extracorporeal drug removal

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EXTRACORPOREAL METHODS OF DRUG REMOVAL Presented by Rejin Jose First Year M.Pharm (Pharmaceutics)

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Extracorporeal therapy is a medical procedure which is performed outside the body Methods available for drug removal Hemodialysis Peritoneal dialysis Hemofiltration Hemodiafiltration Hemoperfusion

Slide 3:

For patients with end-stage renal disease and drug overdose to remove accumulated drug and its metabolites Objective: To remove rapidly the undesirable drugs and metabolites from the body without disturbing the fluid and electrolyte balance in the body


Dialysis Process of separating elements in a solution by diffusion across a semipermeable membrane down a conc.gradient

Slide 5:



HEMODIALYSIS: method for removing waste products such as creatinine and urea , as well as free water from the blood when the kidneys are in renal failure Principle: involves diffusion of solutes across a semipermeable membrane

How Does Hemodialysis Work?:

How Does Hemodialysis Work? - A dialysis machine pumps small blood out of the body, mixed with anticoagulant and circulated through a filter called dialyzer. - inside the dialyzer, a porous artificial membrane separates blood from the dialysis fluid (dialysate) - diffusion of extra fluid and wastes from the blood into the dialysate - purified blood is then pumped back into the body.

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Membrane is permeable to water and small ions but is impermeable to blood cells,lipids, or plasma proteins utilizes counter current flow ,ie. dialysate is flowing in the opposite direction to blood flow in the extracorporeal circuit. Counter-current flow maintains the conc. gradient across the membrane at a maximum and increases the efficiency of the dialysis. Pressure in the dialysate compartment is lower than blood compartment

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Hemodialysis machine


Requires access to the blood vessels to allow blood to the dialysis machine and back to the body. TYPES OF HEMODIALYSIS ACCESS For temporary access - a shunt is created in the arm, with one tube inserted in an artery and another in a vein. -tubes are joined above the skin For permanent access -an arterio-venous fistula or graft is created by a surgical procedure How is blood removed and replaced?

How is blood removed and replaced?:

How is blood removed and replaced? An intravenous catheter An arteriovenous (AV) fistula A synthetic graft


Catheters Catheter is introduced (teflon, polyurethane or silicone rubber) into the subclavian or femoral vein Consists of two lumens which is inserted into a large vein to allow large flows of blood to be withdrawn from one lumen, to enter the dialysis circuit and to be returned via the other lumen.

Catheters are of two types:

Catheters are of two types Non-tunnelled - for short term access - catheter emerges from the skin at the site of entry into the vein Tunnelled - for short to medium term access - tunnelled under the skin from the point of insertion in the vein to an exit site some distance away

AV fistula:

AV fistula With minor surgery, an artery is joined to a vein together through anastomosis under the skin. This is most often done in an arm.

AV graft:

AV graft – With minor surgery a soft plastic tube is used to join the artery and vein under the skin -graft is made of polytetrafluoroethylene or chemically treated sterilized veins of animals are used.

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A “Fistula” is the surgical linking of an artery to a vein providing access to blood vessels A “Graft” is tubing surgically placed under the skin, linking an artery to a vein Radial Artery Vein Graft Vein Artery Venous Line Arterial Line

Water system:

Water system Purification is done by water is filtered and adjust temp. Correct pH by adding acid or base Water is run through a tank containing activated charcoal to adsorb organic contaminants Force water through a membrane with very tiny pores (reverse osmosis) Pass water through a tank with ion-exchange resins for final removal of leftover electrolytes


Dialyzer Consists of cylindrical bundle of hollow fibers with semipermeable walls This assembly is then put into a clear plastic cylindrical shell with four openings One opening at each end of cylinder communicates with blood compartment and other two ports with dialysate compartment

A dialyser acts as an artificial kidney:

A dialyser acts as an artificial kidney

Dialysis membrane:

Dialysis membrane Made primarily of cellulose or synthetic materials (eg. polyacrylonitrile, polysulphone, polycarbonate) Membrane with smaller pore size are called Low-flux Those with larger pore size are called High-flux

Dialysis solution:

Dialysis solution Similar to normal body fluids without toxins Contains water, dextrose, electrolytes (K, NaCl, Bicarbonate, acetate, Ca) NaHCO 3 is added in higher conc. to correct blood acidity hypertonic with dextrose to avoid absorption of water from dialysis solution into the circulation

hemodialysis unit's dialysate solution tanks:

hemodialysis unit's dialysate solution tanks

Hemodialysis solution:

Hemodialysis solution Sodium chloride 204.75g Potassium chloride 3.92g Calcium chloride 9.0g Magnesium chloride 5.32g Sodium acetate 166.60g Purified water to 1000ml

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Types of hemodialysis conventional hemodialysis daily hemodialysis nocturnal hemodialysis

Conventional hemodialysis :

Conventional hemodialysis Done 3 times per week, for about 3-4hrs for each treatment, during which patient’s blood is drawn out through a tube at a rate of 3-400cc/min. During treatment, the patient’s entire blood volume circulates through the machine every 15 minutes

Daily hemodialysis:

Daily hemodialysis Used by patients who do their dialysis at home Usually done for 2 hours, six days a week

Nocturnal hemodialysis:

Nocturnal hemodialysis Performed six nights a week and six-ten hours per session while the patient sleeps.

Factors affecting dialyzability of drugs:

Factors affecting dialyzability of drugs Physicochemical and pharmacokinetic properties of the drug Water solubility Protein binding Mole.wgt Drugs with large vol. of distribution Insoluble/fat soluble drugs are not dialyzed. eg. glutethimide Tightly bound drugs are not dialyzed. eg. propranolol Mole. wgt less than 500Dalton are easily dialyzed Dialyzed more slowly

Characteristics of dialysis machine:

Characteristics of dialysis machine Blood flow rate Dialysate Dialysis membrane Transmembrane pressure Higher blood flows give higher clearance rates Composition of the dialysate and flow rates Permeability characteristics and surface area Ultrafiltration increases with increase in transmembrane pressure


Applications Mainly used in chronic renal failure and in poisoning by certain agents such as salicylates, phenobarbitone, methanol,ethylene glycol and lithium .

Dialysis clearance:

Dialysis clearance Measure of how effectively a dialyzer can remove a drug from blood Can be determined by: a. Extraction from blood b. Rate of recovery in dialysate c. Amount recovered in dialysate

Extraction from blood:

Extraction from blood By taking difference b/w rates at which substance enters (Q b,in .C b,in ) and leaves the dialyzer (Q b,out .C b,out ) Cl bD = Q b,in is the blood flow to the dialyzer C b,in is the conc.in the blood entering the dialyzer

Rate of recovery in Dialysate:

Rate of recovery in Dialysate Uses net rate at which substance leaves in the dialysate fluid Q D,out and Q D,in are the dialysate flows leaving and entering the dialyzer C D,out and C D,in are the respective conc.

Amount recovered in dialysate:

Amount recovered in dialysate Using the ratio of amount recovered in the dialysate (V D .C D ) to the area under arterial blood conc. time curve during collection period , V D is the volume of dialysate collected during interval C D is the drug conc.in the dialysate Cb,in is the conc.in the blood entering the dialyzer

Extraction ratio/coefficient:

Extraction ratio/coefficient Under steady state, rate of removal relative to the rate of presentation is a measure of efficiency of a dialysis system Extraction coefficient = Q b,in is the blood flow to the dialyzer

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Effectiveness of dialysis may be evaluated by comparing the half-lives during and between dialysis treatment Supplementary dose is administered in hemodialysis patients to replace the amount lost in the dialysate during the treatment period

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Side Effects of Hemodialysis During treatment patient may: • Feel tired and sleepy • Feel dizzy • Be cold • Have muscle cramps • Have nausea

Slide 40:

Peritoneal dialysis

Peritoneal dialysis:

Peritoneal dialysis Introducing dialyzing fluid into the peritoneal cavity via a catheter and after a period, the fluid is drained and discarded. Principle osmosis and diffusion

Peritoneal dialysis:

Peritoneal dialysis

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The process uses the patient's peritoneum in the abdomen as a membrane across which fluids and dissolved substances ( electrolytes , urea , glucose , albumin and other small molecules) are exchanged from the blood . Membrane restricts the movement of formed elements(eg.erythrocytes) and large molecules(eg.protein) but allows the movement of smaller molecules according to the conc.gradient.

Techniques used for peritoneal dialysis:

Techniques used for peritoneal dialysis Manual intermittent peri.dialysis Automated cycler intermittent peri.dialysis Continuous ambulatory peri.dialysis

Manual intermittent peri.dialysis:

Manual intermittent peri.dialysis Bags containing fluid are warmed to body temp; fluid is infused for 10mins,allowed to remain there for 60 to 90 mins and then drained in about 10 to 20mins

Automated cycler intermittent peri.dialysis :

Automated cycler intermittent peri.dialysis Timed device, performed by people in their home. People set the cycler at bedtime so the dialysis takes place while they are sleeping Performed 6 or 7 nights a week

Continuous ambulatory peritoneal dialysis:

Continuous ambulatory peritoneal dialysis During the day by keeping 2L of fluid in the abdomen at all times Exchanging the fluids 4-6 times per day Connect Drain

Slide 49:

Fill Disconnect/dwell

Peritoneal Dialysis solution:

Peritoneal Dialysis solution Sodium chloride 5.6g Calcium chloride 0.26g Magnesium chloride 0.15g Sodium lactate 5.0g Anhydrous glucose 13.60g Water for inj. To 1000ml Glucose increases osmotic pressure and thereby determines the rate of fluid transfer and facilitates ultra filtration

Dialysis clearance:

Dialysis clearance Expressed as amount of a drug or substance recovered in the drained dialysate relative to the AUC during the dwell time , after administration by any route CL PD = V PC is the dialysate volume in the peritoneal cavity,C PC is the drug conc.in the dialysate,C is the conc.in the blood entering the dialyzer

Slide 52:


Hemofiltration :

Hemofiltration Convective solute transport ie. Movemet of dissolved substances with fluid flow through filtering membrane blood is passed through a set of tubing (a filtration circuit ) via a machine to a semipermeable membrane (the filter ) where waste products and water are removed. Replacement fluid is administered to the patient for volume replacement purified blood is returned to the patient.

Slide 55:

dialysate is not used. positive hydrostatic pressure drives water and solutes across the filter membrane from the blood to the filtrate compartment, from which it is drained. Removes nonprotein bound,small molecules from blood


Continous veno-venous hemofiltration hemofilter is placed between cannulated femoral, subclavian or internal jugular veins Continous arteriovenous hemofiltration blood passes through a hemofilter that is placed between a cannulated femoral artery and vein Types of hemofiltration




Clearance Cl = S x rate uf rate uf = ultrafiltration rate S = Sieving coefficient (ratio of solute conc.in the ultrafiltrate to the conc.in the retentate) Hemofiltration provides a creatinine clearance of 10mL/min used for drugs such as aminoglycosides,cephalosporins and acyclovir

Slide 59:



Hemodiafiltration Hemofiltration in combination with hemodialysis Blood is pumped through the blood compartment of a high flux dialyzer, and a high rate of ultrafiltration is used So high rate of movement of water and solutes from blood to dialysate that must be replaced by substitution fluid that is infused directly into the blood line. Dialysis solution is also run through the dialysate compartment of the dialyzer

Slide 63:

Blood pump is used to drive blood flow through the filter Access is achieved through a catheter Good removal of both large and small mole.wgt solutes



Hemoperfusion :

Hemoperfusion Blood is passed through an adsorbent material which attracts toxic substances. Adsorbent is fixed to a solid surface inside a column. Patient’s blood is passed through the column and toxins bind to the adsorbent material, allowing cleansed blood to flow out of the column.

Slide 67:

Adsorbents used: a.Activated charcoal b.Amberlite resin (Amberlite XAD-2/XAD-4) - Activated charcoal adsorbs both polar and nonpolar drugs -Amberlite resins are available as insoluble polymeric beads, each containing agglomerate of polystyrene microspheres; greater affinity for nonpolar drugs

Slide 68:

heparin is given at the beginning of the procedure and at 15-20mins interval Treatment takes about 3 hrs Useful for rapid drug removal in accidental poisoning and reducing blood conc.of lipid soluble or protein-bound drugs such as medium and short-acting barbiturates and theophylline

Factors for drug removal by hemoperfusion:

Factors for drug removal by hemoperfusion 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

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Drug removed by hemoperfusion is determined from the amount within the cartridge


Reference Malcolm Rowland and Thomas N. Tozer; Clinical Pharmacokinetics; page 443-457 Robert Berkow; THE MERCK MANUAL OF MEDICAL INFORMATION; page 597-601 Leon Shargel; Applied Biopharmaceutics and Pharmacokinetics; page 696-705 Walter Lund; The Pharmaceutical Codex;page 620-625 D.M.Brahmankar; Biophamaceutics and pharmacokinetics a treatise; page 192-194 Milo Gibaldi; Biopharmaceutis and clinical pharmacokinetics; page 278 Howland C.Ansel; Pharmaceutical dosage forms and drug delivery systems; page 502 www.en.wikepedia.org

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Thanks for your attention

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