TACRINE

TACRINE
(tac'rine)
Cognex
Classifications: cholinergic; cholinesterase inhibitor; antidementia agent;
Therapeutic: antidementia; cholinesterase inhibitor
Prototype: Neostigmine
Pregnancy Category: C

Availability

10 mg, 20 mg, 30 mg, 40 mg capsules

Action

Cholinesterase inhibitor, presumably elevates acetylcholine in the cerebral cortex by slowing degradation of acetylcholine release by the remaining intact neurons. Balances pathologic changes in neurons that result in deficiency of acetylcholine in early stages of Alzheimer's disease.

Therapeutic Effect

Slows manifestations of Alzheimer's disease.

Uses

Improvement of memory in mild to moderate Alzheimer's dementia.

Unlabeled Uses

HIV infection (severe dementia), tardive dyskinesia, acute anticholinergic syndrome with possible advantage over physostigmine.

Contraindications

Hypersensitivity to tacrine; patients who develop jaundice while taking tacrine; pregnancy (category C).

Cautious Use

Anesthesia, sick sinus rhythm, bradycardia; history of ulcers, GI bleeding, abnormal liver function; patients with asthma, hypotension, hyperthyroidism, urinary tract obstruction, intestinal obstruction; lactation. Safety and efficacy in children are not established.

Route & Dosage

Alzheimer's Disease
Adult: PO 10 mg q.i.d. (taken between meals if tolerated), increase in 40 mg/d increments not sooner than q6wk (max: 160 mg/d)

Hepatic Impairment
Dose-related hepatotoxic effects have been observed; use with caution or not at all in patients with history of past or current liver disease.

Administration

Oral

Give at least 1 h before meals; bioavailability reduced 30–40% when taken with food. Effectiveness depends on administration at regular intervals.
Titrate dose upward as long as serum transaminase (ALT) levels remain ≤3 x upper limit of normal (ULN).
Reduce daily dose by 40 mg/d when ALT exceeds 3 x ULN but is ≤5 x ULN. Resume titration when ALT returns to normal.
Stop treatment if ALT exceeds 5 x ULN.
Store at room temperature, 15°–30° C (59°–86° F), away from moisture.

Adverse Effects (≥1%)

CNS: Agitation, dizziness and confusion, ataxia, insomnia, somnolence, hallucinations. GI: Nausea, vomiting, belching, diarrhea, abdominal discomfort, anorexia, hepatotoxicity. Skin: Purpura. Urogenital: Excessive micturition and incontinence with UTI infections. Body as a Whole: Diaphoresis.

Interactions

Drug: Prolongs action of succinylcholine and possibly other neuromuscular blocking agents due to inhibition of plasma pseudocholinesterase. Increases theophylline concentrations two-fold. Cimetidine increases concentration of tacrine by 64%. Herbal: Echinacea may increase risk of hepatotoxicity.

Pharmacokinetics

Absorption: Approximately 17% absorbed from GI tract. Food decreases rate and extent of absorption by 30–40%. Onset: 30–90 min. Peak: 2 h. Steady state in 24–36 h. Distribution: Penetrates blood–brain barrier. Protein binding is 55%. Metabolism: Metabolized in the liver by cytochrome P450 system. At least three hydroxylated metabolites have been identified that may be biologically active. Females have lower activity in cytochrome P450 isoenzymes so plasma levels are approximately 50% higher than men with same dose. Elimination: Less than 3% of dose recovered in urine in 24 h. Half-Life: 3.5 h.

Nursing Implications

Assessment & Drug Effects

Monitor for clinical improvement (defined as a 4-point improvement in Alzheimer's Disease Assessment Scale/Cognitive Subscale). Improvement has been observed after 1–4 wk; may take 6 mo for maximum benefit.
Lab tests: Monitor serum transaminase (ALT) levels according to following schedule: Every 2 wk for first 16 wk, then monthly for 2 mo, then every 3 mo thereafter; resume weekly monitoring for 6 wk with each dose increase; continue weekly monitoring if ALT remains more than 2 times normal; if therapy is interrupted more than 4 wk then restarted, resume full ALT monitoring schedule.
Monitor I&O because tacrine may cause bladder outflow obstruction.
Monitor for seizure activity and take appropriate precautions.
Monitor patients with history of angle-closure glaucoma for a worsening of this condition.
Monitor for GI distress and bleeding, especially in patients with a history of peptic ulcer disease or on concurrent NSAID therapy.
Supervise ambulation because dizziness occurs in more than 10% of patients.
Monitor cardiovascular status including periodic ECG monitoring. Assess for fluid retention and worsening of CHF.
Monitor periodically for development of drug-induced diabetes.

Patient & Family Education

Be aware of adverse effects related to initiation of therapy or dosage increases (e.g., nausea, vomiting, diarrhea) as well as delayed effects (e.g., rash, GI bleeding, jaundice). Report adverse effects to the physician.
Do not discontinue or reduce dosage of 80 mg/d or more abruptly because it may precipitate acute deterioration of cognitive function.
Make sure to have regular follow-up and liver function tests.
Tacrine may induce seizures, vertigo, and syncope. Use appropriate precautions.
Understand that tacrine therapy is not a cure and will become ineffective at some point as the disease progresses.

Common adverse effects in italic, life-threatening effects underlined; generic names in bold; classifications in SMALL CAPS; Canadian drug name; Prototype drug

(75)