week 3 NSAID pharma

Morphini hydrochloridum (Morphine)

Full agonist of opioid receptors.

Mechanism of action of all opioids:
Opioid receptor agonist causes
-presynaptic Ca2+ blockage (inhibiting NT release)
-postsynaptic K+ channels opening (K+ leaves; hyperpolarization, excitability down)

Binds primarily to μ (mu)-receptor (but also delta & kappa)
Analgesia (supraspinal + spinal)
Respiratory depression
Pupil constriction (miosis)
Reduced GI motility (+decreased gastric, biliary, pancreatic secretion)
Euphoria
Sedation

peripheral vasodilation and hypotenstion due to histamine release

Main side-effects of opioids:
-respiratory depression
-tolerance (increase dose gradually to produce an effect)
-addiction (propensity to use)
-abstinence (pain, epileptic seizures after discontinuation)

nausea, vomiting, suppresion of cough reflex, miosis, constipation, bradycardia, hypotension, itching, urinary retention, less bile-flow, muscle rigidity, euphoria

Indications:
Relief of traumatic pain, postoperative pain (multimodal analgesia), tumor-induced pain (baseline pain), congestive heart failure (CHF) with pulmonary edema (morphine only).

Fentanyl

Full agonist of opioid receptors.
100-150x stronger than morphine!

Mechanism of action of all opioids:
Opioid receptor agonist causes
-presynaptic Ca2+ blockage (inhibiting NT release)
-postsynaptic K+ channels opening (K+ leaves; hyperpolarization, excitability down)

Binds primarily to μ (mu)-receptor (also delta, but partially kappa)
Analgesia (supraspinal + spinal)
Respiratory depression (+depression of cough reflex)
Pupil constriction (miosis)
Reduced GI motility (increase GI & urinary tract tone & increase biliary tract pressure)
Euphoria
Sedation

Mood alterations
Dysphoria
Drowsiness
Nausea & vomiting

Main side-effects of opioids:
-respiratory depression
-tolerance (increase dose gradually to produce an effect)
-addiction (propensity to use)
-abstinence (pain, epileptic seizures after discontinuation)

nausea, vomiting, suppresion of cough reflex, miosis, constipation, bradycardia, hypotension, itching, urinary retention, less bile-flow, muscle rigidity, euphoria

Indications: severe pain, especially breakthrough cancer pain, neiroleptanalgesia (usually in combination with droperidol).

Tramadolum

Weak direct affinity to mu-receptor, but upon binding to metabolite has strong affinity to mu receptor.

Mechanism of action:
1.Centrally acting agonist of mu-opioid receptor.
2.inhibits the reuptake of norepinephrine and serotonin 5-HT

(neurotransmitters involved in the descending inhibitory pain pathway responsible for pain relief).

Main side-effects of opioids:
-respiratory depression
-tolerance (increase dose gradually to produce an effect)
-addiction (propensity to use)
-abstinence (pain, epileptic seizures after discontinuation)

nausea, vomiting, suppresion of cough reflex, miosis, constipation, bradycardia, hypotension, itching, urinary retention, less bile-flow, muscle rigidity, euphoria

Indications: Pain (moderate intensity pain).

Acidum acetylsalicylicum (Aspirinum)

NSAID, anti-aggregant

Mechanism of action.
Aspirin blocks synthesis of COX-1 & COX-2
blocks irreversibly synthesis of COX-1 in platelets;
-thromboxane-A2 (TXA₂) production by platelets (platelet aggregator + vasoconstriction)
-prostacyclin PGI₂ production by endothelial cells (anti-aggregant + vasodilation)

Indications:
-Long term: Low doses (50mg - 150mg/day) → prevention of heart attack, stroke, and blood clot formation.
-High doses (500mg and above) → Anti-inflammatory, analgesic, and antipyretic activity

similar efficacy as paracetamol, with anti-inflammatory effect, but more irritant to stomach.

Mechanism of action NSAIDs;
Inhibition of COX-enzymes (blockade of COX-enzyme site), so arachidonic acid AA cannot be converted into prostanoids (PGE₂ and PGI₂ are the primary inflammation mediators) preventing the development of inflammation.
COX-1: expressed in most cells (especially GI), required for tissue homeostasis!
COX-2: induced by cytokines: IL-1b & TNF-α during inflammation

NSAID effect; provides symptomatic relieve of inflammation (+pain) and anti-pyretic!
Adverse NSAID effect: decreased tissue homeostasis of prostaglandins; protection of GIT, renal homeostasis, platelet aggregation, contraction of uterine smooth muscle
-gastric ulcers

Paracetamolum (acetaminophen)

Co-analgesic agent

Mechanism of action (co-analgesics):
-Non opioid analgesics inhibit prostaglandins biosynthesis and inhibit the action of enzyme cyclooxygenase (COX-3) centrally.
-weak COX-2 inhibitor in peripheral tissue (lack of anti-inflammatory effect)
-high level of peroxides in inflammed tissue (by leukocytes) causes acidity and inhibits paracetamol.

effects:
-analgesic, anti-pyretic but NOT anti-inflammatory effect
-do NOT cause euphoria, addiction, dependence
-do NOT suppress the respiratory centre and cough centre
-do NOT cause drowsiness
-less irritant to the stomach and preffered over aspirin (especially in elderly)

Adverse effects: rashes, blood disorders; acute pancreatitis reported after prolonged use
-hepatic damage if overdosed max. 4g daily (antidote=N-acetyl cysteine)

Indications: Short-term treatment of moderate-intensity postoperative pain, symptomatic treatment of mild to moderate pain, fever

Diclofenacum (Diclofenac sodium)

NSAID
non-selective COX-inhibitor

Side-effects: GI ulceration and bleeding, hypertension, increased risks of heart attacks, kidney damage.

Indications: acute pain, osteoarthritis, rheumatoid arthritis

Mechanism of action NSAIDs;
Inhibition of COX-enzymes (blockade of COX-enzyme site), so arachidonic acid AA cannot be converted into prostanoids (PGE₂ and PGI₂ are the primary inflammation mediators) preventing the development of inflammation.
COX-1: expressed in most cells (especially GI), required for tissue homeostasis!
COX-2: induced by cytokines: IL-1b & TNF-α during inflammation

NSAID effect; provides symptomatic relieve of inflammation (+pain) and anti-pyretic!
Adverse NSAID effect: decreased tissue homeostasis of prostaglandins; protection of GIT, renal homeostasis, platelet aggregation, contraction of uterine smooth muscle
-gastric ulcers

Ibuprofenum

NSAID
non-selective COX-inhibitor

Side-effects: GI ulceration and bleeding, hypertension, increased risks of heart attacks, kidney damage, Combination with alcohol  higher risk of stomach bleeding

Indications: acute pain, osteoarthritis, rheumatoid arthritis,

Mechanism of action NSAIDs;
Inhibition of COX-enzymes (blockade of COX-enzyme site), so arachidonic acid AA cannot be converted into prostanoids (PGE₂ and PGI₂ are the primary inflammation mediators) preventing the development of inflammation.
COX-1: expressed in most cells (especially GI), required for tissue homeostasis!
COX-2: induced by cytokines: IL-1b & TNF-α during inflammation

NSAID effect; provides symptomatic relieve of inflammation (+pain) and anti-pyretic!
Adverse NSAID effect: decreased tissue homeostasis of prostaglandins; protection of GIT, renal homeostasis, platelet aggregation, contraction of uterine smooth muscle
-gastric ulcers

Ketorolacum (Ketorolac)

NSAID
non-selective COX-inhibitor

Ketorolacum effect:
-potent COX-1 inhibitor
Inhibits COX-1 and COX-2 → decreases prostaglandin levels in tissues → reducing postoperative pain and inhibiting surgically induced miosis.
-higher risk of gastric ulcers
-higher risk bleeding complications

adverse Keterolac effects:
most common: drowsiness, dyspepsia (indigestion), GI-pain, nausea
-kidney damage!

indications: not more than 5 days
-reducing postoperative pain and inhibiting miosis otherwise caused by surgery.
contraindication: before surgery (intense anti-platelet effect)

Mechanism of action NSAIDs;
Inhibition of COX-enzymes (blockade of COX-enzyme site), so arachidonic acid AA cannot be converted into prostanoids (PGE₂ and PGI₂ are the primary inflammation mediators) preventing the development of inflammation.
COX-1: expressed in most cells (especially GI), required for tissue homeostasis!
COX-2: induced by cytokines: IL-1b & TNF-α during inflammation

NSAID effect; provides symptomatic relieve of inflammation (+pain) and anti-pyretic!
Adverse NSAID effect: decreased tissue homeostasis of prostaglandins; protection of GIT, renal homeostasis, platelet aggregation, contraction of uterine smooth muscle
-gastric ulcers

Metamizolum (Analginum)

Lornoxicam

NSAID
semi-selective COX-inhibitor (dependent and diminished at higher dosage)
‘oxicams > semi-selective

mechanism of action:
-inhibits COX-2 more than COX-1
-inhibition of prostaglandins, anti-inflammatory, analgesic, anti-pyretic

Effects: anti-inflammatory, analgesic, and antipyretic activity
Side effects: kidney damage
-less side-effects than non-selective COX-inhibitors (ibuprofen, diclofenac)

Indications: pain, osteoarthritis, rheumatoid arthritis

Etoricoxib

NSAID
selective COX-2 inbitor
‘coxib > selective

Mechanism of action:
-reversible inhibition of COX-2
-inhibition of prostaglandins: anti-inflammatory, analgesic, antipyretic activity

Effect: anti-inflammatory, analgesic, antipyretic activity
Side effect: Potential serious cardiovascular adverse effects due to vasoconstriction (stroke, MI)
COX-2 inhibition → ↓ PGI₂ → (↓ vasodilation + ↓ antiplatelet effect ) → ↑ thrombosis → ↑ risk of MI/stroke.

Indications: acute pain, osteoarthritis, rheumatoid arthritis.

Nimesulidum (nimesulide)

NSAID

mechanism of action:
-inhibition of COX-2 → decrease prostaglandin synthesis
effect: anti-inflammatory, analgesic, and antipyretic activity.

indications: acute pain, osteoarthritis, rheumatoid arthritis.

hepatotoxic

Zolmitriptanum (zolmitriptan)

anti-migraine agent
Selective serotonin recepter agonist

Mechanism of action:
5-HT1b and 5-HT1d are presynaptic receptors located at the endings of the trigeminal nerve.
Their stimulation inhibits the release of calcitonin gene-related peptide (CGRP).
CGRP induces neurogenic inflammation and vasodilation of the cerebral vasculature.
Reduction of CGRP concentration prevents migraine-type headache.

5-HT1d agonist, 5-HT1b partial agonist in cranial arteries and sensory nerves of the trigeminal system → constriction of cerebral blood vessels → reduces the pulsation that may be responsible for the pain of vascular headaches  → relief of migraine.

indications: Acute treatment of migraine with or without aura in adults.

Codeinum (Codeine)

Opioid receptor agonist

weak mu-receptor agonist.

Mechanism of action
-converts into morphine
-anti-tussive (anti-cough) effect by depression of medullary cough reflex.

Indications: Moderate intensity pain.

Mechanism of action of all opioids:
Opioid receptor agonist causes
-presynaptic Ca2+ blockage (inhibiting NT release)
-postsynaptic K+ channels opening (K+ leaves; hyperpolarization, excitability down)

Binds primarily to μ (mu)-receptor
Analgesia (supraspinal + spinal)
Respiratory depression
Pupil constriction (miosis)
Reduced GI motility
Euphoria
Sedation

Main side-effects of opioids:
-respiratory depression
-tolerance (increase dose gradually to produce an effect)
-addiction (propensity to use)
-abstinence (pain, epileptic seizures after discontinuation)

nausea, vomiting, suppresion of cough reflex, miosis, constipation, bradycardia, hypotension, itching, urinary retention, less bile-flow, muscle rigidity, euphoria

Benzydamine

NSAID

Mechanism of action:
Inhibits prostaglandin synthesis, inhibits the production of proinflammatory cytokines (no ulcerative action) → Anti-inflammatory, analgesic action, also local anesthetic action

effect:
-local anaesthetic & analgesic
-pain relief & anti-inflammatory
-NOT ulcerative

indications:
-treatment of inflammatory conditions of the mouth and throat
-Gingivitis, pharyngitis, mucosal ulceration and inflammation, tonsillitis