Extracorporeal Removal of Drugs

Extracorporeal Removal of Drugs

Lecture Objectives

• Understand the meaning of extracorporeal removal of drugs.
• Explain the mechanisms of extracorporeal removal techniques.
• Discuss the advantages, disadvantages, and requirements of these techniques.

What is Extracorporeal Removal of Drugs?

• "Extracorporeal" means "occurring outside the body."
• It's a system for removing undesirable drugs and metabolites without disrupting fluid and electrolyte balance.
• It is crucial for patients with end-stage renal disease (ESRD) and drug intoxication who need help removing accumulated toxins.

Functions of the Kidney

• Regulation of ions in blood:
  • Sodium ($Na^+$), potassium ($K^+$), calcium ($Ca^{2+}$), chloride ($Cl^-$), phosphate ($HPO_4^{2-}$).
• Regulation of blood volume:
  • Adjusting blood volume by eliminating fluid in urine.
• Regulation of blood pH:
  • Excreting variable amounts of hydrogen ions ($H^+$) and conserving bicarbonate ($HCO_3^-$).
• Production of hormones:
  • Calcitriol (calcium homeostasis).
  • Erythropoietin (production of RBCs).
• Excretion of waste:
  • Ammonia and urea (from amino acids).
  • Creatinine (from creatinine phosphate).
  • Drugs.
• Metabolic Functions of the Kidney
  • Fluids & Electrolytes Balance
  • Acid-base balance
  • Enzyme production & Endocrinal role
    • Production of certain enzymes (e.g., renin)
    • Endocrinal roles:
      • Activation of vitamin D
      • Production of erythropoietin

Techniques of Extracorporeal Removal

The most frequently used techniques are:

• Hemodialysis
• Hemoperfusion
• Peritoneal dialysis
• Hemofiltration
• CRRT (Continuous Renal Replacement Therapy)

Hemodialysis

• Principle: Uremic blood is equilibrated with dialysis fluid across a dialysis membrane to remove waste metabolites.

• The dialysate is a balanced solution with electrolytes, dextrose, and other elements similar to normal body fluids but without the toxins.

• The patient's blood is pumped through a dialyzer, exposing it to a semipermeable membrane.

• Blood flows through fibers, and dialysis solution flows around the outside; water and wastes move between the two solutions.

• The cleansed blood is returned to the body.

• Requires access to blood vessels, often through a shunt in the arm (artery and vein).

Process

• An arterial needle allows blood to flow to the dialysis machine, and blood is returned to the patient via a venous needle.
• Heparin is used to prevent blood clotting during dialysis.

Unfractionated Heparin vs. Low Molecular Weight Heparin (LMWH)

Safety of LMWH vs. UFH in Hemodialysis

• LMWH is at least as safe as UFH for extracorporeal circuit anticoagulation in chronic hemodialysis.
• Larger studies are needed to evaluate the safety of LMWH in chronic hemodialysis patients, especially regarding osteoporosis and HIT.

Molecular Weights

Blood Values

• Na = 140 mEq/L
• K = 4.5 mEq/L
• Cl = 100 mEq/L
• $CO_2$ = 24 mEq/L
• BUN = 30 mg/dL
• Cr = 5 mg/dL
• Glucose = 100 mg/dL
• Calcium = 1.2 mmole/L
• Phosphorus = 4 mg/dL
• Magnesium = 2 mg/dL
• Vit B12 = 500 pg/mL
• Albumin = 4 g/dL

Dialysate Values

• Na = 140 mEq/L
• K = 2 mEq/L
• Cl = 100 mEq/L
• $HCO_3$ = 35 mEq/L
• Urea = 0 mg/dL
• Cr = 0 mg/dL
• Dextrose = 200 mg/dL
• Calcium = 2.5 mEq/L
• Phosphorus = 0 mg/dL
• Magnesium = 1.2 mg/dL
• Vit B12 = 0
• Albumin = 0

Arteriovenous Fistula or Graft

• For permanent access, a surgical arteriovenous fistula or graft is created to allow access to the artery and vein.

• Diffusion effectively removes small molecular weight solutes.

Diffusion vs. Osmosis

• Diffusion: Solute moves from high to low concentration across a semipermeable membrane.
• Osmosis: Solvent (water) moves from low to high concentration across a semipermeable membrane.
• Diffusion: process resulting from random motion of molecules by which there is a net flow of matter from a region of high concentration to a region of low concentration.
• Osmosis: diffusion of water across a partially permeable membrane from a dilute solution (high concentration of water) to a concentrated solution (low concentration of water).

Factors Affecting Dialyzability of Drugs

• Characteristics of the dialysis machine: Frequency, duration, transmembrane pressure.
• Membrane: Dialysis membrane.
• Dialysate: Blood flow rate, acid concentrate, NaCL, CaCL, KCL, MgCl, Acetic acid, Dextrose, Final dialysate concentrate, $NaHCO<em>3$, Na, Cl, Ca, Acetate, K, Pure $H</em>2O$, $HCO<em>2$, Mg, Dextrose, $H</em>2O$

Final Dialysate Concentrate

• Na = 137 mEq/L
• Cl = 105 mEq/L
• Ca = 3.0 mEq/L
• Acetate 4.0 mEq/L
• K = 2.0 mEq/L
• Pure $H_2O$
• $HCO_3$ 33 mEq/L
• Mg 0.75 mEq/L
• Dextrose 200 mg/dL

Advantages of Hemodialysis

• Low mortality rate.
• Better control of blood pressure and abdominal cramps.
• Less diet restriction.
• Better solute clearance effect for the daily hemodialysis.
• Better tolerance and fewer complications with more frequent dialysis.

Disadvantages of Hemodialysis

• Restricts independence, as people undergoing this procedure cannot travel.
• Requires more supplies such as high-water quality and electricity.
• Requires reliable technology like dialysis machines.
• The procedure is complicated and requires that caregivers have more knowledge.
• Requires time to set up and clean dialysis machines, and expense with machines and associated staff.

Indications for Hemodialysis

• When rapid removal of the drug from the body is important, as in overdose or poisoning.
• End-stage renal failure.
• Early dialysis is appropriate for patients with acute renal failure in whom resumption of renal function can be expected.
• Renal transplanted.

Hemoperfusion

• During hemoperfusion, blood passes through a cartridge containing a sorbent material that can adsorb toxins.

• Three types of sorbents: charcoal-based, synthetic resins, and anion exchange resins.

  • Examples: Activated charcoal, polystyrene resin, antibody-coated adsorbent.

• Antibody-coated adsorbents target specific substances for increased clearance.

• Charcoal efficiently removes water-soluble protein bound substances in the 1000 – 1500 kDa range.

• Resins are more effective in removing protein-bound and lipid-soluble molecules.

• Clearance depends on size and the affinity of the charcoal or resin for that molecule.

• Direct contact between blood and adsorbent material ensures removal of molecules with great affinity.

Mechanisms of Hemoperfusion

• Adsorption: Charcoal binds substances by Van Der Waals forces, which is irreversible.
• Resin binds substances in a reversible way and can be cleaned with organic solvents.
• Important factors for drug removal:
  • Affinity of the drug for the adsorbent.
  • Surface area of the adsorbent.
  • Absorptive capacity of the adsorbent.
  • Rate of blood flow through the adsorbent.
  • Equilibration rate of the drug from the peripheral tissue into the blood.

Advantages of Hemoperfusion

• Shows outstanding absorption capacity.
• Offers a wide absorption spectrum that includes lipophilic and hydrophilic drugs.
• Requires minimal preparation to make ready for use.
• Offers maximum safety against fine particle release.

Disadvantages of Hemoperfusion

• Hemoperfusion cartridges are expensive.
• Mild transient thrombocytopenia and leukopenia can occur but levels usually return to normal within 24 to 48 hours.
• Adsorption or activation of coagulation factors: may be clinically significant in patients with liver failure.

Differences Between Hemodialysis and Hemoperfusion

• Hemoperfusion has a higher rate of clearance.
• Hemoperfusion is associated with complications like bleeding, thrombocytopenia, and hypocalcemia.
• Hemoperfusion is more efficient at clearing protein-bound and lipid-soluble drugs.
• Hemodialysis has a lower complication rate.
• Hemodialysis is more efficient at clearing drugs with small Vd.
• Hemodialysis has an increased risk of causing hypotension.

Peritoneal Dialysis

• Peritoneal dialysis uses the peritoneal membrane in the abdomen as the filter.

• The peritoneum provides a large natural surface area for diffusion of approximately 1–2 m2 in adults; it is permeable to solutes of molecular weights ≤30,000 Dalton.

• Only a small portion of the total splanchnic blood flow (70 mL/min out of 1200 mL/min at rest) comes into contact with the peritoneum and gets dialyzed.

• Placement of a peritoneal catheter is surgically simpler than hemodialysis.

• Does not require vascular surgery and heparinization.

• A sterile solution containing glucose is run through a tube into the peritoneal cavity.

• The peritoneal membrane is a layer of tissue containing blood vessels that lines and surrounds the abdominal cavity and internal organs.

• Waste metabolites in the body fluid are discharged into the dialysis fluid.

• The dialysate is drained, and fresh dialysate is re-instilled and then drained periodically.

• Slower drug clearance rates than hemodialysis, thus requiring longer dialysis time.

• The dialysate is left there for a period of time to absorb waste products and then drained out through the tube and discarded.

Peritoneal Dialysis Principle

• Transfer by diffusion is the passive transfer of solutes across the membrane, without the passage of solvent (water).

• Diffusion: for solutes

  • From high concentration gradient to low concentration gradient

• Osmosis: for water

  • Depends on concentration of sugar in the dialysate fluid

• The fluid and solute removal can be enhanced by increasing the volume of dialysate and the number of exchanges

• This cycle or "exchange" is normally repeated 4-5 times during the day (sometimes more often overnight with an automated system).

• Each time the dialysate fills and empties from the abdomen is called one exchange.

• A dwell time means the time of dialysate stay in the patient's abdominal cavity.

• Wastes, chemicals, and extra fluid move from the patient's blood to the dialysate across the peritoneum.

Advantages of Peritoneal Dialysis

• No Extracorporeal circuit is needed which avoids the need for anticoagulation

Disadvantages of Peritoneal Dialysis

• Poor solute clearance.
• Poor uremic control.
• Risk of peritoneal infection and mechanical obstruction of pulmonary and cardiovascular performance.

Hemodialysis vs Peritoneal Dialysis

Hemofiltration

• Hemofiltration is a similar treatment to hemodialysis, but it makes use of a different principle

• The blood is pumped through a dialyzer or "hemofilter" as in dialysis, but no dialysate is used

• Reduced efficacy of diffusion for larger MW solutes was the rationale for developing hemofiltration (HF)

• HF has the advantage of removing solutes small enough to pass through the ultrafilter in proportion to their plasma concentration rather than their concentration gradient, as with diffusion

• Driving force is a pressure gradient rather than a concentration gradient

• The rate of solute removal is proportional to the applied pressure that can be adjusted to meet the needs of the clinical situation

• Mechanism: Convection (and not diffusion as in hemodialysis)

• A pressure gradient is applied; as a result, water moves across the very permeable membrane rapidly, "dragging" along with it many dissolved substances, including ones with large molecular weights, which are not cleared as well by hemodialysis

• Salts and water lost from the blood during this process are replaced with a "substitution fluid" that is infused into the extracorporeal circuit during the treatment

• HF requires a large flux of water across a semi- permeable membrane

• Water flux is induced by a pressure gradient from the blood side to the so-called filtrate side of the membrane

• Water flux drags solutes across the membrane

• Selectivity of the process is determined exclusively by the sieving properties of the membrane

• The removal of large amounts of plasma water from the patient requires volume substitution

• Substitution fluid, typically a buffered electrolyte solution close to plasma water composition, can be administered pre or post filter (pre-dilution mode, post-dilution mode)

Hemofiltration - Convection

*Membrane / Filter
Convection
HIGH pressure
Pressure Gradient
Solute dissolved in Solvent
SOLVENT DRAG
LOW
pressure

Difference between Hemodialysis and Hemofiltration

Advantages of Hemofiltration

• Availability
• Less haemodynamic effects and so better tolerated by seriously poisoned patients
• Greater removal of high molecular weight substances e.g. Aminoglycosides, iron-dfo complex
• Continuous technique & so rebound in drug concentration is less likely

Disadvantage of Hemofiltration

• Poorer/slower clearance of low molecular weight substances (< 500D) (this includes most drugs)

CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT)

• The goal of continuous renal replacement therapy (CRRT) is to replace, as best as possible, the lost function of kidneys
• CRRT provides slow and balanced fluid removal that even unstable patients-those with shock or severe fluid overload-can more easily tolerate
• It substitutes for impaired renal function over an extended period of time and applied for or aimed at being applied for 24 hours a day

INDICATION FOR INIATION OF CRRT - RENAL CAUSES

• ARF with cardiovascular instability
• ARF with septicemia
• ARF with septicemia and ARDS
• ARF with cerebral edema

CONTINUOUS RENAL REPLACEMENT THERAPY (CRRT) - NONRENAL CAUSES

• Systemic inflammatory response syndrome
• Crush syndrome
• Lactic acidosis
• C.H.F

Requirements for CRRT

• CRRT requires:
  • A central double-lumen veno-venous hemodialysis catheter
  • An extracorporeal circuit and a hemofilter
  • A blood pump and a effluent pump
• With specific CRRT therapies dialysate and/or replacement pumps are required

Various types of CRRT available

• Slow Continuous Ultrafiltration (SCUF)
• Continuous Veno-venous Hemofiltration (CVVH)
• Continuous Veno-venous Hemodialysis (CVVHD)
• Continuous Veno-venous Hemodiafiltration (CVVHDF)

Slow Continuous Ultrafiltration (SCUF)

• Slow continuous ultrafiltration:
  • Requires a blood and an effluent pump
  • No dialysate or replacement solution
  • Fluid removal up to 2 liters/hr can be achieved
• Primary Goal Safe management of fluid removal
• Large fluid removal via ultrafiltration
• removes fluid but does not allow for significant solute clearance
• usually used for volume overloaded patients with or without renal failure
• rate = 2000 mL/hr (maximum patient fluid removal)
• small amount of ultrafiltration, therefore, you do not have significant solute clearance, just only volume removal
• no replacement fluid

Transport Mechanism: Ultrafiltration

• The movement of fluid through a semi-permeable membrane driven by a pressure gradient (hydrostatic pressure)
• The effluent pump forces plasma water and solutes across the membrane in the filter
• This transport mechanism is used in SCUF, CVVH, CVVHD and CVVHDF
• The fluid that is removed is sometimes referred to as “Ultrafiltrate”

Continuous Veno-venous Hemofiltration CVVH

• This type of CRRT removes large volumes of fluids and waste from the patient.
• It then uses replacement fluids (also known as a substitution solution), which are devoid of toxins, to maintain electrolyte and acid base balance

CVVH-Convection

• Continuous veno-venous hemofiltration
• Requires blood, effluent and replacement pumps
• Dialysate is not required
• Plasma water and solutes are removed by convection and ultrafiltration
• Aims for maximizing convective removal of middle to large molecules
• solutes are removed by convection, no dialysate is used
• usually UF rate of 1-2 L/hr is used
• much higher ultrafiltration rate, therefore, you will have more convection (plasma water moves along concentration gradient) and receive clearance of solute
• rate = 1000 mL/hr (maximum patient fluid removal)
• electrolytes and acid-base are corrected by replacement fluid (R)
• highly permeable membrane which removes low and high molecular weight molecules

Transport Mechanism: Convection

• Removal of solutes, especially middle and large molecules, by convection of relatively large volumes of fluid and simultaneous
• This transport mechanism is used:
  • CVVH
  • CVVHDF

Continuous Veno-venous Hemodialysis (CVVHD)

• This type of therapy primarily uses diffusion along with a cleansing fluid known as a dialysate solution to boost the removal of waste products
• With CVVHDF, large volumes of fluids and waste are removed from the patient.
• Cleansing fluids (dialysate solution) and replacement fluids (substitution solution) are used to replace the “dirty plasma” with clean fluid
• This allows for the removal of large volumes of toxin-filled plasma, while still maintaining electrolyte balance