Treatment of Gout (Acute and Chronic)

Gout is an important topic for all 3 USMLE steps. Below is a summary of key potential facts that may be questioned in these exams with regards to the treatment of Gout.

Treatment of Acute Attacks of Gout

-First the diagnosis should be confirmed. Septic arthritis has the potential to look exactly like gout, hence the initial step is always arthrocentesis unless the patient has a known diagnosis.

-Next step is pain management. Nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and ACTH are the mainstays of treatment. Co-existent health conditions determine which drugs are used. For example renal failure may contraindicate use of certain NSAIDS.

-When comorbidities limit the use of NSAIDs or colchicine, intra-articular steroid injection may be indicated.

-One must remember that control of the underlying hyperuricemia is contraindicated until the acute attack is controlled as it may intensify and prolong the attack. However if the patient is already on allopurinol or probenecid, they should be continued.

Medications for acute gout:

Nonsteroidal anti-inflammatory drugs
NSAIDs are the first drugs of choice in most patients (typically indomethacin is used except in elderly because of CNS adverse effects). Contraindications to NSAIDS use include peptic ulcer disease or GI bleeding, renal failure, abnormal liver function and patients on warfarin (selective COX-2 inhibitors like celecoxib can be used). Additional caution in needed for those patients who are on ACE inhibitors as both ACE inhibitors and NSAIDS can decrease the GFR. NSAIDS are given at full dose for about 4-5 days and then dose is gradually decreased.


Colchicine
Colchicine is a mitotic inhibitor and has now become a second line treatment because of risk of adverse effects. To be effective colchicine therapy must be initiated within 24 hours of onset of the acute attack. Common adverse effects include diarrhea and vomiting, in 80% of patients. A number of dosing regimens are proposed with recent recommendations favoring lower doses with a maximum of 2.5 mg/24 hours and 6 mg over 4 days. Contraindication to colchicine include severe renal insufficiency (GFR less than 10 mL/min), hepatic dysfunction and biliary obstruction.

Colchicine is one agent that can be used in acute gout as well as for Gout prophylaxis (0.6mg BID). Myopathy is an important side effect of chronic colchicine therapy.

Corticosteroids
Corticosteroids can be given to patients with gout who cannot use NSAIDs or colchicine, but ACTH is generally preferred over steroids.

Treatment of Chronic Gout

-Firstly attempt should be made at avoiding the use of medications that elevate uric acid. For example thiazides should be avoided and losartan should be considered in stead. (Losartan is uricosuric at 50 mg/day doses). If the patient has tophaceous disease, probenecid should not be used.

-Probenecid (uricosuric agent) and allopurinol (decrease production of uric acid) are the two main drugs used. Probenecid is preferred by some.

-Patients with very high uric acid excretion will benefit from Allopurinol. It is also the drug of choice in patients with existing renal disease.

Medications for chronic gout:


Probenecid 
Probenecid inhibits tubular reabsorption of uric acid. Some physicians recommend alkalizing the urine when starting probenecid to reduce the risk for renal stone formation. All patients should be advised to drink plenty of liquids (>2L a day).


Allopurinol
Allopurinol is xanthine oxidase inhibitor and thus reduces the generation of uric acid. Therefore, it should be used in patients who overproduce uric acid (also used in patients at risk of tumor lysis syndrome). Common side effects include dyspepsia, headache, diarrhea, and rash. Allopurinol hypersensitivity is a wellknown but rare complication with high mortality. Allopurinol is also associated with the drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. For these reasons Allopurinol should be discontinued in patients who develop a rash.


Febuxostat
Febuxostat is a newer nonpurine selective inhibitor of xanthine oxidase, and is a potential alternative to allopurinol.


Other treatments:


Rasburicase
Rasburicase is an extremely potent (and expensive) drug that can metabolize uric acid into soluble substances. It is used in treatment of tumor lysis syndrome. It is very prone to causing allergic reaction and its role in treatment of gout is not clear.


Diet and Activity
Foods very high in purines include hearts, sweetbreads (eg, pancreas, thymus), smelt, sardines, mussels, anchovies, trout, haddock, scallops, mutton, veal, liver, bacon, salmon, kidneys, and turkey. These should be avoided as much as possible. Patients with gout should limit alcohol as it can precipitate gout. This is especially true for beer and hard alcohol but mild-moderate wine drinking is well tolerated by most.

Increasing dairy intake, folic acid intake, and coffee consumption may reduce gout flares. Weight reduction in patients who are obese can improve hyperuricemia.

Mechanism of action of common antibiotics

Betalactams (e.g. penicillins and cephalosporins): Inhibit cell wall synthesis.

Fluoroquinolones (e.g. ciprofloxacin and nalidixic acid): Bind to bacterial DNA gyrase and topoisomerase IV, interfering with bacterial DNA synthesis.

Tetracyclines: Bind to the bacterial 30S ribosome, inhibiting bacterial protein synthesis.
Aminoglycosides (e.g. gentamicin): Bind to 30S ribosome unit as well.

Macrolides (e.g. azithromycin): Reversibly bind to the 50S ribosomal subunit.

Sulfonamides (e.g. sulfamethoxazole): Inhibit steps in bacterial folic acid synthesis.

This stuff is high yield for Step 1.

Lead screening, levels and treatment in children

Current guidelines state that health-care professionals should use blood lead tests to screen children at ages 1 and 2 years. Older children should be screened in certain high risk situations.

The American Academy of Pediatrics policy statement recommends the use of venous samples for initial screening whenever possible. If capillary testing is performed and the lead concentration is greater than 10 mcg/dL, the lead concentration must be confirmed by a venous sample because capillary sampling is more likely to yield false-positive results due to contamination from skin.

Chelation therapy should be considered if lead concentrations are higher than 44 mcg/dL. The role of chelation is not clearly defined for children whose blood lead concentrations range from 20 to 45 mcg/dL. Levels below 20 mcg/dL can be monitored periodically.

Succimer is the drug of choice for children whose blood lead concentrations are > 45 mcg/dL. For levels >70 mcg/dL calcium-disodium EDTA can be added. The first dose always is succimer, followed 4 hours later by EDTA, because EDTA when given alone can worsen lead encephalopathy.

Extrapyramidal side effects of antipsychotics

Akathisia refers to an urge to keep moving. Typically the patients will pace about in the house and sit down and get up again. First line treatment of akathisia is propranolol although benzodiazepines have also been used. Akathisia can occur any time after starting the medication.

Tardive duskinesia (TD) refers to involuntary movements which can be perioral (such as lip smaking, chewing and darting tongue movements) or choreoathetoid movements of extremities or other body parts. TD usually does not occur within the first 3 months of starting the medications. TD can be difficult to treat and may require changing to medications that do no cause this side effect such as clozapine.

Dystonia occur within hours or days of starting the therapy. Characteristic features include muscle spasms (e.g. torticollis). Treatment of dystonia is acomplished by antihistaminic medications like diphenhydramine (Benadryl) or anticholinergics like benztropine or trihexphenidyl.

Neurolept maligant syndrome is a known side of antipsychotics that presents with hyperthermia, muscle rigidity and mental status changes. It usually occurs after 1-2 weeks of starting the therapy. Treatment includes stopping the medication and use of dantrolene, bromocriptine and amantidine.

Commonest antipsychotics leading to these side effects inlcude: chlorpromazine (Thorazine, Largactil), Fluphenazine (Prolixin) - Available in decanoate (long-acting) form, Perphenazine (Trilafon), Prochlorperazine (Compazine), Thioridazine (Mellaril, Melleril), Trifluoperazine (Stelazine), Mesoridazine, Periciazine, Promazine, Triflupromazine (Vesprin), Levomepromazine (Nozinan), Promethazine (Phenergan), Pimozide (Orap), Chlorprothixene (Cloxan, Taractan, Truxal), Clopenthixol (Sordinol), Flupenthixol (Depixol, Fluanxol), Thiothixene (Navane), Zuclopenthixol (Cisordinol, Clopixol, Acuphase)

Erectile Dysfunction and its treatment with PDE5 inhibitors(sildenafil, tadalafil, vardenafil)

ED affects close to 20 million men in the US. It is often associated with cardiovascular risk factors like diabetes, hypertension and smoking.

International index of erectile dysfunction can assist in diagnosis.

Treatment includes ruling out treatable organic causes and sildenafil citrate. Sildenafil (Viagra) is an oral phosphodiesterase-5 inhibitor and works by increasing blood flow to the spongiform tissue of the penis.


PDE5 inhibitors(sildenafil, tadalafil, vardenafil) are relatively safe drugs. Contraindications to their use include cardiovascular disease(severe), heart attack within 3 months, stroke within 6 months, heart failure within 6 months(moderate or severe), unstable angina or coital angina, poorly controlled arrhythmias, poorly controlled blood pressure, and hereditary degenerative retinal disorders. Vardenafil can also cause QT-interval prolongation. Caution is recommended when using other vasodilator drugs because the resulting hypotension may be severe.

prGCD - plant cell expressed recombinant Glucocerebrosidase enzyme (GCD) for use in Gaucher's disease

This is a newly approved (partially approved for use by the Food and Drug Administration-FDA) drug for the treatment of patients with Gaucher's Disease.

Gaucher's disease is the most common lysosomal storage diseases in humans. It is caused by a hereditary deficiency of the enzyme glucocerebrosidase (also known as acid β-glucosidase). The enzyme acts on glucocerebroside which accumulates in its absence. Fatty material collects in the liver, kidneys, lungs, spleen, brain and bone marrow. The disease is inherited in autosomal recessive manner. The locus is on chromosome 1.

Traditionally Gaucher's disease has been classified in the following 3 types.

Type I (or non-neuropathic type) is the most common form of the disease. It occurs in 1 in 50,000 births. It is much more frequent in children of Ashkenazi Jewish heritage. Symptoms include enlarged liver and spleen. Bone marrow replacement can cause anemia, thrombocytopenia and leukopenia. The brain is usually not affected. Rarely there is lung or kidney impairment. These patients may live well into adulthood.

Type II (or acute infantile neuropathic form) typically begins in infancy and occurs in approximately 1 in 100,000 births. The diagnostic symptom of this type is extensive and progressive brain damage. Affected children do not usually live longer than 2 years of age.

Type III (the chronic neuropathic type) has a variable onset. Incidence is 1 in 100,000 births. It is characterized by slowly progressive but milder neurologic symptoms. Other major symptoms include an spleen and/or liver enlargement, seizures, bone marrow disorders and respiratory problems.

Colchicine

Colchicine – inhibits Leukocyte Migration and Phagocytosis by blocking Tubulin Polymerization. The side effects are Nausea and Diarrhea, should not be used in Renal Insufficiency. It is important to remember that colchicine has no role in acute gout. Acute gout managed by NSAIDs and Steroids.

Methicillin Resistant Staphylococcus Aureus (MRSA)

Methicillin resistance is most often due to alteration of Penicillin Binding Proteins in the wall of the bacteria.

TCA (tricyclic antidepressant) toxicity

In tricyclic antidepressants poisoning the cause of death is usually arrhythmias precipitated by blockage of fast Sodium channels which normally inhibit reuptake of Norepinephrine and Serotonin.

Treatment is gastric lavage or activated charcoal, depending on how the overdose has progressed. If the overdose is with an especially high concentration of TCAs, then haemodialysis may be required. Alkalization of urine is sometimes used to promote excretion in the urine.

Malignanat Hyperthermia

Malignant Hyperthermia – occurs as a complication of inhalation anesthetics. It is treated with Dantrolene, which binds Ryanodine Receptors and inhibits the release of Calcium into the cytoplasm.

Aspirin adverse effects

Gastrointestinal:
Aspirin use increases the risk of gastrointestinal bleeding. Enteric coating does not seem to reduce this risk. Combining aspirin with other NSAIDs increases the risk.

Central effects:
Large doses of salicylate can cause tinnitus.

Reye's syndrome:
Acute afebrile encephalopathy and fatty liver. Can occur when children or adolescents are given aspirin for a fever or other illnesses or infections. Especially influenza and chicken pox.

Hives:
It is an uncommon reaction to aspirin. Aspirin can induce angioedema in some people.

Ginseng, Ginkgo and Garlic

Ginseng (Asian): It is an alternative medicine promoted as an adaptogen (a drug which increases body's resistance to stress). It is also used as an agent for lowering blood glucose, treating erectile dysfunction, hepatitis C and menopausal symptoms. Important side effects are insomnia, hypoglycemia, high blood pressure, headaches, epistaxis, menstrual irregularitites and mastalgia

Ginkgo biloba: It is another herbal medicine commonly used as a memory and concentration enhancer. Some trials have proved its efficacy in Alzheimers disease. It is also used in intermittent claudication and as an anti-vertigo agent and for treatment of vitiligo. Important side effects include increased bleeding risk, GI distress and allergies.

Garlic: Most commonly used as a dietary supplement to prevent high blood pressure, high blood cholesterol, heart diseases and certain types of cancer like stomach and colon carcinomas. Common side effects are halitosis, GI symptoms and increased risk of bleeding. It has been found to reduce the efficacy of saquinavir (protease inhibitor used against HIV).

Iloprost

5 day intravenous infusion Of Iloprost has been proved effective in the treatment of severe Raunaud's secondary to Scleroderma. It is also of proven efficacy in Heparin induced thrombocytopenia, Macular degeneration, Angina pectoris. However it is not FDA approved for these purposes.
FDA has approved its use only in pulmonary arterial hypertension

Malaria prophylaxis in pregnant women

Mefloquin is the only drug recommended. (Thanks to Anonymous for pointing out this error on this blog).

Rabies vaccine and Chloroquine

Chloroquine can blunt the immune response to intradermal rabies vaccines. Hence while on Chloroquine(for example while on travel prophylaxis) the Intramuscular form of antirabies vaccine should be preferred.

Methotrxate and Rheumatoid Arthritis

Methotrexate (Trexall, Rheumatrex) is one of the first line agents used in the treatment of RA. It is important to remember however that this drug can flare up Rheumatoid Nodules.

Retinopathy causing drugs

Common drugs causing retinopathy as a toxic effect: Thioridazine (An antipsychotic medication), Hydroxychloroquine (Used as a disease modifying agent in Rheumatoid arthritis).

Depressed anyone?

CYMBALTA (Duloxetine hydrochloride)is a combined serotonin and nor epinephrine reuptake inhibitor (SNRI). It is a sustained release drug formulation.
Indications------ Major depressive disorder, General anxiety disorder, Diabetic peripheral neuropathic pain and Fibromyalgia. USFDA no longer approves it for Stress urinary incontinence.
S/E------ Nausea, constipation, dry mouth, orthostatic hypotension, syncope, weight loss. Cymbalta and thioridazine should not be co-administered.

Panic Attacks

Intravenous Na-lactate and Cholecystokinin tetrapeptide (CCK-4) and inhaled CO2 can induce panic attacks in susceptible individuals.
Emergency treatrment of panic attack-- Rapidly acting Benzodiazepine like Alprazolam/Clonazepam
Long term maintenance therapy-- SSRIs like Paroxetine considered to be first-line agents                                        

Quit smoking!

CHANTIX^® (varenicline) is a relatively recently introduced (Approved by FDA in May 2006) non-nicotine prescription drug to help adults (>18 yrs) in smoking cessation.

 Mech of action: It competitively binds to α₄β₂ nicotinic ACh  receptors in the brain and has agonistic as well as antagonist effects.

 Adverse Effects: Some patients reported changes in behavior, agitation, depressed mood, suicidal thoughts which caused much concern to its use. Other more common S/E include nausea, vomiting, sleep problems (insomnia, bizarre dreams etc), constipation etc