Treatment for Extravasation of Non-Chemo Drugs

• Non-chemotherapy drugs are not generally considered to be vesicants. However, extravasation or infiltration of non-chemotherapy drugs can still cause harm to skin and soft tissue. 
• Some general advice in the case of extravasation includes immediately stopping the
  drug infusion and elevating the affected limb to minimize swelling.
• Cold compresses (dry not moist) may also reduce swelling and are generally preferred for most vesicant or irritant drugs.
• Warm compresses (dry not moist) can cause vasodilation and help distribute the drug, reducing local drug concentrations.
• Other treatments can depend on the drug. Hyaluronidase given subcutaneously around the affected site can help distribute the drug away from the site. 
• Phentolamine can counteract local vasoconstriction caused by extravasation of vasoconstrictors. Quicker treatment may result in better outcomes for patients, but surgical intervention may be required for severe cases of extravasation.
• Treatments for extravasation are generally based on case reports in the literature,
  as opposed to more solid evidence. 

 

1. Cold or warm compresses should generally be applied for 20 minutes, every six to eight hours, for up to three days.
2. The dose of hyaluronidase (U.S. only) for adults for extravasations is generally 150 units/mL, 0.2 mL intradermally or subcutaneously at each of five sites of the edges surrounding the affected area. A concentration of 15 units/mL (same instructions as above) has also been used for non-chemo agents. Hyaluronidase should be used within about one hour of extravasation.
3. The dose of phentolamine for adults is generally 5 to 10 mg diluted in 10 to 15 mL of normal saline injected subcutaneously into the area of extravasation as ten 1 mL injections. It should be used within 12 hours of extravasation.
4. Different formulations of topical nitroglycerin have been used (per case reports) for extravasation including 2% topical nitroglycerin ointment

References:
Treatment for Extravasation of Non-Chemo Drugs, 2011. www.pharmacistsletter.com

Safety of ACE-inhibitors in Pregnancy and Lactation:

First trimester exposure

• A 2006 epidemiologic study first suggested that ACE inhibitors are not safe in early pregnancy
• Although recent researches has questioned the association between first trimester ACE inhibitor use and congenital (particularly cardiac) abnormalities, given the proven risks of exposure in second and third trimester, they continue to recommend that these drugs be avoided throughout pregnancy
• Although there is less information about the risk of congenital malformations associated with first trimester exposure to ARBs , the available literature suggests that these agents have the same risks as ACE inhibitors

Second and third trimester exposure

• systematic review and meta-analysis provides good evidence that second and third trimester exposure to ACE inhibitors and ARBs is associated with serious adverse fetal/neonatal effects
• The use of drugs that act directly on the renin-angiotensin system has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death
• The most common problems are related to impaired fetal/neonatal renal function, which results in oligohydramnios during pregnancy (amniotic fluid is largely derived from the fetal kidneys), and anuria and renal failure after delivery
• Oligohydramnios increases the risk of umbilical cord compression and, in turn, fetal death.
• Severe oligohydramnios can lead to poor pulmonary development (pulmonary hypoplasia) and development of limb contractures and skeletal deformations
• Hypocalvaria, retinopathy, and prolonged neonatal hypotension have also been observed with second or third trimester ACE inhibitor exposure

Lactation

• ACE inhibitors are transferred into breast milk, but have very low levels in the milk.
• ACE inhibitors and angiotensin II receptor antagonists are generally not recommended for use by breastfeeding mothers, they are not absolutely contraindicated.
• Healthcare professionals may prescribe these medicines during breastfeeding if they consider that this treatment is essential for the lactating mother
• Captopril and enalapril have been reviewed by the American Academy of Pediatrics and are claimed compatible for use in lactation.
• However, newborns may be more susceptible to the hemodynamic effects of these drugs, such as hypotension, and sequelae, such as oliguria and seizures.
• hemodynamic status of the infant should be taken into account when deciding whether women taking these drugs should breastfeed
•  There is no information on the use of ARBs during breastfeeding.

 Risk Categories and Available ACE Inhibitors in Hospital

	Pregnancy Risk	Lactation
Captopril	D	NR	Because of the low levels of enalapril in breastmilk, amounts ingested by the infant are small and would not be expected to cause any adverse effects in breastfed infants
Enalapril	D	NR
Perindopril	D	NR	Because of the low reported levels in milk with similar drugs, it is unlikely that any of the ACE inhibitors reach clinically important levels in breastmilk. However, use of an ACE inhibitor that has been studied is preferred.
Ramipril (not available)	D	NR	Because no information is available on the use of ramipril during breastfeeding, an alternate drug may be preferred, especially while nursing a newborn or preterm infant

Pregnancy risk factor D = Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage

NR= Not recommended 

References:

1. www.uptodate.com
2. https://www.gov.uk/drug-safety-update/clarification-ace-inhibitors-and-angiotensin-ii-receptor-antagonists
3. http://www.aafp.org/afp/2001/0701/p119.html
4. www.drugs.com
5. http://www.bmj.com/content/343/bmj.d5931
6. http://www.australianprescriber.com/magazine/35/2/47/50

Adverse Effect of HAART on Menstrual Cycle

Effect of HIV

• Overall, HIV infection did not increase the likelihood of having a cycle longer than 40 days (i.e., a longer interval between periods).
• However, HIV positive women with more advanced immunosuppression (CD4 counts less than 200 cells/mm³) were more likely to have long cycles.
• The researchers concluded that HIV serostatus had little effect on menstrual cycle length, and that other factors -- for example, advanced disease, age, race, malnutrition, wasting, and substance use -were more important
• women with HIV were more likely to experience amenorrhea for more than three months and had intervals greater than six weeks between menstrual cycles
• HIV positive women with varying degrees of wasting, 20% overall had experienced amenorrhea. Among the women with amenorrhea, muscle mass was significantly lower, as was the total level of estradiol

Amenorrhea

• women who used HAART had a reduced risk for developing this complication.
• The longer women used HAART, the less likely this problem would occur.

Oligomenorrhea

• This problem was also less likely to occur the longer women used HAART.
• women who used HAART for less than two years still experienced this complication.
• However, once women used HAART for more than two but less than four years, the risk of this problem decreased significantly.
• women who used HAART for more than four years had the least risk of skipping periods.

Intermenstrual bleeding

• Using HAART for less than two years was associated with an increased risk of bleeding between periods.
• However, once women used HAART for two or more years, this risk was reduced.
• Increased CD4+ cell counts were also linked to a decreased risk of intermenstrual bleeding.

Menorrhagia

• The longer women used HAART, the lower their risk of experiencing prolonged periods (lasting more than one week).
• For instance, there was almost no risk of prolonged periods for women who had used HAART for four or more years.
• Women who had used HAART for between two and four years had a slightly increased risk for prolonged periods.
• But for women who had used HAART for less than two years the risk of experiencing menorrhagia was three times greater than normal.
• Also, as CD4+ counts increased, the risk for this problem was reduced.

Points to Consider

• No established side effect profile and reports on effect of HAART on menstrual cycle
• benefit may have been contributed by the overall health of the women improved over time
• study team did not specifically assess any differences among different classes of anti-HIV medications for their effects on menstrual functions. For instance, there are reports that women who use protease inhibitors can sometimes experience heavier bleeding during periods

References:

1. http://www.catie.ca/en/catienews/2006-10-31/impact-hiv-and-haart-menstruation
2. http://www.thebody.com/content/art40771.html
3. http://www.indianjmedsci.org/article.asp?issn=0019-5359;year=2010;volume=64;issue=6;spage=245;epage=252;aulast=Nagpal

Renal Dose Adjustment of Oral Unasyn

Availability:

• Sultamicillin (Ampicillin and Sulbactam Prodrug) 375 mg
• Unasyn syrup (250mg/5ml)

Adjustment:

• Based on patient information leaflet, the dose of sultamicillin in sere impairment patients (<30ml/min) should be administered less frequently in accordance with usual practice for ampicilin
• However no dose adjustment was given for product

Evidences:

• Patients with renal failure who were administered parenteral doses of sulbactam plus ampicillin had increased plasma concentrations and delayed excretion of both drugs.
• Single oral doses of sultamicillin (750mg) administered to 4 groups of 5 patients with varying degress of renal impairment produced similar results
• Additionally, in a clinical trial of oral sultamicillin in 30 patients (mean age 62 years) with acute exacerbations of chronic bronchitis, increases in mean AUCs and prolonged half-lives for both sulbactam and ampicillin were seen
• However, in these studies a dose of 750mg OD was used.

Recommendations

• Patients with renal dysfunction should receive reduced dosages of sultamicillin in accordance with the usual practice for ampicillin
• Based on these information, it is recommended to either reduce the dose or the interval of Unasyn for patients.
• For patients undergoing haemodialysis, it is recommended for doses to be given after the haemodialysis

References:

1. Drug Information leaflet
2. https://www.medicines.org.uk/emc/medicine/26423
3. Sultamicilin Drug Review

Vitamin B for Peripheral Neuropathy

• can present in a variety of forms and follow different patterns
• Symptoms vary depending on whether motor, sensory, or autonomic nerves are damaged

Vitamin B related Causes

• Heavy Alcohol Consumption
• common cause of peripheral neuropathy
• Damage to the nerves associated with long-term alcohol abuse may not be reversible when a person stops drinking alcohol, however, doing so may provide some symptom relief and prevent further damage.
• frequently leads to nutritional deficiencies (including B12, thiamine, and folate) that contribute to the development of peripheral neuropathy

• Metformin-induced Vitamin B12 Deficiency
• vitamin B12 deficiency with metformin is undoubtedly due to malabsorption of vitamin B12 at its absorption site in the terminal ileum
• Thirty percent of patients on metformin malabsorb vitamin B12
• With an absolute vitamin B12 deficiency, it takes twelve to fifteen years to totally deplete pre-existing vitamin B12 stores

• Proton Pump Inhibitors and Histamine H2 antagonists
• H2RAs and PPIs have been documented to interfere with B-12 absorption
• showing a 53% drop in protein-bound B-12 absorption with H2RA

• Vitamin B12 Deficiency
• can cause serious anemia, nerve damage and degeneration of the spinal cord.
• common for anemia to develop first, but this is not always the case, especially if a person is taking a folate supplement
• lack of B12 damages the myelin sheath that surrounds and protect nerves.
• Without this protection, nerves cease to function properly and conditions such as peripheral neuropathy occur

Benefit of Supplementation

• Insufficient evidence for benefit of vitamin B supplementation, even when extensively used for PN
• Most treatment guidelines for peripheral neuropathy do not include supplementation as treatment option
• One small trial in alcoholic peripheral neuropathy reported slightly greater improvement in vibration perception threshold with oral benfotiamine for eight weeks than placebo.
• In another small study, a higher dose of oral vitamin B complex for four weeks was more efficacious than a lower dose in reducing symptoms and signs.
• Vitamin B administered by various routes for two to eight weeks was less efficacious than alpha‐lipoic acid, cilostazol or cytidine triphosphate in short‐term improvement of clinical and nerve conduction study outcomes

Recommendations

• Supplementation confer greatest benefit depending on the cause of disease
• do not require high doses if patients do not deficiencies or risks

Condition	Choice of Vitamin B
Taking AntiTB medications	B6
Alcoholism	B1, B12
Diabetes, on Metformin H2RA PPI	B12

Vitamin	NEUROBION	Individual Tab	RDA / for PN
B1 / Thiamine	100mg	10mg	·  5-30mg daily ·  Up to 300mg in deficiency
B6 / Pyridoxine	200mg	10mg	·  50-300mg ·  1–6 g oral pyridoxine per day for 12–40 months can cause severe and progressive sensory neuropathy characterized by ataxia (loss of control of bodily movements)
B12 / Cyanocobalamin	200mcg	500mcg [mecobalamin]	·  50-6000mcg/day ·  Bioavailability 25%

References:

1. http://www.ninds.nih.gov/disorders/peripheralneuropathy/detail_peripheralneuropathy.htm
2. http://www.diabetesincontrol.com/metformin-induced-vitamin-b12-deficiency-presenting-as-a-peripheral-neuropathy/\
3. http://www.cochrane.org/CD004573/NEUROMUSC_vitamin-b-for-treating-disorders-of-the-peripheral-nerves
4. Peripheral Neuropathy and Vitamin B6. University of Virginia.
5. http://askdis.blogspot.my/2015/07/maximum-dose-of-neurobion.html