Baclofen : Poisoning

• centrally acting skeletal muscle relaxant
• an agonist at gamma-aminobutyric acid B (GABAB) receptors.
• It is used primarily to treat severe muscle spasms, secondary to conditions such as multiple sclerosis and spinal cord injuries.
• The mechanism of action has not been fully established.
• proposed that baclofen inhibits the influx of calcium at the spinal cord preventing the transmission of excitatory synaptic reflexes.
• Baclofen is primarily renally excreted; therefore, patients with renal impairment are at risk for developing toxicity at therapeutic doses.
• Overdoses of baclofen may occur due pediatric ingestions, intentional ingestions by adults or due to complications and malfunctions with intrathecal pumps and spinal catheter systems.

Overdose Symptoms

• CNS depression, lethargy, somnolence, hallucinations, agitation, mydriasis, nausea and vomiting.
• Severe toxicity is associated with bradycardia, hypotension or hypertension, respiratory failure, hypothermia, seizures, coma and death.
• Rarely, status epilepticus, rhabdomyolysis, and conduction disturbances may occur.

Pharmacokinetics

• Urine toxicology screens do not routinely test for baclofen and serum concentrations are not readily available or useful.
• After a single therapeutic dose, baclofen is rapidly absorbed from the gastrointestinal tract. Blood levels peak within 2 hours.
• serum half-life is 2–6 hours, which can be significantly prolonged after an overdose.
• majority of this drug is excreted unchanged in the urine
• Clinical effects of baclofen overdose may last four to eight hours.
• While improvement in mental status was shown to parallel the fall in serum concentration in one study, Lipscomb et al., noted that serum elimination half-life may not reflect a slower elimination rate from the central nervous system.
• Delayed diffusion across the blood-brain barrier is thought to account for the lag of a few hours in clinical recovery observed in some people

Treatment

• Treatment of baclofen overdose consists of supportive care (e.g. IV fluids, endotracheal intubation, mechanical ventilation).
• Activated charcoal - may be warranted in acute ingestions.
• Benzodiazepines - may be required for agitation and/or seizures.
• Vasopressors - hypotensive patients may require it
• There are case reports of mild to moderate overdoses being treated with physostigmine with a slight benefit, but evidence to support its use is controversial.
• Hemodialysis increases the clearance of baclofen and shortens the duration of toxicity in patients with or without impaired renal function.
• Most ESRD patients experienced marked improvement in clinical toxicity following haemodialysis, compared with patients who did not receive haemodialysis

References

1. Marryland Poison Centre Weekly Update, Feb 2012.
2. Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study. Nephrol Dial Transplant (2005) 20: 441–443
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229794/
4. http://emj.bmj.com/content/22/9/673.full

Rheumatic Fever : Aspirin & Anti Inflamatory

• Anti-inflammatory agents are used to control the arthritis, fever, and other acute symptoms.
• Salicylates are the preferred agents, although other nonsteroidal agents are probably equally efficacious.
• Steroids are also effective but should probably be reserved for patients in whom salicylates fail.
• None of these anti-inflammatory agents has been shown to reduce the risk of subsequent rheumatic heart disease.

Aspirin

• Low doses (typically 75 to 81 mg/day)
• are sufficient to irreversibly acetylate serine 530 of cyclooxygenase (COX)-1.
• This effect inhibits platelet generation of thromboxane A2, resulting in an antithrombotic effect.
• Intermediate doses (650 mg to 4 g/day)
• inhibit COX-1 and COX-2, blocking prostaglandin (PG) production, and have analgesic and antipyretic effects.
• High doses (between 4 and 8 g/day)
• are effective as antiinflammatory agents in rheumatic disorders; the mechanism(s) of action at these high doses may include both PG-dependent (particularly COX-2-dependent PGE2) and independent effects  
• However, the usefulness of aspirin at these high doses is limited by toxicity, including tinnitus, hearing loss, and gastric intolerance.

Other NSAIDS

• efficacy of agents such as naproxen and tolmetin are comparable with that of aspirin, but side effects are typically less frequent.
• Nonetheless, the majority of centers continue to use aspirin as first-line therapy for ARF
• anti-inflammatory therapy should be continued until all symptoms have resolved, as long as the medication is well tolerated
• The efficacy of other anti-inflammatory drugs in the setting of active rheumatic carditis is uncertain, and their potential side effects are comparatively greater than aspirin. Thus, these alternative agents are rarely used.

Glucocorticoids

• One exception is the use of low-dose glucocorticoids in patients who do not tolerate or are allergic to aspirin.
• A meta-analysis of eight randomized trials including 996 patients with ARF found that other agents with more significant potential side effects (eg, glucocorticoids, intravenous immune globulin [IVIG]) were not superior to aspirin with regard to development of heart valve lesions and cardiac disease

Practice and Guides

• if a diagnosis of rheumatic fever has not been established, salicylate therapy is withheld and simple analgesics such as paracetamol and codeine are recommended.
• Salicylates are withheld to facilitate diagnosis; they reduce arthritic pain but do not affect the long-term outcome of the disease
• Dose: 80 to 100 mg/kg per day in children and 4 to 8 g/day in adults. [children: 50-60 mg/kg/day orally given in divided doses every 4 hours, may increase to 80-100 mg/kg/day if required]
• Most patients will only require treatment for 1 to 2 weeks, although some patients need it for up to 6 to 8 weeks.
• The arthritis caused by acute rheumatic fever is usually exquisitely sensitive to aspirin. Alternate diagnoses should be considered in unresponsive patients
• If arthritis is refractory following 2 weeks of therapy, then the dose of aspirin can be increased; however, the risk of salicylate toxicity is very high and salicylate levels should be monitored if facilities are available.
• As the dose is reduced, joint symptoms may recur (so-called 'rebound phenomenon'). This does not represent a recurrence of rheumatic fever, and can be simply treated with another brief course of high-dose aspirin
• Stopping aspirin therapy should be considered in the setting of a concurrent viral illness because of the risk of Reye's syndrome. If aspirin is given during the influenza season, then influenza vaccine may be given as a precautionary measure.
• Toxic effects include tinnitus, headache, and tachypnoea, and may start to occur above levels of 20 mg/100 dL. They will usually resolve within a few days of stopping aspirin

References:

1. http://www.ncbi.nlm.nih.gov/pubmed/22696333
2. http://emedicine.medscape.com/article/236582-treatment
3. www.bmj.com
4. www.uptodate.com

Treatment of Acne

Acne medications

Medications	Dose	Select adverse effects
Topical retinoids
Tretinoin	Once daily, at bedtime	Local skin irritation, dryness, and flaking; sun sensitivity NOTE: Micronized gel tretinoin 0.05% (Atralin) contains soluble fish proteins, use with caution in patients with known sensitivity or allergy to fish
Adapalene	Once daily, at bedtime	Local skin irritation, dryness, and flaking; sun sensitivity
Tazarotene	Once daily, at bedtime	Contraindicated in pregnancy; local skin irritation, dryness, and flaking; sun sensitivity
Isotretinoin (not available in United States)	Once daily, at bedtime or twice per day	Contraindicated in pregnancy and lactation; local skin irritation, dryness and flaking; sun sensitivity
Topical antimicrobials*
Benzoyl peroxide (BPO)	Twice daily	Local skin irritation; may bleach hair or clothing
Clindamycin	Twice daily Once daily (foam)	Rare risk of pseudomembranous colitis; usually prescribed with BPO to decrease resistance
Erythromycin	Twice daily	Usually prescribed with BPO to decrease resistance
Dapsone	Twice daily
Topical combination products
Benzoyl peroxide 5%/Clindamycin 1%	Twice daily	Local skin irritation; may bleach hair or clothing
Benzoyl peroxide 2.5%/Adapalene 0.1%	Once daily	Local skin irritation; may bleach hair or clothing
Benzoyl peroxide 2.5%/Adapalene 0.3%	Once daily	Local skin irritation; may bleach hair or clothing
Azelaic acid	Twice daily	Local skin irritation
Salicylic acid	Once to three times daily	Local skin irritation; potential for salicylate absorption
Oral antibiotics¶Δ
Tetracycline	500 mg twice daily	Photosensitivity, gastrointestinal distress; contraindicated in pregnancy and young children
Doxycycline	50 to 100 mg twice daily or 100 mg once daily or Delayed release formulation: 100 mg every 12 hours for one day, then 100 mg per day Subantimicrobial dosing: 20 mg twice daily or Delayed release formulation given as 40 mg once daily	Photosensitivity, gastrointestinal distress; contraindicated in pregnancy and young children
Minocycline	50 to 100 mg twice daily or Extended release formulation: 1 mg/kg/day (round to nearest available strength)	Dizziness, drug-induced lupus, skin discoloration; contraindicated in pregnancy and young children
Erythromycin	500 mg twice daily (base)	Gastrointestinal distress
Trimethoprim-sulfamethoxazole	160 mg/800 mg once to twice daily	Stevens-Johnson syndrome, toxic epidermal necrolysis
Azithromycin	Intermittent dosing due to long drug half-life; optimum regimen unknown	Gastrointestinal distress
Hormonal agents¶◊
Combination oral contraceptives (estrogen/progestin)	Once daily	Nausea, breast tenderness, weight gain, thromboembolic events
Spironolactone	25 to 200 mg/day in one or two equally divided doses; doses of 50 to 100 mg/day may be as effective as higher doses and reduce side effects	Contraindicated in pregnancy; menstrual irregularity, breast tenderness, minor gastrointestinal symptoms, orthostatic hypotension, hyperkalemia, dizziness, headaches, fatigue
Oral retinoid§
Oral isotretinoin	0.5 mg/kg/day, increasing to 1 mg/kg/day in one or two equally divided doses; total dose 120 to 150 mg/kg over 20 weeks	Teratogenicity (absolutely contraindicated in pregnancy), mucocutaneous effects, hypertriglyceridemia, others

%: percent; BPO: Benzoyl peroxide (topical).
* Topical sulfacetamide (eg, gels, creams, lotions, other) with and without sulfur are also available but not typically used and have limited data; refer to topic.
¶ Usual oral dose for adult or adolescent.
Δ BPO may be prescribed with oral antibiotics to reduce resistance.
◊ For additional information refer to topic review of hormonal therapy for acne vulgaris.
§ For additional information refer to topic review of oral isotretinoin therapy for acne vulgaris.

References:

1. www.uptodate.com
2. http://www.dermnetnz.org/treatments/isotretinoin.html
3. http://www.nhs.uk/conditions/acne/pages/treatment.aspx
4. http://www.nps.org.au/publications/health-professional/health-news-evidence/2013/oral-antibiotics-for-acne
5. http://emedicine.medscape.com/article/1069804-medication#1

Antibiotics in Acne

Mechanism

• They reduce the number of bacteria on the skin surface and in the follicles, including Propionibacterium acnes
• They have an anti-inflammatory action

Topical Antibiotic

• Clindamycin
• Erythromycin

Concerns with Topical AB

• Dryness of the treated area is usually mild but is a common side effect of topical antibiotics. If the skin is visibly scaly, apply a light non-oily moisturiser.
• Skin irritation from topical antibiotics is rarely severe. Occasionally, irritation means that the patient should stop using the product. Lotions are less likely to cause irritation than solutions or gels.
• Contact dermatitis (red, dry, itchy skin) can be due to irritancy or allergy. It can be treated with a topical corticosteroid such as hydrocortisone cream (available at a NZ pharmacy without prescription).
• Bacterial resistance to antibiotics most frequently arises with intermittent use of topical antibiotics. 
• To reduce the chance of bacterial resistance, apply topical antibiotics liberally twice daily and also use benzoyl peroxide and/or a topical retinoid.

Oral Antibiotics

• Limit courses to 3–6 months to minimise antibiotic resistance and adverse effects.
• After acne has cleared, maintenance therapy for 3–12 months or longer with a topical retinoid is a good option to prevent recurrence
• Tetracycline
• doxycycline [50–100 mg daily], limecycline, minocycline
• These are not suitable for children younger than 10 years old because they may stain teeth yellow
• Erythromycin 
• erythromycin 250–500 mg orally, twice daily is an alternative
• Trimethroprim
• Cotrimoxazole

Concerns with Oral AB

• Allergy – oral antibiotics can cause a variety of rashes in those susceptible. These can be mild or life-threateningly severe. Allergy to a tetracycline or to erythromycin is very uncommon, but more than 2% of those on trimethoprim or cotrimoxazole become allergic to it.
• Photosensitivity may be a problem for those taking doxycycline. Taking the medicine after the evening meal reduces the risk of sunburn. Dress up and protect your skin from exposure to the sun.
• Gastrointestinal disturbance affects about 5% of patients and includes nausea, colicky pain and diarrhoea.
• Thrush (Candida albicans infection) affects 5% of treated women and most often affects the vagina. Thrush can also affect the oral mucosa or body folds (intertrigo), particularly in diabetics or in obesity. Thrush is less likely with erythromycin than with tetracycline.
• Bacterial resistance may occur but is less common with the use of oral antibiotics than with topical antibiotics.
• Acne antibiotics are unlikely to result in failure of the oral contraceptive pill but if you are concerned, add a barrier method and talk to your doctor about your risks

Considerations

• Acne is an inflammatory disease and is not an infection
• Antibiotics  are often prescribed for months or years, because acne is a chronic skin condition
• Topical antibiotics are more likely to induce bacterial resistance than oral antibiotics.
• P. acnes bacterial resistance is common in people treated with antibiotics for acne
• Resistance genes can spread from P. acnes to other types of bacteria such as Staphylococcus epidermidis and S. aureus
• Topical antibiotics alone are no more effective in acne than topical retinoids or benzoyl peroxide.
• Topical or systemic antibiotics should always be used in combination with benzoyl peroxide, a topical retinoid or azelaic acid. In women, they may also be used in combination with antiandrogen therapy or oral contraceptive pill.
• There have been no reports of bacterial resistance being caused by benzoyl peroxide. Benzoyl peroxide has been shown to reduce the prevalence of resistant strains of P. acnes.
• Topical antibiotics should not be used at the same time as oral antibiotics.
• The optimum dose and duration of treatment with oral antibiotics that can be given without inducing bacterial resistance is unknown
• However, low-dose doxycycline (50 mg daily) is probably less likely to induce resistance than standard-dose doxycycline (100–200 mg daily) and may be as effective in controlling the acne.
• Oral antibiotics are known to act by reducing bacterial colonisation and inflammation in the affected follicles, but they do not cure acne.
• There is no benefit to switching antibiotics to improve efficacy in acne treatment. Switching may increase the risk of bacterial resistance

References:

1. Antibiotics for acne. April 2014. http://www.dermnetnz.org/acne/acne-antibiotics.html
2. http://www.nps.org.au/publications/health-professional/health-news-evidence/2013/oral-antibiotics-for-acne
3. http://emedicine.medscape.com/article/1069804-medication#6
4. http://www.australianprescriber.com/magazine/35/6/180/2