Pharmacokinetics and Dosing in Liver Disease

• Bioavailability (BA): proportion of drug delivered to systemic circulation
  • For orally administered drugs: BA is influenced by gut function and first pass metabolism
• Small intestine is the major site of absorption for most orally administered drugs
• Liver disease may cause gastroparesis or impaired GI motility (which delays drug delivery to intestine)
• Vascular congestion (cirrhotic patients with portal hypertension) may slow absorption
• Hepatic insufficiency associated with decreased first pass metabolism and hepatic biotransformation (CYP450 system) leading to increased plasma drug levels
• Quantitative changes in plasma protein levels due to hepatic insufficiency alters protein binding and free drug levels (but likely clinically insignificant)
• Ascites and peripheral edema increase volume of distribution of hydrophilic drugs leading to decreased plasma concentrations
• Therapeutic drug monitoring may be valuable but should be interpreted with caution because changes in protein binding may lead to falsely low estimates
• Always try to measure free drug levels
• Drugs with a small therapeutic window (lithium) should be used with caution or avoided
• Drugs with multi step biotransformation or those with active metabolites (amitriptyline, imipramine, venlafaxine, bupropion) are more complicated to dose
• Generally avoid drugs with long half-lives (e.g., fluoxetine) or extended/slow-release formulations due to unpredictable pharmacokinetics in hepatic insufficiency
• Caution with hydrophilic drugs and/or active metabolites that distribute in TBW as paracentesis, diuresis, and fluid loss can cause rapid changes in fluid status

Adjust dose according to Child Pugh Score:

• Score A (5-6 points): 75-100% regular dose
• Score B (7-9 points): 50% regular dose
• Score C (10-15 points): CAUTION/AVOID USE

Medications Requiring Dose Adjustments in Liver Disease

Psychotropics with hepatotoxic potential:

• Divalproex
• Carbamazepine
• Duloxetine
• Naltrexone
• Disulfiram
• Nefazodone
• Monoamine Oxidase Inhibitors (MAOIs)

Elevated Transaminases (ALT>AST) seen mostly with:

• Olanzapine
• Quetiapine
• Carbamazepine
• Divalproex
• TCAs
• SNRIs
• Benzodiazepines
• NSAIDs
• Acetaminophen
• Statins
• ACEIs
• Omeprazole
• Allopurinol
• Oral Contraceptives

Liver Impairment & Alcohol Withdrawal use:

• Benzodiazepines are usually avoided in patients with encephalopathy, but when needed (e.g., delirium tremens) use benzodiazepines that bypass phase I
• The following benzodiazepines primary undergo glucuronidation and are preferred in patients with hepatic insufficiency (HI):
  • Lorazepam
  • Oxazepam
  • Temazepam

Psychopharmacology in Cardiovascular Disease

• Depression is common after myocardial infarction and in patients with cardiovascular disease.
• Always rule out medical causes (e.g., medications, arrhythmia) of psychiatric symptoms in patients with cardiovascular disease.

Neuropsychiatric Side Effects of Cardiac Medications

Pharmacokinetic Changes in Cardiac Disease

Anxiety/Anxiolytics/Sedative-Hypnotics

• Use Lorazepam, oxazepam, temazepam (No phase 1)
• Benzodiazepines alone have minimal effects on HR/BP
• Uncertain how benzos effect autonomic nervous system
• Buspirone has no cardiovascular effects

Depression/Antidepressants

• Sertraline (Zoloft) – SAD HEART trial (efficacy limited to recurrent depression, depression before cardiac event, or severe depression with HAM-D >20; trend toward reduced adverse cardiac events); ENRICHED trial (reduced mortality, reduced adverse cardiac events)
• Mirtazapine (Remeron) – MIND-IT Trials
• Citalopram (Celexa) – CREATE trial
• Escitalopram (Lexapro) – EsDEPACS trial (Kim et al. 2015)
• Nortriptyline (50-150ng/mL): relatively well tolerated in patients with impaired left ventricular dysfunction (Roose and Glassman 1989); TCAs have Type 1A (quinidine like) properties; TCA Users had increased risk of incident MI (Cohen 2000)
• Paroxetine: Limited data suggesting preferential role in congestive heart failure
• Coronary Artery Disease: Escitalopram, Citalopram, and Sertraline are first line
• Heart Failure: Consider Paroxetine, Mirtazapine, Bupropion, Venlafaxine, or Duloxetine (monitor blood pressure)
• TCAs, Trazodone, and Mirtazapine (antihistamine properties) may increase appetite, promote weight gain, and help insomnia in patients with cardiac cachexia
• Bupropion for weight loss or smoking cessation
• Anti-platelet effect of SSRIs in ischemic Heart disease may be helpful but unknown if clinically significant

Psychosis/Antipsychotics:

QTc prolongation Risk

Risk Factors for Torsades de pointes:

• Hypokalemia
• History of prolonged QT
• High doses
• Multiple QT prolonging agents
• Any history of cardiac disease
• Female gender

Mood Stabilization:

• Lithium:
  • AV Block
  • Bradycardia
  • Avoid in Brugada syndrome
• Valproic acid (Depakote):
  • No direct cardiac effects
  • Thrombocytopenia (↑bleeding risk especially when prescribed in patients taking warfarin)

Psychopharmacology in Renal Disease

• Psychiatric Symptoms in Patients with Renal Disease

• • Depression most common disorder (20%-30%)
  • Systematic review of symptoms in patients with ESRD: fatigue 71%, pruritus 55%, constipation 53%, anorexia 49%, Pain 47%, sleep disturbance 44%, nausea 33%
  • Anxiety in about 50% of ESRD pts (phobia from needles, hemodialysis); PTSD symptoms in 17% of ESRD pts in one study mostly related to hemodialysis
  • Delirium, psychosis, and cognitive dysfunction often accompany acute renal failure with uremia
  • Acute onset of renal failure accompanied by hallucinations should raise suspicion for toxic exposure (e.g., poisonous mushrooms, insecticides)
  • Psychotic symptoms in pts with ESRD may be due to primary psychosis, electrolyte disturbance, stroke, dementia, or toxicity of renal excreted drugs (acyclovir)
  • Uremia presents variably depending on extent and rapidity of renal dysfunction. Mild or chronic uremia: usually mild cog impairment, headache, fatigue
  • Untreated uremia progresses to lethargy, hypoactive delirium, and coma
  • Insomnia affects 50%-80% of dialysis patients (usually associated with metabolic changes, lifestyle factors, depression, and anxiety)
  • Restless leg syndrome especially common in pts on hemodialysis and peritoneal dialysis. Antidepressants and antipsychotics increase risk of RLS in ESRD.
  • Many renal/urological medications can cause psychiatric adverse effects (anxiety, cog impairment, fatigue, confusion, insomnia, decreased libido, irritability)

Psychogenic polydipsia (PP):

• Occurs in 6%-20% of psychiatric patients (most commonly in schizophrenia)
• Resulting hyponatremia is usually mild and asymptomatic unless co-occurring with SIADH or other problem with water excretion
• Diabetes insipidus is distinguished from psychogenic polydipsia by water restriction and measuring urine osmolality. In PP, water restriction leads to urine that is more concentrated
• Treatment of PP*: Water restriction, clozapine, risperidone, olanzapine, B-blockers, acetazolamide, clonidine, enalapril, vasopressin antagonists (vaptans)

*Mostly from case studies, case series, and small RCTs

Pharmacokinetics/Pharmacodynamics in Renal Disease

• Caution with renally excreted drugs in ESRD (lithium, gabapentin, pregabalin, topiramate, paliperidone, risperidone, paroxetine, desvenlafaxine, venlafaxine, memantine)
• Edema is often present in ESRD, increasing volume of distribution for hydrophilic drugs
• Uremic products circulating in ESRD may displace protein bound drugs! Always try to get free drug levels when monitoring as total drug levels can be misleading
• Chronic renal disease can significantly modify phase 1 and 2 hepatic metabolism (reduction in P450 2C9, 2C19, 2D6, 3A4 metabolism).
• Do not overlook potential impairment in renal metabolism as well (drugs are metabolized in the kidney as well as liver).
• In general, in patients with renal insufficiency, use the rule of “two-thirds” (2/3 the normal dose)
• Electrolyte disturbances in renal failure or diuretic therapy may increase the risk of cardiac arrhythmias especially in pts receiving QT prolonging agents

Hemodialysis (HD) Patients:

• Up to 70% of patient older than 55 have moderate to severe chronic cog impairment
• Duloxetine is not properly excreted in HD (CNS Toxic)
• Mirtazapine and Amitriptyline levels ↓ after HD
• Fluoxetine (and norfluoxetine) levels not affected
• TCAs have longer elimination half-life in HD pts
• Lithium in HD patients (give dose after HD treatment)
• Be careful with medications prone to cause orthostasis as HD patients have rapid fluid shifts and are very susceptible to orthostatic hypotension
• Dialyzable drugs (Conventional HD): Gabapentin, Lithium, Pregabalin, Topiramate, Valproate
• Dialyzable drugs (Peritoneal dialysis): Lithium

Medications and effects on Genitourinary (GU) system:

Depression

• All antidepressants may be used in patients with renal failure
• As a general rule, start low and go slow
• Caution with renally excreted antidepressants in ESRD (lithium, paroxetine, desvenlafaxine, venlafaxine*)
• Patients with ESRD more sensitive to side effects of TCAs (nortriptyline and desipramine preferred over other TCAs).

*Note that Venlafaxine half-life is prolonged in renal insufficiency and its clearance is reduced by more than 50% in patients undergoing dialysis

**Note that a large retrospective study found no increased adverse effects of higher versus lower doses of paroxetine, mirtazapine, and venlafaxine

Psychosis

• All antipsychotics may be used in patients with renal failure
• Caution with paliperidone as clearance is reduced in all degrees of renal impairment
• Try to avoid agents prone to cause hyperglycemia in patients with ESRD and diabetes (e.g., Olanzapine, Clozapine)
• In patients with electrolyte disturbances and rapid changes in fluid status, use agents least likely to prolong QT

Mood Stabilization

• Lithium is entirely excreted by the kidneys; Contraindicated in acute renal failure BUT NOT CHRONIC RENAL DISEASE
• For patients on dialysis, lithium is completely dialyzed and may be given as a single oral dose (300-600mg) following HD treatment
• Check Lithium levels at least 2-3 hours after HD treatment because lithium is stored in tissues and needs time to re-equilibrate
• For patients on peritoneal dialysis, lithium can be given in the dialysate
• Careful with Lithium in patients with electrolyte disturbances as Lithium can prolong QT
• Dose adjustment recommendations based on creatinine clearance are available for gabapentin, lithium, topiramate, and carbamazepine (Jacobson 2002).

Infectious Disease Psychiatry

Psychopharmacology in Rheumatology Disorders

Rheumatoid Arthritis and Depression:

• Sertraline (little side effects up to 100mg/day)
• Dothiepin (Effective and well tolerated for depression and anxiety)
• Doxepin (some data)
• Paroxetine (20-40mg/d) and Amitriptyline (75mg-150mg/d): Similar efficacy for pain/depression but paroxetine better tolerated

Osteoarthritis and Depression

• Duloxetine effective in elderly patients with osteoarthritis
• Antidepressants reduce depression and then reduce pain and disability

Pain

• Low dose TCAs (amitriptyline 25mg/day)
• Duloxetine 60-120mg/day

Lupus Cerebritis

• No RCTs
• Corticosteroids first line for CNS inflammation
• Antipsychotics with high D2 receptor potency generally more effective in severe cases for controlling symptoms while on corticosteroids
• Monitor closely for EPS and seizures
• Anticonvulsant mood stabilizers often used for prophylaxis or treatment of seizures as well as mood stabilization
• Avoid benzodiazepines

Drug Induced Lupus (DIL)

• Presentation of DIL: Usually no CNS involvement, mild cytopenia, elevated ESR, elevated antinuclear antibody titers, Antihistone antibodies positive in up to 95% of patient but are not pathognomonic of DIL
• Chlorpromazine and carbamazepine low risk
• Valproic acid, other anticonvulsants, phenelzine, and lithium very low risk
• Isolated reports with sertraline and bupropion
• More commonly caused by rheumatological drugs (infliximab and adalimumab) than psychotropics
• After discontinuing drug, symptoms and titers decline over weeks but recovery can take more than a year

Psychiatric Side Effects of Medications used in treating Rheumatology Disorders

Psychopharmacology in Respiratory Disease

Respiratory depression is commonly seen with:

•   Anticholinergics
•   Benzodiazepines
•   Barbiturates

Evidence for efficacy and safety exists for:

• Citalopram
• Sertraline
• Paroxetine
• Nortriptyline
• Desipramine
• Buspirone
• Modafanil
• Atomoxetine
• Zolpidem
• Zopiclone
• Melatonin
• Ramelteon

Try to avoid the following medications in patients with respiratory diseases:

• Obstructive Sleep Apnea (OSA): Mirtazapine, TCAs, Benzodiazepines
• Asthma/COPD: Highly anticholinergic antipsychotics, beta blockers

Carbamazepine has elevated risk of diffuse parenchymal lung disease​

Psychopharmacology in Patients with Neurological Disease

Post Stroke Depression:

• SSRIs (Citalopram, Sertraline)
• Stimulants (dextroamphetamines, Ritalin)
• Nortriptyline
• Mood stabilizers (valproic acid?)

Pseudobulbar Affect:

• Citalopram
• Sertraline
• Nuedexta

Parkinson’s Disease

Depression:

• Pramipexole
• SSRIs
• TCAs
• Duloxetine
• Pimavanserin? (case studies)

Psychosis (order of what to do):

• Reduce DA agonists
• Lower L-Dopa dose
• Reduce/discontinue anticholinergics
• Pimavanserin
• Clozapine (low dose)
• Quetiapine

Huntington’s Disease

Psychosis/Agitation/Chorea/Tics:

• Haloperidol (low dose)
• Atypical Antipsychotics (clozapine, quetiapine)

Traumatic Brain Injury (click here)

Antipsychotics and Seizure Risk