pregnancy (prenatal closure of fetal ductus arteriosus)
- asthma
- gout (inhibition of renal urate excretion)

Question 3

Diclofenac

Answer 3

NSAID (analgic, antipyretic, antiphlogistic)
► MOA: non-selective COX-Inhibition, mehr COX-2 als COX-1
► IND: - mild/moderate pain, fever
► CI: - active gastric/duodenal ulcers
- pregnancy
- asthma
► ADR: - gastric & duodenal ulcers
(with PPI if administered for several days or at high doses!)

Question 4

Ibuprofen

Answer 4

NSAID (analgic, antipyretic, antiphlogistic)
► MOA: non-selective COX-Inhibition, mehr COX-1 als COX-2
► IND: - mild/moderate pain, fever
► CI: - active gastric/duodenal ulcers
- pregnancy
- asthma
- IBD might be worsened
► ADR: - gastric & duodenal ulcers
(with PPI if administered for several days or at high doses!)
- ibuprofen: highest risk of stroke of all NSAIDs

Question 5

Metamizole

Answer 5

anti-opioid: analgic, antipyretic, spasmolytic, but not antiphlogistic → eigentlich kein NSAID
► MOA: unknown, but COX-Inhibition in CNS + Peripherie → strongest potential of all NSAIDs / non-opioids
► IND: - moderate/severe pain, renal colic
- fever (2nd line)
► CI: - impaired bone marrow function
► ADR:
- less GI, renal, hepatic & cardiovascular ADR than any other NSAID
- but: agranulocytosis (Antibodies against metamizole-binding granulocytes)

Question 6

COX-Inhibitors

Answer 6

MOA:
inhibition of cyclooxygenases 1 (and/or) 2
→ reduced activation of peripheral nociceptors
- COX-1 (constitutive)
- COX-2 (inducible)
They metabolize arachidonic acid to PG-E2 & PG-I2. These PG do not directly activate nociceptors, but sensitise nociceptors to pain mediators!

ADR: ceiling effect (ab bestimmter Dosis: increased ADR without increased pain relief)
- gastrointestinal ADR: gastric & duodenal ulcers, GI bleedings
why? 1) topic acidic effect 2) less NO: mucosal ischemia 3) inhibition of PG-E2 synthesis: less mucus, less HCO3-
- ethanol verstärkt effect of topical acidity + hepatic sythesis of blood clotting factors is reduced = higher bleeding risk

Question 7

Coxibs

Answer 7

• selective COX-2-Inhibition
• Beispiele: Etoricoxib, Celecoxib
• da mehr COX-2 als COX-1 gehemmt wird: higher risk for stroke and myocardial infarction (COX 2 verursacht Vasodilation, COX-1 Vasoconstriction → wenn überwiegend COX-2 Produkte wegfallen, vermehrt Vasoconstriktion)

Question 8

Opioids

Answer 8

MOA: agonism at μ-opioid receptor (MOR)
→ inhibitory G-protein coupled receptor
→ activation of Giα subunit → reduced activity of adenylylcyclase → lower [cAMP] → zusätzlich more activation of hyperpolarising K+ channels
→ generation of action potential is impeded

Effect: via CNS μ-opioid receptors

• analgesia (cerebral cortex)
• respiratory depression (respiratory centre)
• cough suppression (cough centre)
• emetic/antiemetic (stimulation/inhibition of CTZ)
• hypothermia (hypothalamus)
• miosis (activation of the Edinger-Westphal-nucleus) = kleine Pupillen
• hypotension (baroreceptors)
• bradycardia (activation of the Nervus vagus)
• sedation (dopamine-liberation in limbic system)
• euphoria (dopamine-liberation in Nucleus accumbens)
  (but: only “quick peaks“ cause euphoria = no euphoria due to TTS or oral retard formulations)

Effects via peripheral μ-opioid receptors

• analgesia (reduced sensitivity of nociceptors to pain mediators)
• delayed gastric emptying + Spastic constipation (smooth muscle cells)
• urinary retention (contraction of the sphincter vesicae)

Question 9

Opioids examples

Answer 9

Opiates: natural alkaloids / extracted from raw opium
(morphine + codeine)
Opioids: (semi)synthetic derivatives (Fentanyl, Heroin)

weak (schwächer als Morphin):
- Codeine
- Tilidine
- Tramadol
strong (Morphin und stärker):
- Methadone
- Fentanyl
- Oxycodone