1. The document discusses factors to consider when prescribing psychiatric medications in patients with liver disease. Liver disease can impact the pharmacokinetics of drugs by altering absorption, metabolism, protein binding, and excretion. 2. Drugs are categorized based on their hepatic extraction ratio and metabolism. High extraction drugs are more susceptible to fluctuations. Interactions with liver enzyme inducers/inhibitors and alcohol are also discussed. 3. When prescribing for patients with liver disease, the degree of impairment, drug metabolism pathway, interactions, and narrow therapeutic index drugs should be considered. Dose adjustments and monitoring are often needed.

1. PRESCRIBING PSYCHIATRIC
MEDICINES IN LIVER
DISEASE
S. Ahamed Fareed
Registrar in Medicine
21-09-2017

2. PLEASE CONSIDER
HIM BEFORE
GIVING
SOMETHING TO ME

3. Scope of this presentation
• Functions of liver
• Clinical features of liver disease
• Understand the few definitions in defining liver diseases
• Causes of liver diseases
• Judicial use of laboratory investigation in assessment of liver disease
• Models and scoring system in the evaluation of liver disease
• Alterations of pharmacokinetics in liver disease
• Why this is important in psychiatric practice

4. Liver : Functions

6. Liver : Functions
• The liver performs several roles in carbohydrate, protein and lipid
metabolism:
Gluconeogenesis ,Glycogenolysis ,Glycogenesis ,Glycogenesis , Glucose buffer
function, Amino acid synthesis, Protein metabolism (synthesis as well as
degradation), Cholesterol synthesis Lipogenesis, the production of triglycerides
(fats), Lipoprotein synthesis and Beta oxidation.
• Synthesis of proteins and hormones
Albumin, Acute phase proteins. Clotting factors, Steroid binding and other
hormone binding proteins
Erythropoietin, IGF-1, Thrombopoietin, Angiotensinogen, 25 hydrxoy
choolecalciferol

7. Liver : Functions cont
• Detoxification
of toxins, steroids, other hormones, drugs, Bilirubin, Urea formation
• Storage:
Vitamins, Glycogen, Iron, Copper
• Immunity: Kupffer cells
• Hematopoisis

8. Clinical features of liver diseases
• Clinical feature depends the causes, stage , complications of and associated co
morbidities.
• Fatigue
• Nausea, loss of appetite
• Vomiting
• Jaundice
• Right upper quadrant pain
• Bleeding manifestation(echymosis, easy bruising,hematemesis,malena)
• Pruritus
• Clay colored stools
• Abdominal distension, Ascites
• Edema
• Muscle wasting
• Altered sensorium

9. Clinical features of liver diseases

10. Clinical features cont….
Pigmentation of face Pallor Jaundice
KF ring Parotid swelling Gynaecomastia
Spider naevi Palmar erythema Leuconychia
Dupyutren’s contracture Half and half nail Asterixis
Testicular atrophy Scratch marks Echymotic patches
Muscle wasting Clubbing Edema
Hepatomegaly Splenomegaly Ascites Dilated veins
Caput medusa

13. Few definitions
• Hepatitis : inflammation of the liver
• Cirrhosis: Cirrhosis represents a late stage of progressive hepatic
fibrosis characterized by distortion of the hepatic architecture and the
formation of regenerative nodules
• Compensated cirrhosis: Patients with compensated cirrhosis do not
have symptoms related to their cirrhosis, but may have asymptomatic
esophageal or gastric varices
• Decompensated cirrhosis : have symptomatic complications related
to cirrhosis, including those related to hepatic insufficiency jaundice,
and those related to portal hypertension ascites, variceal
hemorrhage, or hepatic encephalopathy.

14. Few definitions….
• Acute liver failure : Development of severe acute liver injury with
encephalopathy and impaired synthetic function (INR of ≥1.5) in a
patient without cirrhosis or preexisting liver disease in <26 weeks.
• Chronic liver failure: Development of liver injury characterized by
encephalopathy and impaired synthetic function (INR of ≥1.5,
albumin < 30g/l), with or without evidence of portal hypertension in a
patient without cirrhosis or preexisting liver disease in > 26 weeks
• NAFLD : in which fat builds up in the liver
• NAFL :hepatic steatosis is present without evidence of significant
inflammation
• NASH : Hepatic steatosis is associated with hepatic inflammation

15. Causes of liver disease

16. Causes of liver disease
• TOXINS
• Chronic alcoholism, Aflatoxins, drugs
• METABOLIC
• NAFLD, Hemochromatosis, Wilson’s disease, Alpha 1 anti- trypsin deficiency
• VIRAL
• Hep A,B,C,D,E
• VASCULAR
• Hepatic vein obstruction, Chronic right side heart failure, portal vein thrombosis
• AUTOIMMUNE
• PBC, PSC , auto immune hepatitis
• Biliary tree Obstruction
• CBD calculi, cholangiocarcinoma, biliary atresia, pancreatic tumors

17. Laboratory investigations in the liver disease
• To assess the extent of hepatocellular damage
• To assess the hepatocellular functions
• To assess the patency of biliary systems and venous drainage
• To assess the possible causes of the disease
• To assess the severity and stage the disease process
• To assess the associated co morbidities
• To assess the efficacy of treatments for liver disease
• To monitor the progression of a disease such as viral or
alcoholic hepatitis.

18. Lab Investigations…
• AST-ALT-ALP
• Bilirubin – total/indirect
• Albumin
• INR
• Glucose (RBS)
• Na-K, PH
• FBC/plt
• Ammonia
• Viral serologies
• ANA-ASMA-AMA
• Ceruloplasmin
• Iron profile, PCM levels
• Blood cultures
The pattern of
abnormalities on these
tests is more accurate
than any of the
individual tests

19. • ALT is present in highest concentration in the liver. AST is found, in
decreasing order of concentration, in the liver, cardiac muscle,
skeletal muscle, kidneys, brain, pancreas, and AST is less specific
than ALT for liver disease.
• AST and ALT are elevated in most liver diseases.
• Elevations up to eight times (300 IU/l) the upper limit of normal
are nonspecific and may be found in any liver disorders.
• AST , ALT > 1000 occur in disorders associated with extensive
hepatocellular injury, such as acute viral hepatitis, ischemic
hepatitis, autoimmune hepatitis and acute drug- or toxin-induced
liver injury (PCM toxicity)

20. • The AST/ALT ratio is approximately 0.8 in normal subjects.
• AST > ALT in alcoholic liver disease and a ratio greater than
2:1 is suggestive of this disorder
• Several other patterns of laboratory abnormalities may also
be supportive of the diagnosis of alcoholic liver disease:
• >2 folds rise in the GGT in patients whose AST to ALT ratio is
> 2 strongly suggests alcohol abuse
• High AST and ALT levels can occur in patients with primary
muscle disease, A concurrent increase in CPK, LDH levels
suggests muscle source

21. NAFLD
• NAFLD may present solely with mild elevations of the serum
aminotransferases.
• The diagnosis of NAFLD requires all of the following
• Demonstration of hepatic steatosis by imaging or biopsy
• Exclusion of significant alcohol consumption
• Exclusion of other causes of hepatic steatosis.
• NAFLD is subdivided into nonalcoholic fatty liver (NAFL) and
nonalcoholic steatohepatitis (NASH)
• NAFLD is more common in women, and associated with obesity,
type 2 diabetes mellitus, hypertriglyceridemia and metabolic
syndrome.

22. • Ratio of AST to ALT is usually less than one (ALT > AST)
• The initial evaluation to identify the presence of fatty
infiltration of the liver is radiologic imaging including
ultrasonography, CT, or MRI
• Radiologic imaging cannot identify inflammation. Thus, the
differentiation between NAFL and NASH requires a liver biopsy

23. • Tests of hepatic injury/inflammation:
• Aspartate aminotransferase (AST)
• Alanine aminotransferase (ALT)
• Gamma-glutamyl transpeptidase (GGT)
• The tests of liver function:
• INR, PT, Albumin, Bilirubin ( measures the liver's ability to detoxify metabolites and
transport organic anions into bile)
• Indicators of cholestasis
• ALP>>AST/ALT
• Conjugated bil>> unconjugated
• ↑GGT,
• USG- Intrahepatic biliary duct dilation

25. Evaluation of liver disease
• Establishing the etiologic diagnosis: hepatocellular, cholestatic or
mixed
• Estimating the disease severity (grading): active or inactive, mild to
severe
• Establishing the disease stage: acute or chronic, pre-cirrhotic,
cirrhotic, or end stage

26. Models and scoring systems to assess the severity
of liver diseases
• The prognosis of liver disease is highly variable since it is influenced by a
number of factors, including etiology, severity, presence of complications, and
comorbid diseases
• NAS :
• NAFLD activity score is a validated score that is used to grade disease
activity in patients with NAFLD.
• The NAS is the sum of the biopsy's individual scores for steatosis
• NAS of 1 or 2 corresponds to NAFL, 3 to 4 corresponds to borderline NASH,
and a score ≥5 corresponds to NASH
• Child-Turcotte-Pugh Score (CTP)
• CTP has been shown to accurately predict outcomes in patients with
cirrhosis and portal hypertension. widely used to assess the risk of mortality
in cirrhotic patients.

27. Child-Turcotte-Pugh Score

28. • Model for End-stage Liver Disease (MELD)
• Estimates the survival probability of a patient with end-stage liver disease
• Include bilirubin, INR and serum creatinine
• Glasgow alcoholic hepatitis score
• A multivariate model predicting mortality in alcoholic hepatitis.
• Include age, bilirubin (day 1 and 6 to 9), blood urea, PT, WBC
Day 28
survival ( % )
Day 84
survival ( % )
Day 1 score
GAHS <9 87 79
GAHS >9 46 40
Day 6-9 score
GAHS <9 93 86
GAHS >9 47 37

30. Pharmacokinetics

31. Effect of Hepatic Disease on Pharmacokinetics
• Hepatic disease may lead to
• Increased or decreased absorption,
• Altered first pass metabolism (development of portosystemic
shunts that may carry a drug absorbed from the gut through
the mesenteric veins directly into the systemic circulation)
• Variable bioavailability after oral administration
• Drug accumulation
• Failure to form an active or inactive metabolite
• Alteration in drug protein binding, and kidney function.
• Drug distribution In the patients with liver cirrhosis: (oedema
and ascites)volume of distribution of hydrophillic drugs is
increased
• Reduction in intrinsic hepatic clearance

32. Some examples of drugs with high and low
hepatic extraction
High extraction ratio Low extraction ratio
Antidepressants
Chlorpromazine/haloperidol
Calcium channel blockers
Morphine
Glyceryl trinitrates
Levodopa
Propranolol
Non-steroidal anti-inflammatory
drugs
Diazepam
Carbamazepine
Phenytoin
Warfarin
Portosystemic shunts will decrease hepatic
blood flow and lower hepatic clearance thus risk
toxicity of drugs with high extraction ratio

33. Hepatic enzyme induction and inhibition
• Liver microsomal enzyme inducers: drugs that increase the activities
of liver microsomal enzymes and increase the metabolism of itself
and other drugs.
• Induction of drug metabolism can lead to unexpected drops in drug
concentration or the build up of metabolites.
• Liver microsomal enzyme inhibitors : drugs that decrease the
activities of liver microsomal enzymes and decrease the metabolism
of itself and other drugs.
• Inhibition of drug metabolism can lead to unexpected accumulation
of drugs.
• The major organ involved in the metabolism is liver, and major
enzyme is CYP 450.

34. Alcohol and liver drug metabolism
• An acute ingestion of alcohol may inhibit a drug's metabolism by competing
with the drug for the same set of metabolizing enzymes.
• Hepatic enzyme induction may occur with chronic excessive alcohol
ingestion resulting in increased clearance of certain drugs (for example
phenytoin, benzodiazepines).
• After these enzymes have been induced, they remain so in the absence of
alcohol for several weeks after cessation of drinking.
• Some enzymes induced by chronic alcohol consumption transform some
drugs (for example paracetamol) into toxic compounds that can damage the
liver

36. Factors to consider when prescribing in liver disease
• Determine the degree of hepatic impairment, by hepatic enzyme
levels , bilirubin level, PT/INR , albumin and possibly as ultrasound of
the liver with portal vein Doppler study.
• Ascertain how much the drug depends on hepatic metabolism
• If > 90% of the drug is excreted unchanged in the urine, then hepatic
impairment is unlikely to play a significant role in accumulation of the drug
• If there is doubt about the degree of hepatic impairment or the drug
has a narrow therapeutic index, then lower the recommended
starting dose by 50% and titrate to effect under careful supervision -
'start low and go slow’
• Determine possible interactions between the new drug and any drugs
the patient is already taking

37. Why this is important in psychiatric practice
• Drugs used in the psychiatric practice are itself hepatotoxic , which
may induce the hepatic insult
• Hepatocellular -Fluoxetine, Paroxetine, Risperidone, Sertraline,
Trazodone, valproate
• Cholestasis- Chlorpromazine
• Mixed –Amitriptyline, Carbamazepine, Cyproheptadine,
Phenobarbital, Phenothiazines, Phenytoin and Trazodone
• Presence of liver impairment will affect the drugs pharmacokinetics in
many ways, which ultimately result in high or low blood levels of drug
• Psychiatric drugs depend on hepatic metabolism and hepatic
excretion
• Drugs High extraction ratio will be shunted to systemic circulation
due to reduced Porto-hepatic blood flow secondary to portal
hypertension
• Antidepressants, Chlorpromazine/haloperidol

38. • Alcoholism is common among psychiatric patients , pharmacokinetic
interaction between alcohol and drugs is more complex
• SSRI are liver enzyme inhibitors therefore there is a possibility of toxic
accumulation of concurrent medication.
• Patient with psychiatric illness may be having drugs for medical
condition which may be altering the effectiveness of psychiatic medicine
via altered liver metabolism

39. How to work out the individual drug
pharmacokinetics and drug-drug interections
• Lets use the tech

41. • A lady of 65 years who is living alone , has been suffering from weakness,
polyuria, weight gain and occasional diarrhoea for two months. She is
hospitalized because of dysarthria , confusion and drowsiness for 48 hours.
She was suffering from depression for long time and took treatments
• FBC
• Hb- 10.5 , WBC 11 000 N 80, L 16 PLT 280
• RBS -5.4 mmol/L
• Na- 155 mmol/L, K- 6.1 mmol/L
• Bicarb – 11.8
• Creat – 1.5 mg/dl
• TSH - 18 (0.3- 5 mIU/ L
• ECG- low voltage , CXR- normal, CT Brain- age specific cerebral atrophy
• What is the most possible diagnosis?
• Suggest three investigations?

42. Take home message
• Prescribing in hepatic impairment is less well defined when compared to
guidelines for prescribing in renal failure.
• Hepatic dysfunction is less overt and may not be apparent until much of the
functioning liver is lost.
• Knowledge of the metabolism of drugs eliminated by the liver is useful along
with close monitoring of the patient for unwanted adverse effects related to
possible toxicity.
• Drugs with a narrow therapeutic range that are extensively metabolized by the
liver (> 20% by hepatic metabolism) should be avoided or used with extreme
caution in patients with significant liver disease
• When introducing long-term treatment with a drug with high hepatic clearance
or a narrow therapeutic index, assess liver function (clinically and with baseline
liver function tests)