EXCRETION OF DRUG

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EXCRETION OF DRUG

• Dr. Muslim Suardi, MSi., Apt.
• Faculty of Pharmacy
• University of Andalas
• 2009

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Excretion of Drug

• Removal of the intact drug
• Metabolites
• Drug molecules

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Renal
Sweat
Bile

EXCRETION
Nail
Saliva
Other fluids
Hair
Milk
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Excretion of Drug
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• RENAL
• EXCRETION

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RENAL EXCRETION

• Nonvolatile drug
• Polar (easily removal)
• Water soluble
• Low MW, lt300
• Metabolites
• Slowly biotransformed by the liver

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Feces

• Drug not absorbed by GIT
• Bile excretion, no absorption in intestinal

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Biliary Excretion
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Drug Excretion
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Breast Milk

• Affect on baby

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Lung

• Important in excretion of general anesthetic drug
  
• Non polar
• Gas
• Drug/metabolites in small amount

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Tears

• Example Rifampicin
• Important in drug information services to
  patients

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Saliva

• Example Excretion of Potassium Iodide

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Sweat

• Smelly

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Kidney

• Main excretory organ for removal of metabolite
  waste
• Plays major role in maintaining the normal fluid
  composition
• Maintain salt water balance kidneys excretes
  electrolytes, water, waste product
• Located in the peritoneal cavity
• Nephrons basic functional unit

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Nephrons

• Basic functional unit
• Responsible for the removal of metabolite
• Maintain of water electrolyte balance
• Reabsorb of water by longer loops of Henle

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Kidney blood supply

• Kidney is supplied by blood via the renal artery
• Afferent arteriole carries blood toward a single
  nephron into glomerular portion of nephron
  (Bowmans capsule)
• Filtration of blood occurs in the glomeruli in
  Bowmans capsule

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Kidney blood supply

• From glomerulus, the blood flow out via the
  efferent arterioles
• Then into a second capillary network that
  surrounds the tubules

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RENAL DRUG EXCRETION

• Include any combination of
• Glomerular filtration
• Active tubular secretion
• Tubular re-absorption

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Glomerular Filtration

• About 180 L of fluid/day are filtered through the
  kidneys
• Average urine volume is 1-1.5 L
• Besides fluid regulation, the kidney also
  regulates the retention or excretion of various
  solutes electrolytes

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Glomerular Filtration

• Most small molecules are filtered through
  glomerulus from plasma
• The filtrate contains some ions, glucose,
  essential nutrients as well as waste products

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Glomerular Filtration

• Waste products such as urea, phosphate, sulfate,
  other substances
• The essential nutrients water are reabsorbed at
  various sites including the proximal tubule,
  loops of Henle, distal tubules

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Glomerular Filtration

• Both active reabsorption secretion are involved
  
• The urine volume is reduced
• Urine generally contains a high concentration of
  metabolic wastes elimination drug products

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Glomerular filtration

• Unidirectional process for most small MW
• Including Non-ionized ionized drugs
• Protein bound drugs (large), not filtered
• Pore diameter of glomeruli capillary 70 nm
• Hydrostatic pressure

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Renal Function

• An indication of the state of the kidney its
  role in physiology
• Creatinine, urea, electrolytes, inulin were
  used to determine renal function.
• These measures are adequate to determine whether
  a patient is suffering from kidney disease.

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GFR

• To know renal patients
• GFR is measured by using a substance that is
  eliminated by filtration only
• The substance is neither reabsorbed nor secreted

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Glomerular Filtration Rate

• Inulin Creatinine
• Clearance of inulin will be equal to the GFR
  (125-130mL/min)

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Calculation of GFR

• By comparing urine creatinine levels with the
  blood test results.
• It gives a more precise indication of the state
  of the kidneys.

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Inulin

• Polyvalent carbohydrate
• No protein binding
• No secretion into tubule
• No reabsorption from tubule
• Excretion into urine merely by glomeruli
  filtration
• Plasma inulin is excreted by filtration only no
  reabsorption

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Glomerular filtration

• The value for the GFR correlates fairly well with
  BSA
• GF of drugs is directly related to the free drug
  concentration in plasma
• As the free drug concentration in plasma
  increases, the GF for the drug will increase
  proportionally

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GFR

• The GFR is expressed in mL/min.
• For most patients, a GFR over 60 mL/min is
  adequate.
• GFR measurements can aid a nephrologist in
  deciding when to initiate dialysis or renal
  transplantation.

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Corrected GFR

• Very often, the GFR is expressed as ml/min/1.73
  m2.
• GFR needs to be corrected for the BSA
• Most adults have a BSA that approaches 1.7
  (1.6-1.9), extremely obese or slim patients
  should have their GFR corrected for their actual
  BSA.
• BSA can be calculated on the basis of weight
  height.

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Ampicillin

• Excretion mainly via glomeruli filtration
• Therapeutic ratio very wide
• May be excreted via bile
• GFR decrease, non renal excretion increase
• No individualization in dosage regiment

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Furosemide

• GFR decrease, non renal excretion increase
• No individualization in dosage regiment

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Kanamycin

• Excretion primarily by renal clearance
• Narrow therapeutics index
• If Cl lt 35 mL/min
• 1. Dose should be reduced
• 2. Usage should be considered

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NOMOGRAM

• Relationship between GFR Dose
• Avoid over dose
• Calculation the proper dosage regimen
• A quick dosage regimen adjustments for patient
  with characteristics requiring adjustments such
  as
• Age
• BW
• Physiology state

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NOMOGRAM

• Some nomograms make use of certain physiologic
  parameters, such as serum creatinine
  concentration, to help modify the dosage regimen
  according to renal function
• For marketed drugs, the manufacturer often
  provides tabulated general guide-lines for use in
  establishing a dosage regimen for patient,
  including L M dose

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NOMOGRAM

• The result displayed diagrammatically on special
  scaled axes to produce a simple dose
  recommendation based on patient information

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Active Renal Secretion

• A carrier-mediated system that requires energy
  input, because the drug is transported against a
  concentration gradient
• Carrier system is capacity limited may be
  saturated
• Drugs with similar structures may compete for the
  same carrier system

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Active Renal Secretion

• 2 active renal secretion systems weak acids
  weak bases
• Ex probenecid will compete with penicillin for
  the same carrier system (weak acid)
• Active tubular secretion rate is dependent on
  renal plasma flow
• Compound commonly used to measure active tubular
  secretion PAH, Diodrast

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Active Renal Secretion

• Both of substances are filtered by the glomeruli
  secreted by the tubular cells
• Active secretion is extremely rapid
• All the drug carried to the kidney is eliminated
  in a single pass.
• The clearance of these compounds, reflects the
  effective renal plasma flow (ERPF)
• 425-650 mL/min

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Active Renal Secretion

• Drug that is excreted solely by glomerular
  filtration, t1/2el may changed markedly in
  accordance with the binding affinity of the drug
  for plasma protein
• In contrast, protein binding has very little
  effect on t1/2el of a drug excreted mostly by
  active secretion

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Active Renal Secretion

• Because drug protein binding is reversible, the
  bound drug free drug are excreted by active
  secretion during the first pass through the
  kidney.
• Ex Some of the penicillin are extensively
  protein bound, but their elimination half lives
  are short due to rapid elimination by active
  secretion.

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Tubular Reabsorption

• Occurs after the drug is filtered through the
  glomerulus
• Can be active or passive
• If a drug is completely reabsorbed (eg. glucose),
  then the value for the clearance of the drug is
  approximately zero
• For drugs that are partially reabsorbed,
  clearance value will be lt GFR of 125-130 mL/min

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Tubular Reabsorption

• Reabsorption of drugs that are acids or weak
  bases is influenced by the pH of the fluid in the
  renal tubule (ie. urine pH) pKa of the drug.
• Both of these factors together determine the of
  ionized unionized drug
• Generally, unionized species is more lipid
  soluble has greater membrane permeability

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Tubular Reabsorption

• The unionized drug is easily reabsorbed from the
  renal tubule back into the body
• This process of drug reabsorption can
  significantly reduce the amount of drug excreted,
  depending on the pH of the urinary fluid pKa of
  the drug
• The pKa of the drug is constant, but the normal
  urinary may vary from 4.5 to 8.0

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Tubular Reabsorption

• Variation of urinary pH depending on
• 1. Diet
• 2. Pathophysiology
• 3. Drug intake
• Higher urine pH caused by
• Vegetable diets
• Lower urinary pH caused by
• Diets rich in carbohydrates
• Diets rich in protein

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Drug

• Ascorbic acid NH4Cl may decrease the urine pH
• Antacid (Na2CO3) may increase the urinary pH
• I.V fluids, such as solutions of HCO3- or NH4Cl,
  are used in acid-base therapy.
• Excretion of these solution may drastically
  change urinary pH alter drug reabsorption
  drug excretion

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Tubular Reabsorption

• of ionized weak acid drug corresponding to a
  given pH can be obtained from the
  Henderson-Hasselbalch equation

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Tubular Reabsorption

• Henderson-Hesselbalch Equation
• For weak acids
• ionized drug
• pH pKa log ______________
• unionized drug

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Tubular Reabsorption

• The extent of ionization is more greatly affected
  by changes in urinary pH with a pKa of 5 than
  with a pKa of 3
• Weak acids with pKa values lt 2 are highly ionized
  at all urinary pH values are only slightly
  affected by pH variation

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Tubular Reabsorption

• Henderson-Hesselbalch Equation
• for weak base
• unionized drug
• pH pKa log ______________
• ionized drug

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Tubular Re-absorption

• The greatest effect of urinary pH on
  re-absorption occurs with weak base drugs with
  pKa values of 7.5 - 10.5

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Tubular Re-absorption

• From the Henderson-Hesselbalch relationship, a
  concentration ratio for the distribution of a
  weak acid or basic drug between urine plasma
  may be derived

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Tubular Re-absorption

• Urine-plasma ratio for weak acids
• 1 10 (pH urine pKa)
• U/P -------------------------
• 1 10 (pH plasma pKa)

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Tubular Reabsorption

• Urine-plasma ratio for weak bases
• 1 10 (pKa - pH urine)
• U/P -------------------------
• 1 10 (pKa - pH plasma)

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Amphetamine

• Weak base
• Will be reabsorbed if the urine pH is made
  alkaline more lipid-soluble non-ionized species
  are formed

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Amphetamine

• In contrast, acidification of the urine will
  cause the amphetamine to become more ionized
  (form a salt)
• The salt form is more water soluble less likely
  to be reabsorbed has tendency to be excreted
  into the urine more quickly

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Salicylic acid

• Weak acid
• Alkalination of the urine causes more rapid
  excretion of the drug

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Clinics

• Weak base drug will be excreted or will not be
  absorbed in big amount in acidic urine
• Weak acid drug will be excreted rapidly in
  alkaline urine
• In clinics important in barbiturate toxicity
  treatment. Barbiturate a weak acid with pKa of
  7.2
• The ratio of ionized form may be change by urine
  pH modification

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DRUG CLEARANCE

• A pharmacokinetic term for describing drug
  elimination from the body without identifying the
  mechanism of the process
• Vol of fluid clear of drug per time unit

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DRUG CLEARANCE

• The fixed vol of fluid (containing the drug)
  cleared of the drug per unit of time
• The units of clearance are vol/time (mL/min,
  L/hr)
• Ex if Cl? of penicillin is 15 mL/min in a
  patient penicillin has a Vd of 12 L, then from
  the definition, 15 mL of the 12 L would be
  cleared of drug per min

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DRUG CLEARANCE

• Alternatively, Cl? may be defined as the rate of
  drug elimination divided by the plasma drug
  concentration
• The volume of plasma eliminated of drug per unit
  time
• Practical way to calculate clearance based on
  plasma drug concentration data

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• BILLIARY EXCRETION

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BILLIARY EXCRETION

• An important system for the secretion of bile
  excretion of drugs
• The common bile duct empties into the duodenum
• Bile primarily consists of water, bile salts,
  bile pigments, electrolytes, to a lesser
  extent, cholesterol fatty acids

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BILLIARY EXCRETION

• Molecular weight excretion
• gt 500 mainly excreted in the bile
• 300-500, excreted both in urine bile. For these
  drugs, a decrease in one excretory route results
  in a compensatory increase in excretion via other
  route
• lt 300, almost exclusively excreted via kidney

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BILLIARY EXCRETION

• Drugs excreted into bile are metabolites, very
  often glucuronide conjugates
• Formation of a glucuronide increases the MW by
  the nearly 200, as well as increasing the
  polarity
• Excreted into bile digitalis glycosides, bile
  salts, cholesterol, steroids, indomethacin

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BILLIARY EXCRETION

• Compounds that enhance bile production stimulate
  billiary excretion of drugs normally eliminated
  by this route
• Phenobarbital may stimulate the billiary
  excretion of drug
• In contrast, compounds that decrease bile flow or
  pathophysiologic conditions that cause
  cholestasis will decrease billiary drug excretion

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BILLIARY EXCRETION

• The route of administration may also influence
  the amount of the drug excreted into bile
• Drugs given orally may be excreted by the liver
  into the bile to a greater extent than if the
  drugs are given iv-ly

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Enterohepatic circulation

• Drug in faeces
• Oral due to billiary excretion or incomplete
  absorption?
• Parenteral Drug was excreted in the bile!

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Enterohepatic circulation

• The cycle in which the drug is absorbed,
  excreted into the bile, reabsorbed in duodenum
  
• Some drugs excreted as a glucoronide conjugate
  will become hydrolized in the gut back to the
  parent drug by the action of a Beta-glucuronidase
  enzyme present in the intestinal bacteria. Parent
  drug becomes available for reabsorption

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