PHA6126 Pharmacology 2 - Lesson 1.3: Drugs Used in Gout and Other Analgesics

Comprehensive 100-card question-and-answer review set covering PHA6126 Pharmacology 2 (Lesson 1.3: Drugs Used in Gout and Other Analgesics). Includes detailed purine metabolism pathways, acute gout treatments, urate lowering therapy, IL-1 inhibitors, acetaminophen toxicity, ketorolac, and tramadol.

How is inflammation defined in the lecture notes?

A physiological response to tissue injury and infection.

What is the primary goal of administering nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammation?

Relief of symptoms of acute inflammation.

What is the primary goal of administering disease-modifying antirheumatic drugs (DMARDs) in inflammation?

Maintenance of function, slowing or arrest of tissue-damaging processes, usually seen in chronic inflammation.

How is gout defined as a metabolic disease?

A metabolic disease characterized by recurrent episodes of acute arthritis due to deposits of monosodium urate in joints and cartilage.

How is gout defined as a systemic disease?

A systemic disease caused by the buildup of uric acid in the joints, which causes inflammation, swelling, and pain.

What is the most common first symptom of gout?

Pain in one joint of a lower extremity, often in the big toe of the foot.

What is hyperuricemia?

A condition where there is an abnormally high level of uric acid in the blood, serving as a precursor and risk factor for gout.

Does every individual with hyperuricemia develop gout?

No, not everyone with hyperuricemia will have gout, but hyperuricemia remains a key risk factor.

What serum urate level defines hyperuricemia in men?

Urate level $> 8\,\text{mg/dL}$

What serum urate level defines hyperuricemia in women?

Urate level $> 7\,\text{mg/dL}$

What two intermediate molecular forms are produced during the breakdown of purine nucleotides?

Inosine and hypoxanthine

Which enzyme catalyzes the rate-limiting step in the formation of uric acid?

Xanthine oxidase

What conversion does xanthine oxidase catalyze prior to converting xanthine to uric acid?

The conversion of hypoxanthine to xanthine.

What final chemical conversion does xanthine oxidase catalyze in purine nucleotide metabolism?

The conversion of xanthine to uric acid.

What molecule is the final end-product of purine metabolism?

Uric acid (urate)

What is the normal serum level of uric acid in humans?

$4\text{ to }6\,\text{mg/dL}$ ($240\text{ to }360\,\mu\text{M}$)

What is the normal serum level of uric acid in mice?

$< 1\,\text{mg/dL}$ ($60\,\mu\text{M}$)

What is the total normal body content of uric acid in humans?

$$1\text{ to }2\,\text{g}$$

What known biological functions does uric acid serve in the body?

Uric acid serves no known biological functions.

In the context of purine nucleotide metabolism shown in the diagram, what pathway leads from inosine to renal calculi or gout?

Inosine is converted to hypoxanthine, then xanthine, then urate via xanthine oxidase; hyperuricemia causes urate crystal deposition (gout) and hyperuricosuria causes uric acid crystals (renal calculi).

What is hyperuricosuria?

A condition characterized by high levels of uric acid in the urine.

What percentage of uric acid is excreted via the kidneys?

$70\%\text{ to }80\%$ (specifically $80\%$ as indicated in the metabolism diagram)

What percentage of uric acid is excreted through the gastrointestinal tract?

About $20\%$

What is primary gout, and what three defects can cause it?

An innate defect in purine metabolism or uric acid excretion caused by: 1. Uric acid overproduction (overproducers), 2. Impaired renal clearance of uric acid (under-excreters), or 3. A combination of both.

What is the underlying etiology of primary gout?

It is usually an inherited metabolic disorder attributed to genetics.

What is secondary gout?

Gout caused by an underlying medical condition or lifestyle factor that affects uric acid metabolism.

Which general category of disease disorders can cause secondary gout?

Hematologic disorders

Which specific drugs and substances are listed as causes of secondary gout?

Salicylates, thiazide diuretics, ethambutol, pyrazinamide, nicotinic acid, ethanol, niacin, and cyclosporine.

What is the first treatment goal in managing gout?

Relieve pain and inflammation associated with sudden, severe gout attacks.

What is the second treatment goal in managing gout?

Reduce serum uric acid concentration and gout attacks which may lead to severe cases like urate lithiasis.

What is the third treatment goal in managing gout?

Prevent recurrent gout attacks by managing underlying conditions that contribute to hyperuricemia and reducing the risk of uric acid crystal formation.

What defines an acute gouty arthritis attack?

A sudden and severe type of arthritis caused by the buildup of uric acid crystals in the joints, characterized by intense pain, swelling, redness, and tenderness in the affected joint (often the big toe).

Which three drug classes are used to manage acute gouty arthritis attacks?

Colchicine, NSAIDs, and Corticosteroids.

What type of drug is colchicine, and from what plant is it isolated?

An antimitotic alkaloid isolated from autumn crocus (Colchicum autumnale).

How does colchicine's benefit-to-toxicity ratio compare to NSAIDs?

It has a low benefit-to-toxicity ratio and is used less often than NSAIDs (like ibuprofen or naproxen) due to more serious side effects at higher doses.

Within what timeframe after attack onset is colchicine most effective?

When initiated within $12\text{ to }36\,\text{hours}$ of the attack.

How does delaying colchicine treatment longer than 48 hours affect therapeutic outcome?

The likelihood of success decreases substantially if treatment is delayed longer than $48\,\text{hours}$ after symptom onset.

What dose-dependent GI adverse effects occur with oral colchicine, and in what proportion of patients?

Nausea, vomiting, bloating, emesis, and diarrhea occurring in up to $80\%$ of patients.

Within what timeframe does colchicine relieve pain and inflammation of gouty arthritis, and does it affect urate metabolism?

Relieves pain and inflammation in $12\text{ to }24\,\text{hours}$ without altering urate metabolism or excretion.

In which patient group is colchicine often selected over NSAIDs for acute gout flares?

In patients who cannot tolerate NSAIDs.

Why are NSAIDs considered the mainstay of therapy for acute gout flares?

Due to their excellent efficacy and minimal toxicity with short-term use compared to colchicine.

What is the recommended dosing and tapering schedule for NSAIDs in an acute gout attack?

Initiated at maximum recommended dose at symptom onset, continued for $24\,\text{hours}$ after resolution, then tapered quickly over $2\text{ to }3\,\text{days}$.

What are the most common gastrointestinal adverse effects associated with NSAIDs in gout treatment?

Gastritis, bleeding, and perforation.

Which NSAID is the most extensively studied in the treatment of an acute gouty arthritis attack?

Indomethacin

How do NSAIDs work in managing acute gout flares?

They work by reducing pain and inflammation, which are the primary symptoms of gout.

What cellular process do NSAIDs inhibit during an acute gout flare?

Inhibit urate crystal phagocytosis.

Why is aspirin NOT used to treat acute gout?

At lower doses it causes renal retention of uric acid, and at uricosuric doses ($> 3.6\,\text{g/day}$) it inhibits excretion, leading to increased uric acid levels in the blood.

At what daily dose threshold does aspirin exhibit uricosuric activity?

Doses $> 3.6\,\text{g/day}$

Which specific NSAIDs/salicylates are EXCEPTIONS that have NOT been successfully used to treat acute gouty episodes?

Aspirin, salicylates, and tolmetin.

Which specific NSAID possesses the unique ability to lower serum uric acid?

Oxaprozin

How do newer NSAIDs compare to indomethacin regarding safety profile in acute gout?

Newer NSAIDs often have a better safety profile with a lower risk of gastrointestinal bleeding compared to older drugs like indomethacin.

How does the anti-inflammatory efficacy of corticosteroids compare to NSAIDs for acute gout flares?

Corticosteroids are potent anti-inflammatory medications with equivalent efficacy to NSAIDs.

Through which routes can corticosteroids be administered for acute gout flares?

Intra-articularly, intravenously (IV), orally, systemically, or subcutaneously.

How do corticosteroids act on inflammatory cells?

They decrease activation, proliferation, and survival of various inflammatory cells.

Which inflammatory cells, cytokines, and mediators are inhibited by corticosteroids?

They decrease migration of neutrophils, and inhibit prostaglandins and proinflammatory cytokines such as Interleukin 1B ($\text{IL-1}\beta$).

In which patient populations are corticosteroids a good alternative for acute gout flares?

In patients in whom NSAIDs or colchicine are contraindicated, and in those with renal impairment or chronic kidney disease (CKD).

By what route is Prednisone administered in gout therapy?

Oral route.

What are the characteristics and routes of administration for Triamcinolone acetonide and Methylprednisolone?

They are long-acting corticosteroids given IM or intra-articularly, useful if the patient is unable to take oral Prednisone.

What is the goal target serum uric acid concentration in urate lowering therapy?

Achieve and maintain a serum uric acid concentration $< 6\,\text{mg/dL}$ and preferably $< 5\,\text{mg/dL}$.

What are the two primary mechanisms by which serum urate concentration can be lowered?

1. Decreasing uric acid synthesis (Xanthine oxidase inhibitors)
2. Increasing renal excretion of uric acid (Uricosurics)

Should uric acid lowering therapy be initiated during an acute gouty arthritis attack?

No, it is not to be used during an acute gouty arthritis attack.

Which two drugs are classified as Xanthine Oxidase Inhibitors?

Allopurinol and Febuxostat

How do xanthine oxidase inhibitors reduce uric acid levels?

By reducing uric acid synthesis or impairing the conversion of hypoxanthine to xanthine and xanthine to uric acid.

Why are xanthine oxidase inhibitors effective in treating primary gout?

Because they are effective in both overproducers and underexcreters of uric acid.

What is the clinical role of xanthine oxidase inhibitors in recurrent gout?

They are the most widely prescribed agents for long-term prevention of recurrent gout attacks.

What chemical class does allopurinol belong to, and what is its mechanism?

It is a purine analogue that inhibits xanthine oxidase, resulting in a fall in plasma urate levels and decrease in overall urate burden.

Based on the structure and reaction diagram provided, how is allopurinol converted and how does it inhibit uric acid synthesis?

Allopurinol is oxidized by xanthine oxidase to alloxanthine, and both allopurinol and alloxanthine inhibit xanthine oxidase to block uric acid synthesis.

What is the first-line agent for the treatment of chronic gout between attacks?

Allopurinol

What is the 'intercritical period' in gout, and how does allopurinol affect it?

The intercritical period refers to the time between gout attacks; allopurinol tends to prolong this period.

How long does it take for allopurinol to achieve its full therapeutic benefits?

It may take several months to see its full benefits.

How long is allopurinol therapy typically maintained?

Continued for years, if not for life, to maintain low uric acid levels and prevent future attacks.

Which active metabolite of allopurinol acts alongside allopurinol to inhibit xanthine oxidase?

Alloxanthine

What chemical classification distinguishes Febuxostat from Allopurinol?

Febuxostat is a potent and selective non-purine inhibitor of xanthine oxidase.

Does Febuxostat affect other enzymes in purine or pyrimidine metabolic pathways?

No, it reduces xanthine and uric acid formation without affecting other enzymes in the purine or pyrimidine metabolic pathway.

When is Febuxostat indicated in chronic gout management?

As an alternative in patients who cannot tolerate allopurinol.

What is the primary mechanism of action of uricosuric drugs?

They increase renal clearance or excretion of uric acid by inhibiting post-secretory renal proximal tubular reabsorption of uric acid.

Which drug is one of the oldest uricosuric agents and often used as first-line uricosuric treatment?

Probenecid

What is the current regulatory status of Sulfinpyrazone?

Discontinued (DC)

What is Lesinurad and what is its regulatory status in the United States?

A newer and more potent uricosuric drug that has been discontinued (DC) in the United States.

When are uricosuric drugs initiated in gouty patients?

In gouty patients with underexcretion of uric acid when allopurinol or febuxostat is contraindicated.

How can uricosuric drugs be prescribed in relation to xanthine oxidase inhibitors?

Used as monotherapy or in combination with a xanthine oxidase inhibitor (allopurinol or febuxostat).

Which three medications belong to the Interleukin-1 (IL-1) inhibitor class in gout?

Canakinumab, Anakinra, and Rilonacept

What is the primary target pathway of Interleukin-1 (IL-1) inhibitors?

They inhibit the IL-1 receptor pathway.

Which specific cytokine is the main proinflammatory cytokine responsible for crystal-induced inflammation in gout attacks?

Interleukin-1B ($\text{IL-1}\beta$)

Are Interleukin-1 (IL-1) inhibitors FDA-approved for gout treatment?

No, they are not yet FDA-approved for the treatment of gout.

By what route are all three Interleukin-1 (IL-1) inhibitors administered?

Subcutaneously

How are analgesics defined in the notes?

Agents that bring about insensibility to pain without loss of consciousness.

What is the alternative generic name for acetaminophen?

Paracetamol

When is acetaminophen indicated for pain management?

In the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary.

Acetaminophen is the active metabolite of which former drug?

Phenacetin

What is acetaminophen's cyclooxygenase (COX) inhibition profile in peripheral tissues?

A weak COX-1 and COX-2 inhibitor in peripheral tissues.

Interactions with which three endogenous receptor/neurotransmitter systems account for acetaminophen's antinociceptive effects?

Endogenous opioid, cannabinoid, and serotonergic systems.

What is the elimination half-life of acetaminophen, and how does it determine dosing frequency?

Half-life is $2\text{ to }3\,\text{hours}$ (sometimes $4\,\text{hours}$), which is why the administration frequency is every $6\,\text{hours}$.

How does acetaminophen differ from aspirin regarding uric acid levels, uricosurics, and platelets?

Acetaminophen does not affect uric acid levels, does not antagonize uricosuric agents, and lacks platelet-inhibiting effects.

In which specific patient populations is acetaminophen preferred over aspirin?

In patients with hemophilia, history of peptic ulcer, and those in whom bronchospasm is precipitated by aspirin.

What is the typical maximum daily dose of acetaminophen in adults, and what is seen at this limit?

Maximum daily dose is $4\,\text{grams}$, which is associated with increased liver function test abnormalities.

What early symptoms indicate hepatic damage from acetaminophen toxicity?

Nausea, vomiting, diarrhea (NVD), and abdominal pain.

At what dose threshold does acetaminophen promote brain cell damage, and what is the antidote for toxicity?

Doses greater than $10\,\text{grams}$ promote oxidative stress and brain damage; the antidote is acetylcysteine (providing sulfhydryl groups to neutralize NAPQI).

What toxic metabolite is formed in acetaminophen overdose, and what is its abbreviation?

$N\text{-acetylparabenzoquinone imine}$ (NAPQI)

Why is phenacetin (acetophenetidin) no longer available in many countries?

Because it is more toxic than acetaminophen, causes kidney damage, and has potential toxicity risks.