Warfarin: Bridging Anticoagulation

suggest the use of bridging in individuals taking warfarin for one of the following conditions

• Embolic stroke or systemic embolic event within the previous three months
• Mechanical mitral valve
• Mechanical aortic valve and additional stroke risk factors
• Atrial fibrillation and very high risk of stroke (eg, CHADS₂ score of 5 or 6, stroke or systemic embolism within the previous 12 weeks)
• Venous thromboembolism (VTE) within the previous three months (preoperative and postoperative bridging)
• Recent coronary stenting (eg, within the previous 12 weeks)
• Previous thromboembolism during interruption of chronic anticoagulation

Other Conditions

• For most other patients on warfarin with atrial fibrillation (ie, for most individuals not included in the list of examples above), we suggest not using bridging anticoagulation.
• avoiding bridging the lower the patient’s baseline thromboembolic risk (eg, lower CHADS₂ or CHA₂DS₂-VASc score and the higher the risk of bleeding.
• This practice is supported by the BRIDGE trial (Bridging Anticoagulation in Patients who Require Temporary Interruption of Warfarin Therapy for an Elective Invasive Procedure or Surgery)
• A potential role for bridging in reducing the risk of "rebound hypercoagulability" has also been proposed; however, this premise is not supported by data from the BRIDGE trial discussed above

Heparin Products

• LMW heparins have similar efficacy compared with unfractionated heparin, are more convenient to use, and generally do not require monitoring
• Heparins can be dosed at prophylactic doses, therapeutic doses, or doses intermediate between the two.
• There are no clinical trial data or practice standards to guide dosing, and clinical judgment is required to determine the appropriate dose for each patient

• Therapeutic dosing
• Therapeutic dosing (also called "full dose") is appropriate for bridging anticoagulation for individuals with a potential arterial thromboembolic source (eg, atrial fibrillation, mechanical heart valve) or VTE within the preceding month.
• enoxaparin, 1 mg/kg subcutaneously twice daily
• Intermediate dosing 
• Intermediate dose anticoagulation may be appropriate for individuals with atrial fibrillation or VTE within the preceding month when bridging is needed but concerns about bleeding are greater.
• enoxaparin, 40 mg twice daily
• Prophylactic dosing 
• Prophylactic dose anticoagulation (also called "low dose") generally is not used for bridging in patients with atrial fibrillation, because there is no evidence that prophylactic dose heparin prevents stroke in this setting.
• This dose level may be reasonable in patients who have had a VTE event between within the preceding 3 to 12 months.
• enoxaparin, 40 mg once daily

Timing of bridging: Preoperative

• initiate heparin bridging three days before a planned procedure (ie, two days after stopping warfarin), when the PT/INR has started to drop below the therapeutic range.
• discontinue LMW heparin 24 hours before the planned surgery or procedure, based on a biologic half-life of most subcutaneous LMW heparins of approximately three to five hours

Timing of bridging: Postoperative

• For those undergoing major surgery or those with a high bleeding risk procedure, therapeutic-dose unfractionated heparin or LMW heparin should be delayed for 48 to 72 hours after hemostasis has been secured
• For most minor procedures associated with a low bleeding risk in which bridging is used (eg, laparoscopic hernia repair), therapeutic-dose unfractionated heparin or LMW heparin can usually be resumed 24 hours after the procedure

Reference

www.uptodate.com

Statins: Cost Effectiveness of Splitting Doses

• In the United States, some major drug plan insurers have implemented tablet-splitting programs that target statins.
• Tablet splitting has been shown to reduce prescription costs substantially without negatively affecting laboratory outcomes or compliance
• In addition, patients have found tablet splitting to be simple and acceptable

Supporting Evidence

• A retrospective chart review of total cholesterol and LDL cholesterol values of patients instructed to split simvastatin or atorvastatin between January 1999 and November 2000
• The overall results for this review demonstrated no statistically significant increase in total cholesterol and LDL cholesterol concentrations. Total cholesterol and LDL cholesterol values actually decreased from presplitting to postsplitting, p = 0.017 and p = 0.003, respectively.

Manufacturers Recommendations

• No information provided on tablet splitting
• Most drug companies oppose pill-splitting. They say it can be dangerous. But studies to date have not shown any adverse impact on health on the drugs listed safe to be split

Not To be Split

• combination medications such as Liptruzet (atorvastatin/ezetimibe), Advicor (lovastatin/niacin) or Vytorin (simvastatin/ezetimibe)
• time-release drugs, such as Altoprev (lovastatin sustained-release tablets), or Lescol XL (fluvastatin sustained-release tablets)

Ways to Split

• don’t use a knife—studies show doing so can result in unequal halves. Instead, get a pill splitter device.
• A good practice is to split your pills one at a time, and take the second half as your next dose

References:

1. https://www.consumerreports.org/cro/news/2014/03/is-it-safe-to-split-my-statin-cholesterol-drug-to-save-money/index.htm
2. https://www.ncbi.nlm.nih.gov/pubmed/11847935
3. Dormuth CR, Schneeweiss S, Brookhart AM, Carney G, Bassett K, Adams S, Wright JM. Open Med 2008;2(3):5–13
4. January 1, 2006 University of Michigan Prescription Drug Plan

Lactulose in Diabetes

Lactulose

• consists of the monosaccharides fructose and galactose
• In the colon, lactulose is broken down primarily to lactic acid, and also to small amounts of formic and acetic acids, by the action of via evolved-beta galactosidase from colonic bacteria, which results in an increase in osmotic pressure and slight acidification of the colonic contents.
• This in turn causes an increase in stool water content and softens the stool.
• In treating heptic diseases (hepatic encephalopathy) it is thought that lactulose draws out ammonia from the body in the same way that it draws out water into the colon.

Affect on Sugar level

• The interaction of lactulose and diabetes is categorised as ‘moderate’
• Product information states that there is a possibility of affected glycaemic control
• Lactulose may contain more than 5 g lactose/galactose/epilactose depending upon the dose taken. This should be taken into account in patients with diabetes mellitus. [15 ml of Lactulose contain 42.7 KJ (10.2 kcals) = 0.21 BU]

Glycaemic Index

• In terms of glycaemic Index, comparatively lactose (45) and galactose (25) has lower index compared to glucose (100).
• However do keep in mind that GI value represents the type of carbohydrate in a food but says nothing about the amount of carbohydrate typically eaten. Thus, a higher consumption of lower index food is still able to increase the sugar level

Studies: Galactose

• Following galactose ingestion, there was a modest transient increase in peripheral glucose and insulin concentrations. This was associated with a modest increase in the glucose Ra (rate of glucose appearance)
• conversion of galactose to glucose in the liver may have been greater than suggested by the increase in glucose appearance in the circulation due to substitution for other gluconeogenic substrates
• Oral galactose is a relatively potent insulin secretagogue, and the insulin response is also additive to that following glucose ingestion

Studies: Lactose

• decrease in the glucagon area response observed with 25 g galactose + 25 g glucose or 50 g lactose was less than that with ingestion of 25 g glucose alone. The latter suggests inhibition of the glucagon response to glucose by the added galactose

Studies : Lactulose

• In a study to test the effects of a preparation containing fibre and lactulose in the form of biscuits on glucose and insulin levels in obesity, they found a contradicting trend that glucose and insulin in response to breakfast and to lunch were blunted by dietary fibre and lactulose, without any trend towards post-meal hypoglycaemia
• However, there is also a single case report that reported a case of a patient with diet-controlled diabetes and cirrhosis who experienced a marked deterioration in glycemic control, requiring insulin use, when he began using a different brand of lactulose syrup. The hyperglycemia resolved and insulin was discontinued after use of the original brand of lactulose syrup was resumed

Recommendations

• Most references suggest of being cautious to the addition of lactulose. However this is not a contraindication
• While may affect the sugar level, most likely it will not affect levels significantly to the extent of impacting diabetes control
• Based on guidelines and data from published literature, food and dietary change with exercise and lifestyle change should be the first step in management. For patients recalcitrant to these changes, laxatives should be the next step of treatment. Treatment should begin with bulking agents such as psyllium, bran or methylcellulose followed by osmotic laxatives if response is poor

References:

1. https://www.drugs.com/disease-interactions/lactulose.html
2. https://www.ncbi.nlm.nih.gov/pubmed/11172481
3. http://www.metabolismjournal.com/article/0026-0495(93)90151-D/pdf
4. https://www.medicines.org.uk/emc/medicine/25597
5. https://beta.nhs.uk/medicines/lactulose/
6. https://www.ncbi.nlm.nih.gov/pubmed/9145450
7. https://www.ncbi.nlm.nih.gov/pubmed/7716610
8. https://www.ncbi.nlm.nih.gov/pubmed/27987136
   

ADR: Bullous on Acyclovir Infusion

Availability in Hospital Keningau:

• IV Acyclovir 250mg

Indication:

• Treatment and prophylaxis of herpes simplex in immunocompromised, severe initial genital herpes and Varicella -Zoster.

 Skin Reactions

• According to previous report, adverse cutaneous reactions have been reported with all routes of administration
• Local inflammation or phlebitis at the injection site are well-known dermatologic reactions of intravenous acyclovir therapy.
• Common dermatological reactions include alopecia, erythema multiforme, photosensitive rash, pruritus, rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, and urticaria
•  Severe local inflammatory reactions, including tissue necrosis, have occurred following infusion of acyclovir into extravascular tissues
• There are rarely reported on acyclovir infusion induced the bullous.
• But recently, Yorulmaz et al., 2015, present a case of localized bullous eruption and phlebitis associated with intravenous acyclovir treatment in a patient with metastatic breast cancer
• Others case reported of acyclovir infusion induced bullous which mostly appeared after 10-15 days of infusion.

References:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271519/
2. https://www.ncbi.nlm.nih.gov/pubmed/26911608
3. https://aidsinfo.nih.gov/drugs/8/acyclovir/39/professional
4. http://www.jacionline.org/article/S0091-6749(16)31818-8/fulltext
5. Formulary Ubat KKM August, 2017

Vitamin C in reducing uric acid level

Availability in Hospital Keningau:

• Tablet Ascorbic Acid 100mg

Vitamin C as serum uric acid lowering:

• According to older research, consuming of vitamin C results serum uric acid reduction

• Research by Juraschek et al., 2010 state that, meta-analysis suggest that oral vitamin C supplementation results in modest SUA reduction.

• While, another research on 2012 conclude that, dietary vitamin C was shown to be more effective than vitamin C tablets in reduction of serum acid concentration 

Vitamin C NOT as serum acid lowering:

• Recent study on 2013 shown that supplemental vitamin C at a dosage of 500 mg/day does not lead to a clinically significant reduction in the SU level in patients with gout.

• The study shown that vitamin C may reduce the production of serum uric acid and risk of developing gout.

• No data that support the use of vitamin C supplementation as a urate-lowering therapy in patients with established gout.

Recommendation:

• Prescribing of vitamin C to gout patient for serum uric acid lowering were not indicated as recent study shown not significantly reduce in SUA level.

• Besides, according to latest FUKKM, vitamin C only indicated for vitamin C deficiency.

• May suggest to patient taking more dietary vitamin C instead of prescribing vitamin C tablet.

References:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3169708/pdf/nihms-300040.pdf
2. https://www.researchgate.net/publication/230562792_Implementing_High_Vitamin_C_Treatments_to_Decrease_Blood_Uric_Acid_Levels_in_Hyperuricemic_Saudi_Patients
3. http://onlinelibrary.wiley.com/doi/10.1002/art.37925/full
4. Formulary Ubat KKM August, 2017

Glyophosate Poisoning Management

• Glyphosate is a non-selective herbicide, widely used in agriculture, forestry, industrial weed control and aquatic environments. 

• Proposed mechanisms of glyphosate surfactant herbicide (GlySH) toxicity to mammals include uncoupling of oxidative phosphorylation and glyphosate-or polyethoxethyleneamine (POEA)-mediated direct cardiotoxicity. 

• It can cause a wide range of clinical manifestations in human beings from skin and throat irritation to hypotension and death

The sign and symptom of Glyphosate toxicity

• Gastrointestinal symptoms are the most common manifestations after oral ingestion. It causes erosion of the gastrointestinal tract, difficulty in swallowing and gastrointestinal hemorrhage. Eye and skin irritation have occasionally been reported from dermal exposure. Inhalation of spray mist may cause oral/nasal discomfort, tingling and throat irritation.

• Cardiovascular, respiratory and renal systems may be affected; and signs and symptoms include tachypnea, dysrhythmias, hypotension, non-cardiogenic pulmonary edema, hypovolemic shock, oliguria and respiratory failure

• Seizures and depressed level of consciousness may also occur. 

• Death was often caused by severe hypotension and respiratory failure.

• Hyperkalemia may occur as a complication of renal failure.

Confirmation of Poisoning

• Glyphosate can be measured in the plasma, with levels above 734 µg/mL being measured in fatal cases

Severity

• The assessment of severity of toxicity is determined by dose ingested and clinical grading of toxicity.
• ingested dose- The ingestions of 5-50 mL may result in no symptoms or minor gastrointestinal symptoms only. 
• Moderate symptoms occur with 50-100 mL of the concentrate and severe symptoms are likely when 100 mL or more of the concentrate are ingested.

Clinical Grading of Toxicity

Asymptomatic

No abnormalities on physical or laboratory examination

Mild	Predominantly gastrointestinal symptoms with stable vital signs and no other organ involvement

Moderate

Gastrointestinal symptoms lasting longer than 24 hours Hypotension, responsive to intravenous fluids Pulmonary dysfunction not requiring intubation Acid base disturbance Evidence of transient hepatic renal damage or temporary oliguria

Severe

Pulmonary dysfunction requiring intubation Renal failure requiring dialysis Hypotension requiring pressor amines Cardiac arrest Coma Repeated seizures Death

Management of Glyphosate Toxicity

• There is no antidote for Glyphosate toicity and treatment is supportive.

• The mainstay of treatment for systemic toxicity is decontamination and aggressive supportive therapy. 

• <1 h after ingestion and who have no evidence of buccal irritation or burns - Gastric lavage or activated charcoal can be administered .

• If the ingestion occurs more than 1 hour, the monitoring should be done as follow:

Supportive 

• Hypotension may develop several hours after ingestion. 
• Cardiac monitoring should be available. 
• Hypotension should be treated initially with intravenous fluids and if unresponsive with pressor amines. 
• There is a risk of pulmonary oedema so aggressive fluid resuscitation is inadvisable. 
• Hyperkalaemia should be corrected.

Respiratory dysfunction

• Respiratory function should be monitored closely, oxygenation assured and intubation with assisted ventilation may be required. 
• If pulmonary oedema occurs positive respiratory pressure may be of value. 
• Urine output should be monitored and prevention of hypovolaemia and hypotension should be a priority. 
• Acidosis usually responds to bicarbonate therapy but may on occasion be resistant.
  

Elimination enhancement 

• Haemodialysis may be of value for renal failure or acidosis which does not respond to bicarbonate.

Severe systemic toxicity 

• The mechanism of action of intravenous fat emulsion (IFE) may be due to the lowering of serum concentration of the free surfactant glyphosate-or polyethoxethyleneamine (POEA)-mediated component of Glyphosate (which are more lipophilic) by dragging into the lipid sink formed by the IFE, thereby blunting its cardiovascular toxicity.

Cloxacillin : Serum Level

Recommended Plasma Concentration

• According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), the MIC threshold to determine the strain sensitivity is 2 mg/L for cloxacillin.
• Until now, the optimal plasma concentration target in order to achieve the best cure rate remains undefined, but as oxa- and cloxacillin are time-dependent antibiotics, a time of 100% above the minimum inhibitory concentration (MIC) was considered to be optimal for efficacy.
• Considering that oxa- and cloxacillin are highly bound to albumin and that their unbound fraction—the available fraction for antibiotic efficacy—in healthy patients is known to be 10%,
• Previous study indicated that a dosing regimen of 1 g dicloxacillin every 6 hours should be effective for S. aureus infections with a mean MIC value of 0.125 µg·mL⁻¹ (achieving 67%T > MIC) (higher bioavailability compared to cloxacillin, 48.8% versus 36.9%)

Population: severe infections treated in ICU

• Defined a target range of total antibiotic concentration of 20–50 mg/L to reach the 100% T > MIC
• At a Median Daily Dosing of 105.5mg/kg [75; 150] produced a median plasma concentration of 134.3mg/L  [65.3; 201].
• Using a percentage of 10% to estimate the unbound fraction of oxa- or cloxacillin, all patients would have had a trough unbound fraction concentration superior or equal to the maximum MIC for oxa- or cloxacillin sensitivity, i.e. 2 mg/L

1. https://annalsofintensivecare.springeropen.com/articles/10.1186/s13613-017-0255-8

Oral Cloxacillin

• At a dose of 2g, average calculated dose based on serum concentration was 649mg (32.9%).
• Oral dose of 500mg cloxacillin produced a peak serum level of 8mcg/ml in adults
• After an oral dose of 500 mg, a peak plasma concentration of 7 to 14 μg per mL is attained in fasting subjects in 1 to 2 hours.
• After an oral dose of 500mg cloxacillin, a peak serum level of about 8 micrograms/mL is reached in about 1 hour.

1. PHARMACOKINETICS OF FLUCLOXACILLIN AND CLOXACILLIN IN HEALTHY SUBJECTS AND PATIENTS ON CHRONIC INTERMITTENT HAEMODIALYSIS. Br. J. clin. Pharmac. (1975), 2, 111-121
2. Infectious Diseases of the Female Genital Tract. By Richard L. Sweet, Ronald S. Gibbs
3. Cloxigen Product Information Leaflet

Intramuscular

• serum level after i.m. cloxacillin is approximately twice that obtained when the same dose is given orally to fasting adults

Concentration in Synovial tissue

• After a 30 min i.v. infusion of 1 g cloxacillin, the concentrations of this antibiotic were measured in plasma and synovial tissue samples from 11 patients undergoing total hip replacement.
• The concentration of free drug in synovial tissue was estimated to be 77% of the total tissue concentration.
• The maximum tissue drug concentration after an i.v. bolus dose is predicted to occur at about 37 min.
• it can be predicted that after an i.v. bolus injection of 1 g cloxacillin the maximum synovial tissue concentration will be reached at 37 min after administration. At this time the estimated free drug concentrations in plasma and tissue should be 0.9 mg/l.

1. Diffusion of cloxacillin into synovial tissue. Br. J. clin. Pharmac. (1992), 34, 275-277

Allergy : Corticosteroid

• Although allergic reactions to corticosteroids do occur, they are, in the vast majority of times, due to intravenous or intramuscular injection.
• Patients can also develop hypersensitivity reactions to nasal, inhaled, oral, and parenteral CS

Systemic Steroids:

• reactions occur more frequently in asthmatic subjects and in patients regularly treated with systemic CSs(e.g. in the case of a missing or transplanted kidney) than in other subjects. 
• However, in these cases, it is difficult to determine whether the higher incidence of allergies observed is due to increased susceptibility, or to greater exposure to CSs.
• Other factors such as hypersensitivity to salicylic acid might also constitute risk factors ; neither can genetic predisposition to CS allergies be excluded
  

Topical Steroids

• The incidence reported in the literature varies between 0.5% to 6%
• People with chronic eczema who require multiple prescriptions of topical steroids are at increased risk of becoming sensitized to topical steroids
• Risk factors for immediate corticosteroids allergy
• Patients requiring repeated doses of steroids e.g., renal transplant patients, severe asthmatics
• Aspirin sensitivity
• Female sex
• Risk factors for allergic contact dermatitis (delayed hypersensitivity) to corticosteroids
• Chronic nonhealing dermatitis / eczema
• Stasis dermatitis
• Chronic hand eczema
• Having allergic contact dermatitis to other chemicals

Cross Reactivity

• There is an antigenic classification of corticosteroids based on their cross-reactivity related to contact dermatitis reactions. 
• Although this deals with delayed hypersensitivity, it could perhaps give one a guide as to what corticosteroid might exhibit the least chance of cross-reacting with 
• Corticosteroids with lower risk of sensitization
• Group C,
• The metylated and halogenated members of Group D,
• Newer synthetic steroids like Fluticasone propionate (cutivate) and mometasone furorate (Elocon) have a lower risk of sensitization

References:

1. http://www.allergyclinic.co.nz/corticosteroid_allergy.aspx
2. https://www.aaaai.org/ask-the-expert/allergic-reaction-prednisone
3. https://www.ncbi.nlm.nih.gov/pubmed/23567983
4. https://www.ncbi.nlm.nih.gov/pubmed/11456363
5. Allergic hypersensitivity to topical and systemic corticosteroids:
   a review. 2009 John Wiley & Sons A/S Allergy 2009: 64: 978–994

Antiepileptic Drugs for Post Stroke Seizure

• Post‐stroke seizure and post‐stroke epilepsy are common causes of hospital admissions, either as a presenting feature or as a complication after a stroke.
• They require appropriate management and support in long term.
•  With an increasingly ageing population, and age itself being an independent risk factor for stroke, the incidence and prevalence of post‐stroke seizure and post‐stroke epilepsy is likely to increase
• The incidence of seizures after stroke has been estimated at 4-20%.
• It is also estimated that epilepsy affects 1% of patients aged over 65 and that the majority of these cases (20-40%) are secondary to cerebrovascular disease.
• There are currently no clear guidelines on use of anti-epileptic drugs (AED) in the management of seizures after a stroke. 
• There is no clear consensus on when to start an AED, which is the best AED to use and for how long to treat patients with an AED. 
• Current practice is often based on the existing guidelines for adult onset epilepsy, both idiopathic and localisation related,and individual physicians experience and preferences

 Choice of AEDs

• The risk of recurrence of post-stroke seizures is 50-90% in those with late-onset seizures

• Both NICE and SIGN guidelines recommend carbamazepine, sodium valproate, lamotrigine or oxcarbazepine as first line treatments for partial seizures and secondary generalised seizures

• The International League Against Epilepsy (ILAE) suggest that lamotrigine and gabapentin are as effective as carbamazepine in partial-onset seizures and that lamotrigine is better tolerated than carbamazepine in older people.

• Both SIGN and NICE guidelines recommend initial AED monotherapy, with trial of a second first-line agent as monotherapy if the first-line drug fails after it has been titrated to a maximum dose
• Postgrade Medical Journal suggests that  carbamazepine, lamotrigine, sodium valproate, and toppiramate as the first line AEDs for both focal (with or without generalised tonic‐clonic) seizures and generalised seizures

• The latest studies regarding post-stroke seizure treatment showed that 'new-generation' drugs, such as lamotrigine, gabapentin and levetiracetam, in low doses would be reasonable because of their high rate of long-term seizure-free periods, improved safety profile, and fewer interactions with other drugs, especially anticoagulant ones, compared with first-generation AEDs. 

• The first-generation drugs, such as phenytoin, carbamazepine and phenobarbital, have the potential to have a harmful impact on recovery, bone health, cognition and blood sodium levels and may interact with other treatments used by the elderly population

Timing to Initiate Therapy

• NICE guidelines suggests to consider AED for a patient after a first unprovoked seizure if the patient has a neurological deficit or abnormality on brain imaging, which could be said to apply to stroke patients.

• The decision to start AED therapy also depends on the perceived risk of recurrent seizures, whose associated risks outweigh the potential side effects of the medications. 

• Based on best available evidence,the recommended treatment is to treat the initial seizure post stroke if it occurs more than seven days after the event.

• The Stroke Council of American Heart Association recommends  that patients with seizure activity more than two weeks after presentation have a higher risk of recurrence and require long term anticonvulsant prophylactic therapy

• Discussion with the patient or relatives about the risks and intended benefits of AED therapy is required

Recommended Duration of Therapy

• Both guidelines suggest discontinuing AED after two years seizure free, although this is a generalised statement and not specific to post stroke seizures.

• Based on another evidence, treating with an appropriate first-line AED, such as lamotrigine or sodium valproate,is recommended for at least 1 year before considering tapering the dose

• Based on The Stroke Council of America Heart Association, early onset seizures need treatment for one month and drug treatment can be stopped if no seizure activity occurred during treatment.

• For late-onset seizures, long term treatment is recommended as the recurrent rate is higher. 

Conclusion

• Most of the guidelines and studies consistently recommend the newer generations of AEDs as the first line treatment of post stroke seizure. 

• According to preferable side effect profile, especially in elder patients,  Lamotrigine is the first option to be initiated in post stroke seizure patients among other newer generation of AEDs.

• If the first-line AED fails to control seizures after being titrated up to an optimal dose as a monotherapy, then switching to another first line agent is recommended with titration up to a maximal dose

• Combination therapy with two or more AEDs is only indicated once two first line agents have been used as monotherapy at optimal doses and should be managed under expert supervision

References

• Use of Anti-epileptic Drugs in Post-stroke Seizures: A Cross-sectional Survey Among British Stroke Physicians January/February 2011. http://www.acnr.co.uk
• Poststroke seizures in the elderly. https://www.ncbi.nlm.nih.gov/pubmed/1868406
• Post‐stroke seizure and post‐stroke epilepsy . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2585721/
• Controlling Post-Stroke Seizure. https://www.strokeassociation.org/idc/groups/stroke-public/@wcm/@hcm/@sta/documents/downloadable/ucm_312968.pdf
• Management of seizures following a stroke: what are the options?. https://www.ncbi.nlm.nih.gov/pubmed/22540349

Hypertensive Urgency : Captopril VS Nifedipine (oral)

• Hypertensive urgencies are defined as severe elevations in blood pressure (diastolic blood pressure above 120 mmHg) without evidence of acute, progressive target organ damage.
• The target organs are primarily the heart, brain, kidneys and large arteries
• Initial treatment should aim for about 25% reduction in BP over 24-48 hours but not lower than 160/90 mmHg.
• A short period (30+ min) of rest in a quiet, dark room often is effective in lowering BP 15-20% & is usually recommended for initial management
• If the initial managment is ineffective, oral drugs proven to be effective and there is no role for intravenous BP lowering drugs.

Oral Drugs for Hypertensive Urgencies: Systematic Review and Meta-Analysis

Drug	Captopril	Nifedipine
Outcome
Total mortality	No trial reported total mortality
Adverse effects	Flushing : (risk ratio 0.22; 95% confidence interval 0.07 to 0.72) Headache (risk ratio 0.34; 95% confidence interval 0.13 to 0.92) (Captopril < Nifedipine)
Proportion of patients with blood pressure decrease	Only one study described this outcome as part of the results, and it showed that the proportion of blood pressure decrease over four hours was 92% for both groups (captopril and nifedipine)
Proportion of patients with target blood pressure of 140/90 mmHg	No trial reported this outcome
Number of patients requiring addition of a second or third drug	_	Four trials reported the outcome of 2 patients in the CCB group required additional drug
Total non-fatal cerebrovascular, cardiovascular and cardiopulmonary events	_	One trial reported one patient with angina after taking CCB to treat hypertensive urgency
Time taken to achieve target blood pressure	Ranged from 30 minutes to 120 minutes	Ranged from 30 minutes to 100 minutes

 

Treatment of Hypertensive Urgencies with Oral Nifedipine, Nicardipine, and Captopril  

(The Journal of Vascular Disease, SAGE publication)

• Nifedipine - BP and HR were assessed for 6 hours after intake of the antihypertensive agents. Within 60 minutes, nifedipine reduced blood pressure by an average of 74.7 mmHg for the systolic and 35.4 mmHg for the diastolic. Average heart rate increased significantly by 11.6 beats/min at within 30 minutes
• Nicardipine and captopril - Produced equivalent falls in systolic (-81.6 and -79.4 mmHg) and diastolic (-37.3 and -33 mmHg) BP respectively, but did not increase HR significantly.
• The authors conclude that nifedipine, nicardipine, and captopril show similar efficacy in the treatment of hypertensive urgencies despite of HR elevation effect. 

Hypertensive Urgency Management - cited from the recent report of the JNC VI (Nov, 1997)

• Concerns regarding short acting nifedipine have arisen due to association with increased AMI, CVA & mortality.
• Revised labeling for short acting nifedipine in the USA recommends against its use in hypertensive crisis. 
• The recent report of the JNC VI (Nov, 1997) also cautioned against the use of nifedipine in hypertensive crisis. 
• In practice, this concern may be greater in older individuals and those at higher risk of cardiovascular/cerebrovascular disease. 
• As always, the risk verses benefit ratio must be considered. 
• Captopril have been suggested as better oral alternatives to nifedipine based on the current understanding of their cardiovascular & cerebral effects. 

Conclusion

• Evidence currently exists to suggest that the use of oral ACEi drugs for hypertensive urgencies produces better outcomes with regard to effectiveness and lower frequency of adverse effects, compared with CCB drugs. 
• Thus, when possible, oral ACEi drugs should be used, except during pregnancy
• However, nifedipine can always be another alternative if captopril is unavailable, contraindicated or untolerated

 References

• Clinical Practice Guidelines: Management of Hypertension 4th Edition
• Oral drugs for hypertensive urgencies: systematic review and meta-analysis. http://www.scielo.br/pdf/spmj/v127n6/09.pdf
• Treatment of hypertensive urgencies with oral nifedipine, nicardipine, and captopril. https://www.ncbi.nlm.nih.gov/pubmed/2042792
• Alternatives to Nifedipine in the Oral Treatment of Hypertensive Urgencies (HU). http://www.rxfiles.ca/rxfiles/uploads/documents/nifed-hu.pdf