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PHAR 300 > L11: Non-Steroidal Anti-Inflammatory Drugs > Flashcards

L11: Non-Steroidal Anti-Inflammatory Drugs Flashcards

1
Q

What does NSAID stand for?

A

Non-Steroidal Anti-Inflammatory Drugs

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2
Q

What are the subdivisions of NSAIDs and give examples for each.

A
  1. Salicylates: Aspirin
  2. Non-Salicylates:
    - traditional (classic) NSAIDs or Non-selective COX-1/2s ex: Ibuprofin
    - COX-2 selective inhibitors ex: Celecoxib
  3. (Acetaminophen: technically not an NSAID)
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3
Q

What do NSAIDs come from?

A

Salicylic acid was extracted from white willow tree bark or a plant called Meadowsweet. Now we have a derivative of it: Acetylsalicylic acid

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4
Q

What was the first drug that was chemically synthesized?

A

Aspirin

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5
Q

What do NSAIDs target?

A

Prostaglandins.

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6
Q

How are prostaglandins made?

A
  1. A section of the plasma membrane can be clipped off by phospholipase A2 to release Arachidonic acid. Arachidonic acid is a substrate for a number of biological products.
  2. Cyclooxygenases (COX-1 and COX-2) make prostaglandins and thromboxanes from Arachidonic acid.
  3. Cyclooxygenases are anchored in the ER and are dimers with 2 equal active sites. The liberated arachidonic acid enters a channel to reach an active site on cyclooxygenase where a ring is formed and 2 oxygens are added to make a prostaglandin.
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7
Q

What are prostaglandins?

A

They are unsaturated carboxylic acids (cyclopentane ring). They are a derivative of arachidonic acid.

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8
Q

What do prostaglandins have an effect on?

A
  1. They are involved in the production of inflammation and pain signalling (amplify response)
  2. Protect the GI tract: gastric mucosa barrier to protect stomach from hydrochloric acid
  3. Effects on the cardiovascular system
  4. Renal homeostasis
  5. Sleep/wake cycle
  6. Reproductive system
  7. Vasodilation and vasoconstriction
  8. Platelet aggregation/inhibition (controls coagulation within circulation)
  9. Blood flow to different organs by controlling vasoconstriction and vasodilation.

They have both autocrine and paracrine function. Therefore, if the production of prostaglandins is blocked, you block a major mechanism of pain and inflammation.

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9
Q

Explain the difference between COX-1 and COX-2.

A

COX-1:

  • Constitutively active enzyme
  • Makes prostaglandins involved in essential physiological processes like kidney function, gastric mucosa barrier to protect stomach from hydrochloric acid, and platelet aggregation
  • Has a smaller channel for arachidonic acid

COX-2:

  • Inducible enzyme and has some constitutive effects.
  • Involved in the production of mediators upon injury causing pain and inflammation.
  • Involved in fevers.
  • Has a wider channel for arachidonic acid
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10
Q

What do classical NSAIDs block?

A

Both COX-1 and COX-2 production of prostaglandins.

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11
Q

What type of receptors do prostaglandins act on?

A

GPCRs called prostanoid receptors.

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12
Q

What physiologic roles of prostaglandins affect pathological conditions?

A

Physiologic -> pathologic

  1. Temperature control -> Fever
  2. Bronchial tone -> asthma
  3. Intestinal mobility -> Diarrhea
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13
Q

What functions of prostaglandins can NSAIDs block?

A

Production of prostaglandins implicated in:

  1. Fever (NSAID=antipyretic)
  2. Pain (NSAID=analgesic)
  3. Inflammation (NSAID=anti-inflammatory)
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14
Q

Explain the pathway of a pain stimulus on your finger.

A
  1. Nociceptors (injury) OR thermoreceptors (heat) send a signal from the periphery starting from the stimulated fibers (increased action potentials)
  2. Stimulus goes up spinal cord
  3. Instantaneous reflex to withdraw from the painful stimulus
  4. Relays in the thalamus
  5. Then the cortex = conscious of the pain
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15
Q

What happens when a cell is injured?

A

Mast cells and macrophages are recruited to the site of injury and release many mediators. They release mediators such as prostaglandins, bradykinin, serotonin, etc. They have an effect on nerve endings in that region. This sends impulses to the spinal cord and up to the brain.

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16
Q

What is the effect of prostaglandins on nociceptive nerve endings?

A

Nociceptive nerve endings have receptors for a lot of different mediators. PGs sensitize the receptors to other mediators to amplify the intensity of the signal of other mediators.

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17
Q

Where do NSAIDS predominantly act?

A

In the periphery at the origin of the painful stimulus and site of inflammation (nocicpetors). They block the synthesis of prostaglandins thus decreasing their availability and the intensity of the painful signal coming from the periphery.

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18
Q

According to the World Health Organization, at what pain level should certain drugs be used?

A
  1. General pain management: NSAIDs
  2. Pain is persistent and increasing: Opioid + NSAID
  3. Extreme pain (ex: cancer): mostly opioids, may or may not also use NSAIDs
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19
Q

Give the therapeutic overview of NSAIDs.

A
  1. Provide relief of mild - moderate somatic pain including: headache, toothache, myalgia (muscle pain), and arthralgia (joint pain).
  2. Relief in inflammatory disorders such as rheumatoid arthritis, osteoarthritis, gout (except acetaminophen because it’s not good for inflammation)
  3. Reduce fevers, which is important because fevers past a certain point are very dangerous.
  4. Prophylaxis (to prevent) of myocardial infarction and stroke (decrease in certain cardiovascular diseases).
  5. Can reduce the risk of certain cancers.
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20
Q

What is inflammation? What are signs of inflammation?

A

Reaction of living tissue to injury when chemical mediators are released from the injured tissue and reach the local capillary bed. These mediators induce vasodilation, permeabilization of the microvasculature, mediators and cells leave the vasculature to go to the tissue of injury.
Signs: swelling, redness, pain, and hot around that area.

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21
Q

What are the different ways you get tissue injury?

A
  1. Trauma
  2. Ischemia (lack of blood)
  3. Neoplasm (certain tumours)
  4. Infectious agent (bacterium, virus, fungus, parasite)
  5. Foreign particle (ex: asbestos)
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22
Q

How do inflammatory mediators contribute to the sensation of pain? Which COX enzyme is induced?

A 
COX-2 enzymes are induced to make prostaglandins which sensitize the receptors on nerve endings.
By sensitizing (via PGE2) and activating (via Bradykinin) nociceptors.
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23
Q

What is the difference between acute and chronic inflammation? Give examples.

A

Acute: short term. Ex: cuts, allergic rxns, etc.
Chronic: long term and is destructive. Ex: cancer, arthritis, cardiovascular diseases, neurological diseases, ect.

24
Q

Why are NSAIDs helpful for chronic inflammation?

A

Because they can be taken for years and you can adjust the dose necessary for pain management associated with chronic inflammation.

25
Q

What is Osteoarthritis?

A

It’s an injury induced joint damage and is very common. Common sites include knees, hips, hands, feet, and in the spine. It’s common in football players and race horses due to it being a high-impact sport.

26
Q

What is Rheumatic arthritis?

A

Independent of the environment. An autoimmune disease in which the body’s own immune system attacks the body’s joints.

27
Q

How is fever induced? Give an example of a pyrogen.

A

It is induced by pyrogens which go to the brain and raise the thermostatic set point in the hypothalamus. In response to the pyrogens, the temperature regulating Center sends out impulses via the autonomic nervous system, leading to increased heat production and decrease heat loss (i.e. shivering, vasoconstriction, and cessation of perspiration)

Examples of pyrogens: prostaglandin E2 generated by COX-2.

28
Q

What are the side effects of NSAIDs?

A

Varies from one person to the next

  1. Main side effects in upper GI tract: dyspepsia (upset stomach), erosions, ulcers (bleeds/perforations), GI bleeding can lead to anemia
  2. Renal effects: dysfunction, failure (acute/chronic)
  3. BP and heart failure
  4. Blood loss due to anti-platelet affect
29
Q

How do NSAIDs affect the gastric mucosa?

A

The gastric mucosa lines the membrane layer of the stomach and is protected by prostaglandins because they continuously replenish the mucosa. When you use NSAIDs the production of prostaglandins is blocked, therefore the mucus layer is gone, and the epithelial cells are vulnerable to gastric acid. With chronic use the side effects in the stomach can be frequent and serious (like causing ulcers) but it varies from one person to the next.

30
Q

What is aspirin the generic name of?

A

Acetylsalicylic acid.

31
Q

What are the effects of aspirin?

A
  1. Analgesic
  2. Anti-inflammatory
  3. Anti-pyretic
  4. Anti-thrombotic
32
Q

What is the mechanism of action of aspirin?

A

Normally arachidonic acid enters the active site of a COX enzyme and gets modified to a prostaglandin or thromboxane and leaves the enzyme.
When aspirin is present the acetyl group of acetylsalicylic acid (aspirin) binds to a serine residue in the cyclooxygenase enzyme (both COX-1 and COX-2) the serine is therefore acetylated. This permanently inactivates the cyclooxygenase (acetyl binds irreversibly). This can be counteracted by making more cyclooxegenases (except in the platelets).

33
Q

Why is low dose Aspirin prescribed to people vulnerable to blood clots?

A

Thromboxane A2 is made by COX in platelets and it causes vasoconstriction and thrombosis. People who are vulnerable to blood clots forming within the vasculature are at risk of heart attacks and strokes. Low dose aspirin is prescribed to these high-risk individuals to decrease the risk of the blood clots as aspirin blocks the production of thromboxane A2 in platelets by irreversibly blocking COX. Platelets don’t have nuclei, so once the thromboxane A2 production is blocked by aspirin, the block last for the lifespan of the platelet (8-12 days) because they can’t make new COX enzymes.

34
Q

What is the half life of aspirin at normal dose and at overdose?

A

Normal: 3 hours
Overdose: 15 hours

35
Q

Describe the metabolism of Aspirin.

A

The metabolism of NSAIDs happens predominantly in the liver by a p450 enzymes. Acetylsalicylic acid is metabolized to salicylic acid. Salicylic acid is then conjugated by glucoronyl transferases to produce a water-soluble glucuronide that can be excreted in the kidney. Salicylic acid can also be excreted in the kidney.

36
Q

Describe the excretion of Aspirin. How can the excretion be used as an advantage in aspirin overdose?

A

Since salicylic acid is an acid, it will get reabsorbed in the kidney if the tubules are acidic (weak acids non ionized in acidic conditions).

Making the urine alkaline means the weak acid won’t be in a non ionized lipid soluble form so it will not be reabsorbed by the kidneys. It will be excreted more into the urine. This increases clearance of the drug.

37
Q

What is aspirin toxicity called and what are the symptoms?

A

Salicylism

  1. Tinnitus (ringing in ear)
  2. Headaches, dizziness, hearing impairment, dim vision
  3. Confusion and drowsiness
  4. Sweating and hyperventilation
  5. Nausea and vomiting
  6. Marked acid base disturbences
  7. Hyperpyrexia (very high fever)
  8. Dehydration
  9. Cardiovascular and respiratory collapse
  10. Coma, convulsions, death
38
Q

What is Reye’s syndrome?

A

It’s a rare neurological syndrome that occurs in children who take Aspirin and it affects the nervous system, the brain, and the liver. Even if this condition is extremely rare, children are given acetaminophen (ex: Tylenol) instead of aspirin to prevent it.

39
Q

Name a traditional NSAID. What does it block?

A

Ibuprofen (ex: Advil and Motrin) blocks COX-1 and COX-2.

40
Q

What is the difference between Aspirin and Ibuprofen?

A
  1. Their side effects are different.
  2. Ibuprofen binds COX enzymes reversibly whereas aspirin binds irreversibly. So if you take Ibuprofen before taking aspirin, aspirin will have no effect. To avoid this, wait for a couple of hours to take aspirin after taking ibuprofen so that Ibuprofen leaves the active site.
41
Q

Describe the metabolism and excretion of traditional NSAIDs.

A

They’re broken down by different CYP enzymes depending on the NSAID. Metabolites get conjugated and are excreted by the kidneys. Inactive metabolites are found in the urine.

42
Q

What was a challenge that was encountered when making COX-2 inhibitory drugs?

A

Originally, Cox-2 inhibitor NSAIDs were supposed to selectively block the production of prostaglandins during pain and inflammation only, while leaving all the normal effects of prostaglandins alone. They did not know that Cox-2 enzymes have some constitutive effects on blood flow, platelet inhibition and vasodilation, and normal renal physiology.

43
Q

How did they manage to make drugs specific to blocking COX-2 and NOT COX-1?

A

COX-2 specific drugs were made to be larger so that they could enter the channel of COX-2 but not the channel of COX-1.

44
Q

What is Celecoxib?

A

A highly selective cox-2 inhibitor compared to aspirin. The large structure of Celecoxib allows it to get into the Cox-2 channel but not Cox-1.

45
Q

Why were certain COX-2 inhibitors removed from the drug market? Give an example of one that stayed and one that didn’t.

A

When they were first put on the market, drug companies ran tests and saw that up to 2% of people taking them experience negative cardiovascular effects compared to about a regular 0.5% from individuals that weren’t taking them. This difference of 1.5% meant that certain cox-2 Inhibitors were removed from the market.
Some COX-2 inhibitors were beneficial for certain groups of people, which is why certain stayed on the market.
Stayed: Celecoxib
Removed: Rofecoxib

46
Q

Why did COX-2 inhibitors have a slightly higher incidence of cardiovascular problems?

A

Normally, there was a balance between a prothrombotic state and an anti-thrombotic state. COX-1 enzymes in platelets are making thromboxane which is a prothrombotic state. COX-2 enzymes in endothelial cells lining blood vessels make prostacyclin which is an anti thrombotic state. Taking aspirin doesn’t disrupt this balance because it acts on both cox-1 and Cox-2 enzymes. Low doses of aspirin actually block Cox-1 more which explains its effects of preventing thrombus. But if you only block cox-2 enzymes the balance is shifted towards a prothrombotic state. This is what caused cardiovascular problems in 2% of people.

47
Q

Where are COX-1 and COX-2 receptors found?

A

COX-1: mainly in the GI tract

COX-2: Brain, kidney, vasculature

48
Q

What distinguishes acetaminophen from other NSAIDs?

A

It is NOT anti-inflammatory but it IS anti-pyretic and an analgesic. Therefore, it is not used for rheumatoid or osteo arthritis or gout.

49
Q

What is the mechanism of Acetaminophen?

A

Not yet understood.

50
Q

What is the half life of Acetaminophen?

A

2-3 hours.

51
Q

Describe the metabolism of Acetaminophen.

A

Cyp450 enzymes create a toxic metabolite out of acetaminophen. Most acetaminophen is broken down in the liver into this toxic intermediate and it is quickly conjugated. The parent compound and the intermediate are conjugated by glutathione which inactivates the intermediate and allows its excretion. It’s important to quickly conjugate the toxic intermediate because it causes cellular necrosis (it reacts with hepatocytes in a toxic manner and kills the liver cells).

52
Q

What happens in an overdose of Acetaminophen?

A

An overdose of acetaminophen easily saturates the enzymes that conjugates the parent compound or the toxic metabolites and minor metabolites. This causes an accumulation of the toxic intermediate which could lead to death as it destroys the liver (necrosis/apoptosis). It’s a hepatotoxic metabolite.

53
Q

Why are alcoholics vulnerable to toxicity of Acetaminophen even at lower doses?

A

Because chronic use of ethanol induces p450 enzymes (1A2, 2E1, 3A4) these induced p450 enzymes are the ones that convert acetaminophen to the toxic metabolite. This causes exacerbation of liver damage (that is already there from alcoholism - cirrhosis) by toxic metabolites of acetaminophen. Ethanol depletes glutathione stores which slows the removal of the toxic metabolites.

54
Q

What are the stages of Acetaminophen poisoning?

A

The effects do not show up immediately.

  • 0-24h: Anorexia, nausea, and vomiting. If this is treated right away you can avoid the next stages.
  • 24-72h: Abdominal pain (right upper region), elevated serum enzymes (indicating liver injury)
  • 72-96h: vomiting and symptoms of liver failure, sometimes renal failure, and pancreatitis
  • > 5days: resolution of hepatotoxicity or progression to multiple organ failure. Sometimes fatal.
55
Q

What’s the antidote to Acetaminophen overdose?

A

A Glutathione precursor called N Acetylcysteine. This is so your liver can conjugate the toxic metabolite BUT it needs to be given BEFORE liver destruction.

PHAR 300 (20 decks)

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