BCM6233 NSAIDs and Local Anesthetics

Non-steroidal anti-inflammatory drugs (NSAIDs)

This type of drugs are weak organic acids as given.

nabumetone

Which NSAID is a ketone prodrug that is metabolized to the (weakly) acidic active drug?

False. Most NSAIDs are well absorbed, and food does not substantially change their bioavailability.

Most NSAIDs are not well absorbed especially with food which substantially changes their bioavailability.

T or F?

direct glucuronidation

Most NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by ____________ (phase II) alone.

inhibition of prostaglandin biosynthesis

The anti-inflammatory activity of NSAIDs is mediated chiefly through inhibition of what pathway?

COX-1

This cyclooxygenase enzyme is active in normal body functions; substantially expressed in all tissues.

COX-2

This cyclooxygenase enzyme is induced in inflammation and injury.

COX-2

Which cyclooxygenase enzyme is inhibited mostly by NSAIDs?

PGH2

COX enzymes (1 & 2) catalyze the conversion of arachidonic acid to ______ which is then further converted by specific synthases into various prostaglandins and thromboxanes depending on the type of tissue/enzyme present.

True.

Reduced prostaglandins reduces pain, inflammation, and fever as well.

T or F?

1. phospholipase A2

2. phospholipase C

3. diacylglycerol lipase

Which 3 enzymes in the COX pathway break down phospholipids to release arachidonic acid?

1. prostaglandins (COX-1 and COX-2)

2. thromboxanes (COX-1)

3. prostacyclins

Under the arachidonic acid pathway (COX-1 (physiologic) and COX-2 (inducible)), which 3 molecules are produced?

leukotrienes (not affected by NSAIDs)

Under the arachidonic acid pathway (LOX), what molecule is produced?

stomach, kidneys, and platelets

COX-1, the housekeeping COX enzyme, is found where (3)?

1. mucosal protection

2. renal blood flow

3. homeostasis

What are the 3 main functions of COX-1?

inflammatory sites, macrophages, synoviocytes (joints)

COX-2, expressed only when there's inflammation, is found where (3)?

1. promotes inflammation;

2. pain and;

3. fever

What are the 3 main functions of COX-2?

prostaglandin H2 (PGH2)

What is the central intermediate in prostanoid biosynthesis which serves as the immediate precursor to prostaglandins and thromboxanes?

prostaglandin D2 (PGD2)

This prostaglandin is usually released during allergic responses (causes sneezing, bronchoconstriction, etc.)

prostaglandin E2 (PGE2)

This prostaglandin promotes fever, pain, and inflammation.

prostaglandin F2α (PGF2α)

This prostaglandin promotes uterine contraction, broncho- and vasoconstriction, and increases intraocular pressure.

prostaglandin I2 (PGI2)

This prostaglandin (a prostacyclin) inhibits platelet aggregation and promotes vasodilation.

thromboxane A2 (TxA2)

This thromboxane promotes platelet aggregation and vasoconstriction.

COX-1

Blocking this COX enzyme reduces the protective PGs in the stomach which can lead to ulcers and bleeding.

COX-2

Blocking this COX enzyme inhibits the regrowth of mucus or re-epithelialization.

True.

COX-2 selective inhibitors reduce inflammation without affecting the stomach too much. But cardiovascular risks are present.

T or F?

leukotrienes

These molecules produced in the LOX pathway are expressed more in asthmatic and allergic responses (bronchoconstriction and mucus production).

COX-1

The normal roles of this COX enzyme in the GI mucosa are PGE2 production, increases mucus and HCO3 secretion, increases mucosal blood flow, and reduces acid secretion.

COX-1

When this COX enzyme is blocked, there could be decreased mucosal protection in the GI mucosa, peptic ulcer formation, and GI bleeding.

glomerular filtration rate

Normally, when COX-1 and -2 are present in the kidney, they aid in producing PGE2 and PGI2 which help dilate (afferent) renal arterioles ultimately leading to increased _________.

PGE2 and PGI2

Which 2 prostaglandins maintain renal blood flow and excrete Na+ and water from the kidneys?

1. Na+ and water retention

2. hypertension

3. hemodynamic acute kidney injury

What are the 3 side effects in the kidney when using NSAIDs?

COX-2 produces PGI2 (vascular role) ; COX-1 produces TXA2 (platelet role)

Which COX enzyme produces PGI2? TXA2?

1. PGI2 inhibition (so no vasodilation)

2. TxA2 is not inhibited

3. increased risk of clots, stroke, MI

Selective COX-2 inhibition results in (3):

low-dose aspirin

(High-, low-dose) aspirin irreversibly inhibits platelet COX-1 only; used to prevent blood clots.

aseptic meningitis

What is a rare CNS adverse effect of NSAIDs?

1. headaches

2. tinnitus

3. dizziness

What are the 3 common CNS adverse effects of NSAIDs?

myocardial infarction and congestive heart failure

What is a rare cardiovascular adverse effect of NSAIDs?

1. fluid retention

2. hypertension

3. edema

What are the 3 common cardiovascular adverse effects of NSAIDs?

ulcers or bleeding

What is a rare GI adverse effect of NSAIDs?

1. abdominal pain

2. dyspepsia

3. nausea

4. vomiting

What are the 4 common GI adverse effects of NSAIDs?

1. rare thrombocytopenia (decreased platelet count)

2. neutropenia

3. aplastic anemia

What are the 3 hematologic adverse effects of NSAIDs?

abnormal liver function test results (increased AST and ALT)

What is a common hepatic adverse effect of NSAIDs?

liver failure

What is a rare hepatic adverse effect of NSAIDs?

asthma

What is a common pulmonary adverse effect of NSAIDs?

1. hypersensitivity reactions (all types of rashes)

2. pruritus (itching)

What are 2 common adverse effects of NSAIDs on the skin?

1. renal insufficiency

2. renal failure

3. hyperkalemia

4. proteinuria

What are the 4 renal adverse effects of NSAIDs?

aspirin (salicylic acid or acetylsalicylic acid)

This NSAID is known to be a non-selective COX inhibitor; a simple organic acid with a pKa of 3.0.

aspirin

This NSAID is absorbed and rapidly hydrolyzed to acetic acid and salicylate by esterase in the tissues and blood.

15 minutes

How long is the serum half-life of aspirin?

nonlinearly (the amount of drug bound to albumin doesn't increase proportionally with the drug concentration)

Aspirin is (nonlinearly, linearly) bound to albumin.

alkalinization

(Acidification, alkalinization) of the urine increases the rate of excretion of free salicylate and its water-soluble conjugates.

8-10 days

Aspirin irreversiblty inhibits platelet COX (COX-1) so that its antiplatelet effect lasts how many days?

6-12 hours

In other tissues, the synthesis of new COX replaces the inactivated enzyme so that ordinary doses of aspirin have a duration of action of how many hours?

1. transient ischemic attacks

2. unstable angina

3. coronary artery thrombosis with MI

4. thrombosis after coronary artery bypass grafting

Aspirin decreases the incidence of (4):

gastric upset (intolerance) and gastric acid duodenal ulcers

What are the 2 main adverse effects of aspirin at antithrombotic doses?

1. hepatotoxicity

2. asthma

3. rashes

4. GI bleeding

5. renal toxicity

What 5 rare adverse effects occur at antithrombotic doses of aspirin?

1. ibuprofen

2. diclofenac

3. ketoprofen

4. naproxen

5. piroxicam

6. mefenamic acid

What are the 6 nonselective NSAIDs administered orally?

CLUE: I Don't Know Nap Please Maybe?

reversible COX-1 and -2 inhibition; inhibits PG synthesis

What is the MOA of nonselective NSAIDs (oral)?

analgesia (musculoskeletal, headache, dysmenorrhea, anti-pyretic, anti-inflammatory)

What are nonselective NSAIDs (oral) used for?

1. GI bleeding (less than aspirin)

2. nephrotoxicity (AKI and intestinal nephritis)

3. hypersensitivity reactions

What are the 3 main side effects of nonselective NSAIDs (oral)?

ketorolac and dexketoprofen

These 2 nonselective NSAIDs (IV and for patent ductus arteriosus (PDA)) are used for post-surgical analgesic control (moderate to severe) and is mainly used for analgesia and NOT for anti-inflammatory effect.

high risk for GI toxicity, nephrotoxicity, and allergic reactions

What is the adverse effect of ketorolac and dexketoprofen?

indomethacin

This nonselective NSAID (IV and for patent ductus arteriosus (PDA)) is used for anti-inflammatory purposes (gout, arthritis) and the closure of patent ductus arteriosus (PDA).

1. GI toxicity

2. nephrotoxicity

3. aplastic anemia

4. thrombocytopenia

5. bowel movement suppression

What are the 5 adverse effects of indomethacin?

celecoxib, etoricoxib, parecoxib

These NSAIDs are selective COX-2 inhibitors and are used as analgesics, antipyretics, and anti-inflammatory drugs.

CLUE: Come Eat Pare

paracetamol (acetaminophen)

This NSAID selectively inhibits COX-3 (CNS/brain) as well as COX-1 and -2 although weakly; used for mild analgesia and anti-pyretic purposes.

1. hepatotoxicity

2. renal papillary necrosis

3. hemolytic anemia

What are the 3 adverse effects of paracetamol (acetaminophen)?

opioids

These include natural opiates and semisynthetic alkaloids derived from the opium poppy, pharmacologically similar synthetic surrogates and endogenous peptides.

1. close voltage gated Ca2+ channels on presynaptic nerve terminals and reduce transmitter release

2. opens K+ channels and hyperpolarize thus inhibiting postsynaptic neurons

The MOA of opioids include having G-protein couple actions on neurons which (2):

Mu1

This opioid receptor is responsible for analgesia, euphoria, low abuse potential, miosis, bradycardia, and hypothermia.

Mu2

This opioid receptor is responsible for analgesia (spinal), depression of ventilation, and physical dependence (addiction).

kappa

This opioid receptor is responsible for analgesia (supraspinal and spinal), dysphoria, sedation, and addiction.

delta

This opioid receptor is responsible for analgesia (supraspinal and spinal) and depression of ventilation.

1. hydrocodone (μ and k)

2. oxycodone (μ and k)

3. dexmetorphan (cough receptors)

4. codeine (cough receptors)

What are 4 opioid partial agonists?

CLUE: Hot Orphans Do Coke

hydrocodone and oxycodone

These 2 opioids are strong agonists at μ and k receptors thereby inhibiting pain neurotransmission at spinal and neurospinal sites; also binds to N-methyl-D-aspartate (NMDA) receptors and antagonizes the effects of glutamate.

1. moderate to severe pain

2. cancer pain

3. neuropathic pain (post-herpetic neuralgia, DM neuropathy)

4. chronic pain

5. opioid dependence

6. opioid withdrawal

What are the 6 uses of hydrocodone and oxycodone?

1. miosis

2. respiratory depression

3. increased intercranial pressure (ICP)

4. postural hypertension

5. constipation

6. urinary retention

7. pruritus

8. addiction liability

9. hypogonadism

10. hearing loss

What are the 10 adverse effects of hydrocodone and oxycodone?

dexmetorphan and codeine

These 2 opioids (partial agonists) decrease the sensitivity of cough receptors by depressing the medullary cough center through sigma receptor stimulation.

cough suppression

What is dexmetorphan and codeine used for?

1. hallucinations

2. confusion

3. excitation

4. increased or decreased pupil size

5. nystagmus

6. seizures

7. coma

8. respiratory depression

9. addiction liability

What are the 9 adverse effects of dexmetorphan and codeine?

propoxyphene and dextropropoxyphene

These 2 opioids are weak agonists at μ receptors but still inhibit pain neurotransmission.

1. mild to moderate pain

2. restless legs syndrome

3. opioid withdrawal

What are the 3 uses of propoxyphene and dextropropoxyphene?

1. miosis

2. respiratory depression

3. increased intercranial pressure (ICP)

4. postural hypotension

5. constipation

6. urinary retention

7. pruritus

8. addiction liability

9. seizures

10. pulmonary edema

11. fatal arrhythmias

What are the 11 adverse effects of propoxyphene and dextropropoxyphene?

buprenorphine and nalbuphine

These 2 opioids are partial μ receptors agonists and partial k and d receptor antagonists; inhibits pain neurotransmission.

1. moderate to severe pain

2. opioid dependence

3. alcohol dependence

4. balanced anesthesia

5. opioid withdrawal states (buprenorphine)

What are the 6 uses of buprenorphine and nalbuphine?

1. sedation

2. dizziness

3. sweating

4. nausea

5. anxiety

6. hallucinations

7. nightmares

8. respiratory depression (less)

9. tolerance

10. dependence liability

What are the 10 adverse effects of buprenorphine and nalbuphine?

morphine and heroin

What are 2 examples of phenanthrenes (full agonist opioids)?

fentanyl and alfentanil

What are 2 examples of phenylpiperidine (full agonist opioids)?

1. morphine (phenanthrene)

2. heroine (phenanthrene)

3. fentanyl (phenylpiperidine)

4. alfentanil (phenylpiperidine)

These 4 full agonist opioids are strong agonists at μ receptors (inhibition of pain neurotransmission at spinal and supraspinal sites); variable activity at d and k receptors.

1. severe pain

2. pain associated with acute MI

3. pulmonary edema

What are the 3 uses of phenanthrenes (morphine and heroin)?

1. severe pain

2. adjunct in anesthesia

3. chronic pain

4. breakthrough cancer pain

What are the 4 uses of phenylpiperidines (fentanyl and alfentanil)?

1. miosis (only phenanthrenes)

2. restlessness

3. respiratory depression

4. increased intercranial pressure (ICP)

5. postural hypotension

What are the 5 adverse effects of phenanthrenes (morphine and heroin) and phenylpiperidines (fentanyl and alfentanil)?

meperidine

This opioid is a full, strong agonist at μ and k receptors, inhibiting pain neurotransmission; muscarinic blocking actions.

1. moderate to severe pain

2. labor analgesia

3. post-operative shivering

4. pre-operative sedation

What are the 4 uses of meperidine?

1. tachycardia

2. hypotension

3. *seizures

4. *delirium

5. restlessness

6. respiratory depression

7. increased intercranial pressure (ICP)

What are the 7 adverse effects of meperidine?

methadone and levomethadyl acetate

What are 2 examples of phenylheptylamines (full agonist opioids)?

methadone and levomethadyl acetate

These 2 full agonist opioids are strong at μ receptors; NMDA antagonists and blocks monoamine reuptake transporters.

1. moderate to severe pain (resistant to morphine)

2. opioid dependence (relapsing chronic heroin addict)

3. opioid withdrawal

What are the 3 uses of phenylheptylamines (methadone and levomethadyl acetate)?

1. hepatic dysfunction

2. QT prolongation (methadone)

What are the 2 adverse effects of phenylheptylamines (methadone and levomethadyl acetate)?