Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSORDEPT. OF PHARMACOLOGYSSIMS & RC.

Excretion is a process whereby drugs are transferred from theinternal to the external environmentExcretion, along with metabolism and tissue redistribution, isimportant in determining both the duration of drug action andthe rate of drug elimination.Principal organs involved

Kidneys, Lungs,Biliary system, IntestinesSaliva and Milk.

EXCRETION OF DRUGS

Kidney is the primary organ of removal for most drugsespecially for those that are water soluble and notvolatile.The three principal processes that determine the

urinary excretion of a drugglomerular filtration,tubular secretion, and

tubular reabsorption (mostly passive back-diffusion)

The ultrastructure of the glomerular capillary wall is such that itpermits a high degree of fluid filtration while restricting thepassage of compounds having relatively large molecular weights.

This selective filtration is important in that it prevents thefiltration of plasma proteins (e.g., albumin) that are important formaintaining an osmotic gradient in the vasculature and thusplasma volume.Several factors, including molecular size, charge, and shape,influence the glomerular filtration of large molecules.

All unbound drugs will be filtered as long as their molecular size,charge, and shape are not excessively large.

Urinary excretion of drugs (i.e., weak electrolytes) is theextent to which substances diffuse back across the tubularmembranes and reenter the circulation.The movement of drugs is favored from the tubular lumen toblood, partly because of the reabsorption of waterThe concentration gradient thus established will facilitate

movement of the drug out of the tubular lumen, given thatthe lipid solubility and ionization of the drug are appropriate.The pH of the urine (usually between 4.5 and 8) can markedlyaffect the rate of passive back-diffusion.Acidification increases reabsorption (or decreaseselimination) of weak acids, such as salicylates, and decreasesreabsorption (or promotes elimination) of weak bases, suchas amphetamines.

A number of drugs can serve as substrates for thetwo active secretory systems in the PCTActively transfer drugs from blood to luminal fluid,are independent of each other; one secretes organicanions, and the other secretes organic cations.The secretory capacity of both the organic anion and

organic cation secretory systems can be saturated athigh drug concentrations.

Each drug will have its own characteristic maximumrate of secretion (transport maximum,Tm).

Organic Anion Transport Organic Cation Transport

Acetazolamide Acetylcholine

Bile salts Atropine

Hydrochlorothiazide Cimetidine

Furosemide Dopamine

Indomethacin Epinephrine

Penicillin G Morphine

Prostaglandins Neostigmine

Salicylate Quinine

Some substances filtered at the glomerulus are reabsorbed byactive transport systems found primarily in the proximaltubules.

Active reabsorption is particularly important for endogenoussubstances, such as ions, glucose, and amino acids, althougha small number of drugs also may be actively reabsorbed.

The probable location of the active transport system is on theluminal side of the proximal cell membrane.

The rate of urinary drug excretion will depend on thedrug’s volume of distribution, its degree of proteinbinding, and the following renal factors:1. Glomerular filtration rate2. Tubular fluid pH3. Extent of back-diffusion of the unionized form4. Extent of active tubular secretion of the compound5. Possibly, extent of active tubular reabsorption

Bile flow and composition depend on the secretory activityof the hepatic cells that line the biliary canaliculi.

As the bile flows through the biliary system of ducts, itscomposition can be modified in the ductules and ducts bythe processes of reabsorption and secretion, especially ofelectrolytes and water.For example, osmotically active compounds, including bile

acids, transported into the bile promote the passivemovement of fluid into the duct lumen.

Hence, drugs with molecular weights lower than those of mostprotein molecules readily reach the hepatic extracellular fluidfrom the plasma.Group A - concentration in bile and plasma are almost identical(bile–plasma ratio of 1).

Ex. Glucose, and ions such as Na, K, and Cl.Group B - ratio of bile to blood is much greater than 1, usually10 to 1,000.

Ex. bile salts, bilirubin glucuronide, procainamideGroup C - ratio of bile to blood is less than 1, for

Ex. insulin, sucrose, and proteins.

Biliary Excretion

The physicochemical properties of most drugs are sufficientlyfavorable for passive intestinal absorption that the compound willreenter the blood that perfuses the intestine and again be carriedto the liver.Such recycling may continue (enterohepatic cycle or circulation)until the drug either undergoes metabolic changes in the liver, isexcreted by the kidneys, or both.

This process permits the conservation of such importantendogenous substances as the bile acids, vitamins D3 and B12, folicacid, and estrogens

ENTEROHEPATIC CIRCULATION

Drugs that Undergo Enterohepatic Recirculation

Indomethacin Methadone

Amphetamine Metronidazole

Estradiol Morphine1,25-Dihydroxyvitamin

D3 Phenytoin

EstradiolPolar Glucuronic Acid

Conjugates

Polar Sulfate Conjugates

Mestranol Sulindac

Any volatile material, irrespective of its route of administration, hasthe potential for pulmonary excretion. Gases and other volatilesubstances that enter the body primarily through the respiratory tractcan be expected to be excreted by this route.

No specialized transport systems are involved in the loss of substancesin expired air; simple diffusion across cell membranes is predominant.The rate of loss of gases is not constant; it depends on the rate ofrespiration and pulmonary blood flow.The degree of solubility of a gas in blood also will affect the rate of gasloss.Gases such as nitrous oxide, which are not very soluble in blood, willbe excreted rapidly, that is, almost at the rate at which the blooddelivers the drug to the lungs.

Sweat and SalivaMinor importance for most drugs.

Mainly depends on the diffusion of the un-ionized lipid-soluble form ofthe drug across the epithelial cells of the glands.Thus, the pKa of the drug and the pH of the individual secretionformed in the glands are important determinants of the total quantityof drug appearing in the particular body fluid.

Lipid-insoluble compounds, such as urea and glycerol, enter saliva andsweat at rates proportional to their molecular weight, presumablybecause of filtration through the aqueous channels in the secretory cellmembrane.

The ultimate concentration of the individual compound inmilk will depend on many factors, including the amount ofdrug in the maternal blood, its lipid solubility, its degree ofionization, and the extent of its active excretion.

The physicochemical properties that govern the excretion ofdrugs into saliva and sweat also apply to the passage of drugsinto milk.Since milk is more acidic (pH 6.5) than plasma, basiccompounds (e.g., alkaloids, such as morphine and codeine)may be somewhat more concentrated in this fluid.

In general, a high maternal plasma protein binding of drug willbe associated with a low milk concentration.

A highly lipid-soluble drug should accumulate in milk fat.

Enzymatic elimination of drugs primarily First OrderKinetics (Michaelis-Menton)Elimination half life t 1/2 = 0.693/k

Elimination is dependent upon concentration, butalmost 97% will be eliminated after 5 half-livesInitial concentration 1 mg%One half life 0.5 mg%Two half lives 0.25 mg%Three half lives 0.125 mg%Four half lives 0.0625 mg%Five half lives 0.03125 mg%or 0.96875 mg% (97%) eliminated

First Order Elimination[drug] decreasesexponentially w/ timeRate of elimination isproportional to [drug]Plot of log [drug] or ln[drug]vs. time are lineart 1/2 is constant regardlessof [drug]

Zero Order Elimination[drug] decreases linearlywith timeRate of elimination isconstantRate of elimination isindependent of [drug]No true t 1/2

Half-life is the time taken forthe drug concentration to fall tohalf its original valueThe elimination rate constant(k) is the fraction of drug in thebody which is removed per unittime.

Steady-state occurs after a drug has been given forapproximately five elimination half-lives.At steady-state the rate of drug administration equalsthe rate of elimination and plasma concentration -time curves found after each dose should beapproximately superimposable.

Ability of organs of elimination (e.g. kidney, liver) to“clear” drug from the bloodstream.Volume of fluid which is completely cleared of drug perunit time. Units are in L/hr or L/hr/kgPharmacokinetic term used in determination ofmaintenance doses.Volume of blood in a defined region of the body that iscleared of a drug in a unit time.

Clearance is a more useful concept in reality than t 1/2 orkel since it takes into account blood flow rate.Clearance varies with body weight.Also varies with degree of protein binding

Dose rate = target Cpss *CL/F

Maintenance dose will be in mg/hr so for total daily dosewill need multiplying by 24

Rate of drug elimination=(Vmax)(C)/Km+CC-plasma concentration, Vmax-maximum rate of drugelimination, Km=plasma concentration

Maintenance Dose = CL x (Steady State plasmaconcentration)CpSSav

CpSSav is the target average steady state drugconcentration

VD is a theoretical Volume and determines the loadingdose.Clearance is a constant and determines themaintenance dose.CL = k VD.CL and VD are independent variables.k is a dependent variable.F-bioavailability

Volume of Distribution = Dose_______Plasma Concentration

An established relationship betweenconcentration and response or toxicityA sensitive and specific assayAn assay that is relatively easy to performA narrow therapeutic rangeA need to enhance response/preventtoxicity