Viva B(iv)a

This viva is relevant to Section B(v) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe the concepts of effect-site and context sensitive half time". 

Define the term "clearance"

• "Clearance" describes the efficiency of irreversible elimination of a drug from the systemic circulation. 
• Clearance is defined as 'the volume of blood cleared of drug per unit time'."
  - Birkett, 2009

What is the difference between clearance and elimination?

• Elimination is the "irreversible removal of the drug from the body", whereas clearance is "volume of fluid cleared of drug per unit time".
• Elimination as the amount of substance cleared from the blood, whereas clearance is the volume of blood cleared of substance.
• In first order kinetics, elimination rate is proportional to dose. The higher the dose, the greater the rate of elimination. However, clearance rate remains dose-independent: it is a totally theoretical volume of blood which is cleared of the drug per every unit of time, a measure which has nothing to do with the drug dose or concentration.

What is the relationship between elimination rate and clearance?

Elimination rate can be described by the equation, 

The equation can be rearranged to solve for clearance:

How do you calculate clearance?

• On the basis of elimination (by observing the drug concentration diminishing in the plasma)

OR:

• On the basis of excreted dose (eg. urinary concentration)
  

How do clearance  and elimination factor into maintenance dose calculations?

and therefore,

Define the term "extraction ratio"

• Extraction ratio  is a dimensionless term that describes the proportion of the substance removed from the blood by the act of being filtered through a clearance organ.
   
  This ratio is expressed as a fraction or percentage. If one knows the extraction ratio of an organ and the blood flow to that organ, one can estimate the contribution it makes to the total drug elimination from the body.

What is the role of the kidney in drug elimination?

• The kidneys excrete a large proportion of clinically relevant drug substances and their metabolites
• This excretion is a combination of passive glomerular filtration and active tubular secretion
• Some of the excreted drugs may also undergo reabsorption, which decreases their overall clearance
• Small molecules may traffic in and out of the tubules directly though the cell membranes
• A minority of substances are also metabolised by the kidney primarily.

What factors affect the glomerular filtration of drugs?

The degree to which a drug will be filtered depends on some physico-chemical features of the drug:

• Protein binding: as mentioned above, only the free fraction of the drug is filtered, which means that highly protein bound drugs are poorly filtered in the glomerulus
• Charge:  theoretically the negatively charged glomerular basement membrane should repel negatively charged drugs, but practically this does not seem to play much of a role (
• Size: molecules less than 30 Angstroms are freely filtered at the glomerulus. According to classical works by Bott and Richards (1941) the molecular weight limit is somewhere around 14 kDa.

Apart from drug properties, glomerular filtration in general is also influenced by such things as renal disease, renal blood flow, age, etc. 

What are the main characteristics of active drug excretion mechanisms in the kidney?

• There are several active transporter systems, most of which are active in the proximal tubule:
  • Weak acid transporters
  • Weak base transporters
  • Nucleoside transporters
  • P-glycoprotein transporters
• The specific clinical relevance of this:
  • These transport mechanisms are saturable.
  • When there are multiple suitable substrates for the transporters, they will compete with each other.
  • The rate of clearance by secretion depends on renal blood flow 
  • Molecules which are too large to be filtered in the glomerulus may still be cleared renally by these mechanisms
  • Protein-bound drugs are not cleared this way; only the unbound fraction is available for active secretion.

Generally speaking, if the renal clearance of a drug is greater than GFR (i.e. it is cleared faster than a marker solute like creatinine) the drug is most likely being cleared by active secretion.

What are some examples of drugs which are excreted by active transport in the kidney?

Notable substrates for active transport include:

• For weak acid transporters:
  • β-lactam antibiotics
  • Frusemide
  • Hydrochlorothiazide
  • Probenecid
• For weak base transporters:
  • Procainamide
  • Ranitidine
  • Trimethoprim
  • Ethambutol
• For nucleoside transporters:
  • Zidovudine
  • Ribavirin
  • Gemcitabine
• For p-glycoprotein transporters:
  • Digoxin
  • Verapamil
  • Cyclosporin

What are the mechanisms by which drugs are reabsorbed in the tubule?

• Active reabsorption
• Passive diffusion

What factors influence passive reasorption of drugs in the tubule? Give some examples.

• Drug concentration (highly concentrated urine will be full of highly concentrated drugs, which promotes reabsorption)
• Urine flow rate
• Urine pH (determines ionisation)
• Drug ionisation (i.e. ionised vs. non-ionised fractions)

What drug factors favour the active reabsorption of a drug?

• The kidneys will make some attempt to reclaim those substances from the tubular fluid which the organism perceives as valuable.
• These substances include organic acids, water-soluble vitamins, ions and various metabolic substrates like glucose and lactate.
• Therefore, in order to be reabsorbed, a drug molecule has have some chemical resemblance to these substances
• Examples include α-methyldopa, dextrose and ascorbic acid

What is the role played by renal metabolism in drug clearance? Give examples.

• The proximal tubule contains many enzymes (eg. peptidases) which are capable of digestion, i.e. breaking down filtered peptides and proteins into amino acids.
• Examples:
  • Imipenem:  metabolised so well by tubular peptidase that its efficacy in treating urinary tract infectious would be minimal if it were not co-administered with cilastatin
  • Insulin: renal metabolism accounts for approximately 30% of overall insulin elimination

When is drug dose adjustment required in renal impairment?

• Adjustment usually required if the drug is more than 50% renally cleared and the renal function is decreased to less than 50% of normal.

How is renal impairment assessed for the purposes of dose adjustment?

• Assessment of the degree of dysfunction is performed by measuring the creatinine clearance, which is a marker of glomerular filtration rate.
  • Renal clearance of drugs is proportional to creatinine clearance, no matter the mechanism of drug elimination

How is dose adjustment performed, with respect to loading dose and maintenance dose?

• Dose adjustment takes into account creatinine clearance and the fraction of the drug eliminated unchanged.
  • Dose is reduced in proportion to the decrease in creatinine clearance
  • Dose adjustment  = non-renal clearance + (fraction of renal clearance × fraction of residual renal function)
  • The loading dose does not need to be adjusted.
  • Maintenance dosing can be adjusted either by reducing the regular dose, or increasing the dosing interval, or both

What are the major determinants of hepatic clearance?

1. Efficiency of drug removal from the blood (hepatic extraction ratio)
2. Blood flow to the liver

As such, hepatic clearance =  blood flow × extraction ratio

Define the term "hepatic extraction ratio"

"Hepatic extraction ratio ... is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver".

Define the term "Intrinsic clearance"

"[Intrinsic clearance] is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding" - Birkett, 2009

The V_max is the maximal rate of enzymatic reaction which is possible for that specific drug-enzyme interaction. If it is presented with unlimited supplies of substrate, the enzyme system would become saturated and drug elimination would become zero-order. The V_max is the reaction rate at this  plateau of activity.

The K_m is the Michaelis-Menten constant which describes the affinity of the enzyme for its substrate. It is the concentration required to achieve 50% of the maximum reaction rate.

How do changes in hepatic blood flow affect drugs with a low intrinsic clearance? 

For drugs with low intrinsic clearance:

• Hepatic extraction ratio will drop more rapidly with increasing hepatic blood flow
• Hepatic clearance will not increase significantly with increasing blood flow

How do changes in hepatic blood flow affect drugs with a high intrinsic clearance?

For drugs with high intrinsic clearance:

• Hepatic clearance will increase in a fairly linear fashion, in proportion to hepatic blood flow
• Increasing the intrinsic clearance will have diminishing effect on total hepatic clearance 

What are some examples of drugs with a high hepatic extraction ratio?

• Glyceryl trinitrate
• Verapamil
• Propanolol
• Lignocaine
• Morphine
• Ketamine
• Metoprolol
• Propofol

What are some examples of drugs with a low hepatic extraction ratio?

• Diazepam
• Lorazepam
• Warfarin
• Phenytoin
• Carbamazepine
• Theophylline
• Methadone
• Rocuronium

How does critical illness affect hepatic drug clearance?

• Early sepsis: hepatic arterial blood flow increased dramatically (it doubled) during this early hyperdynamic stage of sepsis in sheep who had their caecums ligated and punctured.
• Late sepsis: hepatic blood flow decreases significantly, as does blood flow to all other organs
• Haemorrhagic shock: hepatic blood flow decreases significantly with haemorrhage and hypovolaema; in hypovolaemic dogs the half-life of midazolam was increased by 150% (it's a molecule with intermediate intrinsic clearance).
• Cardiogenic shock: obviously, the decreased cardiac output and widepread splanchinc vasoconstriction leads to significantly decreased hepatic blood flow

Define the term "first pass clearance"

"First pass clearance ... is the extent to which a drug is removed by the liver during its first passage in the portal blood through the liver to the systemic circulation" - Birkett, 2009

What mechanisms are responsible for first pass clearance?

First pass clearance is a combination of:

• Metabolism by gut bacteria
• Metabolism by intestinal brush border enzymes
• Metabolism in the portal blood
• Metabolism by liver enzymes 

What are the implications of high first pass clearance for drug dosing, interactions and adverse effects?

• Drugs with a high first pass clearance will have greater individual variability in plasma concentration.
• Drugs with a high first pass clearance will have a greater difference between the oral and IV doses
• The oral bioavailablility of drugs with a high first pass clearance will be more affected by drug interactions which change enzyme kinetics
• In the presence of portosystemic shunts, some portal blood bypasses first pass clearance and therefore bioavailability of drugs with a high first pass clearance will be increased
• Giving IV and oral doses of drugs with high first-pass metabolism and nonzero renal clearance will generate different quantities of metabolites (oral administration will produce more), which is important if these metabolites are toxic

What are the influences of liver dysfunction on pharmacokinetics ? 

The effects of changes in synthetic function

• The liver synthesises plasma proteins; plasma protein binding influences the volume of distribution
• Low plasma protein levels lead to raised free drug levels (the free fraction increases)
• This process is therefore synergistic with the concurrent decrease in liver blood flow and hepatic extraction ratio
• The liver synthesises plasma esterases and peptidases; these metabolise certain drugs
• Significant liver disease can result in prolonged clearance of drugs which are susceptible to these enzymes (eg. suxamethonium)

The effect of changes in secretory function

• Drugs and metabolites which rely on biliary excretion will be retained, and may require dose adjustment
• Drugs which enjoy enterohepatic recirculation may have decreased halflives due to failure of recirculation
• High bilirubin levels may result in the displacement of drugs from albumin as it competes for binding sites 
• Decreased secretion of bile may result in malabsorption 

The effects of portal hypertension on pharmacokinetics

• Portal venous hypertension leads to shunting of portal venous blood into the systemic circulation
• This has the effect of decreasing first pass metabolism