La descomposición salarial de Oaxaca y Blinder

aPTT ratio < goal range: increase the infusion rate

◾

in increments of 20%.

Recheck aPTT 4 hours after increasing infusion

▸ rate.

side effeCts aNd PreCautioNs

Approximately 40% of patients treated with lepirudin for 10 days develop antihirudin antibodies, which reduce its renal clearance rate and may increase its anticoagulant effect. Therefore, monitoring of the aPTT is required to assess the need for dose adjust-ments as clearance is altered.

As with all anticoagulants, the major side effect of lepirudin is bleeding. Bleeding can occur at vir-tually any site. No antidote is available to counter-act bleeding, but the drug should be discontinued immediately if bleeding is noted. Case reports have suggested that hemofiltration or hemodialysis may be useful. Anemia has also been reported with lep-irudin use.

drug iNteraCtioNs

Drug interactions include medications that increase the risk of hemorrhage such as aspirin, warfarin, and NSAIDs. Some cephalosporin and parenteral penicillin antibiotics may enhance the bleeding risk. Contraindications are similar to those for other anticoagulants .

traNsitioNiNg to warfariN

When transitioning patients from lepirudin to war-farin, the dose of lepirudin should be gradually reduced to reach an aPTT ratio slightly above 1.5 times control before beginning oral anticoagula-tion. An overlap of lepirudin with warfarin of 4–5 days is recommended. Loading doses of warfarin are not required. Once the INR is ≥2 lepirudin can be discontinued .

Summary

The prevention and treatment of VTE can be a dif-ficult area to navigate, as the medications for these indications can carry a high risk. Therapy with UFH or LMWH is effective but requires close attention owing to the severity of their potential side effects.

If the immune-mediated adverse effect of HIT is noted, then the utilization of a direct thrombin inhibitor is warranted. Although practitioners may be starting to become more familiar with argatroban

and lepirudin, caution is needed in certain patient populations. Therefore, a thorough understanding of the dosing, side effects, and pharmacokinetic parameters of these medications is essential.

aNtiePilePtiC mediCatioNs

With multiple drug entities on the market, choos-ing an antiepileptic drug (AED) for a patient can be a daunting task. Patient specific characteristics, administration idiosyncrasies, and side effect pro-files must all be considered to select the medica-tion with the best patient-specific fit. After an AED is initiated, monitoring must be performed to ensure efficacy and tolerability, as well as prevent toxici-ties (or minimize them should they arise). Specially trained to evaluate drug interactions, detect subtle side effects, and interpret lab data regarding medi-cations, pharmacists can be a powerful ally in this drug selection process.

Outlined below are several of the AEDs frequently used to treat seizures in the ICU. Specific FDA-approved indications, mechanisms of action (MOA), drug interactions, and adverse effects are discussed for each medication individually.

carbamazepine (tegretol, carbatrol)

Carbamazepine is an AED indicated for the treat-ment of complex partial seizures, generalized sei-zures, and mixed seizure types including those listed above. Use in patients with absence seizures is not indicated.

meChaNism of aCtioN

While the postulated mechanism of action involves the inhibition of voltage-gated sodium channels, the exact mechanism of action of carbamazepine remains unknown.

adverse effeCts

The FDA has placed a black-box warning on the prescribing of this medication for the risk of agran-ulocytosis and aplastic anemia. These hematologic abnormalities occur 6–8 times more frequently in patients on carbamazepine therapy than those in the general public, but the overall risk remains quite low. Nevertheless, it is recommended that a baseline check and periodic monitoring of com-plete blood counts (CBC) be performed. Potentially

99 table 7.4. Antithrombotics used in clinical practice MedicationMechanism of actionDosingonsetHalf-lifereversal agentMonitoringother considerations Heparin (UFH)Binds to antithrombin III causing a conformational change and inhibition of clotting cascade. Inactivates coagulation factors IXa, Xa, XI, XIIa, and IIa and prevents conversion of fibrinogen to fibrin.

Treatment: continuous IV infusion – weight based protocol Prophylaxis: 5000 units SQ q8–12h IV: immediate SQ: 20–30 minutes

Averages 90 minutes (Dose-dependent)Protamine sulfateaPTT levels MOA: Unable to inhibit fibrin- bound thrombin Side effect: Rare but severe thrombocytopenia (HIT) Other: The mean molecular weight of UFH is 15,000 daltons. Low molecular weight heparins

Binds to antithrombin III and inactivates factors Xa and thrombin. Possess a higher affinity for coagulation factor Xa.

Enoxaparin* Treatment: 1 mg/kg SQ q12h or 1.5 mg/ kg daily Prophylaxis: 30 mg q12h or 40 mg SQ daily Dalteparin Treatment: 100 units/kg q12h or 200 units/kg SQ daily Prophylaxis: 2500 units q12h or 5000 units SQ daily 3–5 hoursEnoxaparin 4.5 hours Dalteparin 3.5 hours Protamine sulfate (less effective than with UFH)

Anti-Xa level (Not routinely needed)

MOA: Unable to inhibit fibrin- bound thrombin Side effect: Cross- reactivity possible with risk of thrombocytopenia (continued)

100

table 7.4. (continued) MedicationMechanism of actionDosingonsetHalf-lifereversal agentMonitoringother considerations ArgatrobanReversibly binds to active catalytic site of thrombin. Inhibits fibrin formation and activation of coagulation factors V, VIII, XIII, protein C, and platelet aggregation.

Standard dose: 2 μg/kg per minute continuous infusion Hepatic impairment: 0.5 μg/kg per minute Maximum dosage: 10 μg/kg per minute 30 minutes39–51 minutes (Up to 181 minutes in severe hepatic insufficiency)

NoneaPTT LevelsMOA: Able to inhibit fibrin- bound thrombin Side effect: No cross-reactivity with UFH for HIT Other: Platelet counts returned to normal after day 3 in 53% of patients with HIT Lepirudin Binds irreversibly and with high specificity to thrombin.

Standard dose: 0.4 mg/kg (max 44 mg) slow IV bolus followed by 0.15 mg/kg per hour continuous IV infusion (max 16.5 mg/h) Renal impairment: 0.2 mg/kg IV bolus followed by continuous infusion started at a lower rate Bolus: 10 minutes Infusion: 40 minutes

1.3 hours (Up to 2 days in severe renal insufficiency)

None aPTT Levels MOA: Able to inhibit fibrin- bound thrombin Side effect: No cross-reactivity with UFH for thrombocytopenia *Requires 50% dose reduction in patients with renal insufficiency (CrCl <50 mL/min); dosing choice based on clinical indication.

Neuropharmacology 101

dangerous dermatological reactions (including Stevens–Johnson syndrome) have been reported, though rarely, with carbamazepine therapy. More commonly reported but less severe side effects include dizziness, drowsiness, unsteadiness, nau-sea, and vomiting. These lesser side effects can be minimized by initiating therapy at the lowest doses and increasing gradually to the therapeutic range.

drug–drug iNteraCtioNs

Many drug–drug interactions can occur with car-bamazepine. Carbamazepine is a substrate and inducer for the CYP 450 hepatic enzyme system, and has an active metabolite, the 10, 11-epoxide. While it is agreed that this metabolite does have antiepi-leptic activity, the clinical significance of this has yet to be determined. Medications which induce the CYP 450 isoenzyme 3A4 will decrease the serum concentrations of carbamazepine by increasing the metabolism of the drug. Examples of these induc-ers include, but are not limited to, theophylline, rifampin, and other AEDs such as phenobarbital, primidone, phenytoin, and felbamate. With felbam-ate, however, research has shown an increase in the presence of the active 10, 11-epoxide metabolite, but the clinical significance of this is unknown.

Inhibitors of CYP 450 3A4 will increase the cir-culating levels of carbamazepine in the body by decreasing its metabolism. These inhibitor medi-cations include, but are not limited to macrolide antibiotics, “azole” antifungals, nondihydropyridine calcium channel blockers, loratadine, cimetidine, and acetazolamide. Valproic acid is also included in this list, but with its addition, increased levels of the active 10, 11-epoxide metabolite are seen.

As an inducer of the CYP 450 enzyme system, car-bamazepine can decrease the effectiveness of other medications by increasing their metabolism. These medications include oral contraceptives, corticos-teroids, dihydropyridine calcium channel blockers, tricyclic antidepressants, warfarin, and other AEDs (including ethosuximide, lamotrigine, phenytoin, tiagabine, topiramate, valproic acid, and zonis-amide). The list of medications that carbamazepine affects is extensive and only partially listed here .

gabapentin (Neurontin)

Though indicated for only adjunctive use in patients with partial seizures (with or without secondary

generalization), its lack of drug interactions makes gabapentin a choice agent in patients with multiple AEDs or other drug therapies.

meChaNism of aCtioN

Though structurally similar to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, gabap-entin appears to lack activity at GABA binding sites, is not metabolized to GABA or a GABA analogue, and does not appear to alter the uptake or release of GABA or other neurotransmitters. Further, gabapentin does not appear to bind to other common neuronal bind-ing sites, which may explain its activity. In vitro stud-ies have shown high binding affinity of gabapentin to voltage-gated calcium channels in animal brain tis-sue, but the clinical significance is unknown.

adverse effeCts

Generally, gabapentin is a very well tolerated med-ication, even when doses are escalated to the high end of the therapeutic dosing range. Neurologic side effects such as emotional lability, hostility, thought disorders, and hyperkinesias seen in patients youn-ger than 12 years of age are not appreciably noted in adult patients. Dizziness, somnolence, ataxia, fatigue, and nystagmus were the most frequently reported side effects in adults, all occurring in >10%

of the treatment population.

drug–drug iNteraCtioNs

As gabapentin is excreted unchanged in the urine and is not highly bound to plasma proteins, the inci-dence of drug-drug interactions is negligible.

levetiracetam (Keppra)

Without the need to monitor drug levels, and with no clinically significant drug–drug interactions, levetiracetam, FDA approved for the treatment of partial seizures, is gaining popularity in use.

meChaNism of aCtioN

The exact mechanism of levetiracetam is unknown.

In animal models, a neuronal binding site for leveti-racetam has been elucidated and may explain anti-epileptic activity.

adverse effeCts

Overall, levetiracetam is a very well tolerated med-ication. One relatively unique side effect described

K. Santa and r. Schuman