Pathophysiological Factors Affecting Pharmacokinetics in Renal and Hepatic Disorders

Learning outcome

• Describe the major effects of the following clinical states on the pharmacokinetic behaviour of drugs:
• Renal disorders
• Hepatic disorders

Na + H20
Na +
Aldosterone
Bowman's
capsule
Proximal
tubule
Distal
tubule
Glomerulus
888
ADH
Amino
Glucose acids
H2O
Collecting
tubule
Loop of Henle
1
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Renal disorders

Absorption in Renal Disorders

• little specific information
  (or apparent clinical significance)
• ARF / AKI:
• vomiting (& diarrhoea)
• CRF / CKI:
• Drug/drug interaction - antacids, phosphate
  binders interfere (Ca++, other metal++ )

Distribution in Renal Disorders

• reduced protein binding (\ Cpbound)= ^
  free drug
• displacement and/or low protein levels
• uraemia, hypoproteinaemia both can occur
• total level underestimates free drug
  (phenytoin)
• More free drug = more available for
  Exerting effect
  Distributing
  Eliminating
  Metabolising

Distribution: Oedema and Drug Activity

• oedema
  1 Vd (water soluble drugs)
• tissue displacement
  v Vd (digoxin)
• increased activity of some drugs in CNS due to
  increased levels of "waste"
• increased permeability of BBB
• increased sensitivity - barbiturate, benzodiazepine,
  opiate, phenothiazine

Schematic Representation of Protein Binding

Pharmacologic effect
and clearance
. Free drug
Protein-bound drug
Protein-bound molecules
are not available to exert
pharmacologic effects

Metabolism in Renal Disorders

• renal metabolism rarely significant, except insulin
• 25 hydroxycholecalciferol activation to 1,25 dihydroxycholecalciferol (vitamin D)
• (EPO production)

Excretion in Renal Disorders

• primary importance for many
  drugs/metabolites
• adjust dose or interval for renal
  excreted drugs
• guidelines based on CrCl
• BNF
• Datasheet/SPC
• Specialist renal textbooks
• increase monitoring

Renal Replacement Therapy

• Effects on drugs vary, partially predictable.
  Specialist dose guidelines exist.
• Haemodialysis
  (diffusion - rapid, intermittent, Mw<500)
• Haemofiltration
  (filter - slow, continuous, removes higher Mw)
• Continuous Ambulatory Peritoneal Dialysis
  (CAPD)
  (diffusion; peritoneal membrane - slow/ v slow,
  continuous, usually small effect on drugs)

Haemodialysis Characteristics

• Rapid removal of low Mw
  compounds
• (urea, creatinine, electrolytes).
• Around 4hrs, about 3x weekly
• Very rapid drops during session,
  gradual rise afterwards
• Protein binding, Vd, Mw
• highly bound, large Vd or large
  size "not" dialysed
• If removed, consider
  replacement after session

Haemofiltration Characteristics

• Mostly filtration - less efficient than
  dialysis
• Replace all lost plasma with salt
  solution
• "Gentler" process - safer in
  unstable patient
• Removes most drugs, except v large
• Assume GFR approx 15ml/min
• Haemodiafiltration - combination of
  the 2

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Hepatic disorders

Liver
Right hepatic
duct
Left hepatic
duct
Hepatic
portal vein
Spleen
Common
hepatic duct
Hepatic
artery
Gallbladder
Stomach
Cystic duct-
Pancreas
Duodenum
(first past of
small intestine)
Common
bile duct

Absorption in Hepatic Disorders

• Absorption of fat-soluble
  drugs / nutrients reduced
  in cholestasis
• Bioavailability may be
  increased
• reduced 1st pass
  metabolism
• E.g. if only 10% of your
  drug normally gets
  through, a small reduction
  in 1st pass would DOUBLE
  systemic availability
• reduced enzyme activity
• portal-systemic bypass /
  shunting (advanced
  cirrhosis)

Distribution in Hepatic Disorders

• Ascites can alter total body water
• Possibly worsened by drugs
• NSAID's, sodium containing antacids
• Reduced protein binding (less protein
  made)
• Affects highly protein bound drugs as the
  unbound fraction is increased, so
  interpreting levels is difficult. e.g.
  phenytoin

Ascites is the
accumulation of
fluid within the
abdominal cavity

Schematic Representation of Protein Binding and Pharmacologic Effect

Pharmacologic effect
and clearance
Free drug
Protein-bound drug
Protein-bound molecules
are not available to exert
pharmacologic effects

Metabolism in Hepatic Disorders

• Metabolic capacity of liver generally large
• unless severe hepatic dysfunction
• Depends on individual drug & disease
  type (alcoholic liver disease = high
  metabolism
  ... until very small proportion of cells
  remain)
• Monitor drugs if narrow therapeutic range
• LFT's NOT a measure of enzyme function,
  just level of leakage x number of liver cells
  (many slightly leaky cells = few very leaky
  cells)

Drug Extraction in Hepatic Disorders

• High extraction drugs ("flow
  limited")
• "unlimited" enzyme capacity -
  limited by delivery
• 1st pass metabolism
• e.g. chlormethiazole, verapamil,
  propranolol
• Low/variable extraction
  (capacity limited )
• Either limited enzyme capacity
  exists for that drug or amount of
  free drug present is small (protein
  binding)

Cirrhosis and Drug Metabolism

• Alcohol, drugs, viral hepatitis, toxins
• Widespread necrosis / patchy
  regrowth, diffuse fibrosis, nodules
• Reduced flow through liver, shunting
  of blood
• Affects phase I metabolism rather
  than phase II
  (i.e. Oxidation / Reduction /
  Hydrolysis more than Conjugation)
• Even flow rate limited drugs may be
  affected if severe (i.e. "loss" of large
  % of cells)

Other Factors in Hepatic Disorders

• Synthesis of clotting factors
• impaired vit K absorption and reduced
  capacity
• increased sensitivity to anticoagulants
• warfarin, heparin, (aspirin)
• increased risk if drugs can cause bleeding
• NSAID's (aspirin)
• Removal of "toxic" substances
• Nitrogenous substances from gut (1st pass
  removal)
• If not removed, enter CNS > hepatic
  encephalopathy
• Also, avoid/care with sedative or CNS toxic
  drugs
• opioids, benzodiazepines, tricyclics,
  (antihistamines)

Example: Pain Management in Liver Impairment

• Mr A, 59 year old (M), 100kg
• Background - decompensated liver
  disease (cirrhosis) with ascites.

Analgesic Choice for Mr A

Q. Which ONE of the
following analgesics can be
used for Mr A?
a) Ibuprofen
b) Morphine
c) Paracetamol
d) None of the above
e) All of the above

Pharmacokinetics of Drugs in Liver Disease

PK of the following
drugs in liver disease?
. Absorption - ? fat-soluble drugs
. Distribution - ? protein binding %,
. Metabolism - 1st pass effect, CYP
enzymes
. Elimination - biliary excretion
+ Adverse Drug Reactions?
i.e.) GI bleed. Electrolyte disturbances,
renal impairment, constipation etc ...
+ Hepatotoxicity?

Ibuprofen vs Morphine vs Paracetamol Comparison

• Ibuprofen
  - Lipid soluble
  - Protein binding
  (99%)
  - Extensively
  metabolised via
  liver
  - ADRs?
  o GI bleed
  o Renal impairment
  o Hepatotoxicity
  o
  Fluid retention
• Morphine
  - Low protein
  binding
  - Extensively
  metabolised via
  liver
  - Excreted via
  biliary system
  - ADRs?
  o
  Sedation
  o Respiratory depression
  o
  constipation
• Paracetamol
  - Hepatotoxicity in
  overdose
  (?dose in decomp
  cirrhosis)

Summary of Hepatic Disorders

• normal physiological functions of liver affected (alter kinetics or toxicity of drugs)
• intrinsic capacity of liver may be impaired
• first pass metabolism may be reduced
• liver perfusion may be reduced
• reduce dose of liver metabolised drugs
• cholestasis can affect absorption & clearance
• may also have some renal dysfunction
• avoid hepatotoxic drugs or those that worsen existing imbalance