Drug Elimination and Excretion

Drug Elimination - Learning Tasks

• Drug elimination involves describing elimination routes, renal excretion factors, clearance calculation, and the importance of elimination half-life.

Drug Elimination Components

• Drug elimination consists of metabolism (biotransformation) and excretion.

Excretion process

• Excretion is the process where drugs or metabolites are irreversibly transferred from the body's internal to external environment through renal or non-renal routes.
• Excretion, along with tissue redistribution and metabolism, determines the duration of drug action and elimination rate.

Principal Organs Involved in Drug Elimination

• Kidneys (renal excretion).
• Bile (biliary excretion).
• Lungs (pulmonary excretion).
• Saliva (salivary excretion).
• Milk (mammary excretion).
• Sweat (skin excretion).

Renal Excretion

• Kidneys primarily eliminate drugs from the body.
• Principal renal mechanisms involved in drug excretion include:
  • Glomerular filtration.
  • Active tubular secretion.
  • Active tubular reabsorption.

Kidney Function in Drug Excretion

• The kidneys are the most common route of drug excretion.
• Kidneys excrete water-soluble substances.
• Renal excretion depends on glomerular filtration, tubular reabsorption, and tubular secretion.
• Net renal excretion = (Glomerular filtration + Tubular secretion) - (Tubular reabsorption).

Glomerular Filtration Details

• The glomerular capillary wall facilitates fluid filtration but restricts compounds with large molecular weights.
• Selective filtration prevents the filtration of plasma proteins like albumin, which maintains osmotic gradients and plasma volume.

Glomerular Filtration dependancies

• Glomerular capillaries have large pores.
• All free drugs (lipid or water-soluble) are filtered.
• Glomerular filtration depends on molecular size, plasma protein binding, and renal blood flow.
• Normal GFR is 120 ml/min.

Active Tubular Secretion Process

• Tubular secretion occurs in the proximal tubule and is an active, carrier-mediated process requiring energy.
• Two secretion mechanisms exist:
  • System for secretion of organic acids/anions (e.g., penicillin, salicylates).
  • System for organic bases/cations (e.g., morphine, mecamylamine, hexamethonium).
• OAT and OCT are at the proximal tubules.
• P-gp and MRP2 are located in the luminal membrane of proximal tubular cells.

Drug Interactions in Tubular Secretion

• Probenecid, an organic acid with high affinity for tubular OATP, blocks active transport of penicillin and uric acid.
• Aspirin decreases tubular secretion of methotrexate.
• Quinidine inhibits P-glycoprotein, decreasing renal and biliary clearance of digoxin.

Tubular Reabsorption Mechanism

• Accomplished by passive diffusion, depending on lipid solubility, pKa, and urine pH.

• When urine is acidic, weakly acidic drugs reabsorb more readily.

• Conversely, sodium bicarbonate is used in salicylate and barbiturate poisoning to alkalinize urine, while ascorbic acid can enhance morphine excretion.

• Urine pH can influence the extent of tubular reabsorption for drugs. Acidic urine promotes weak acid drug reabsorption, while alkaline urine favors weak base reabsorption. Acidifying urine reduces weak base reabsorption or enhances excretion.

Drug Overdose

• In case of a drug overdose, the urine pH can be adjusted to increase excretion.
• For pentobarbital, a weak acid, overdose, increasing drug excretion is achieved by making the urine more alkaline with sodium bicarbonate.

Factors Affecting Renal Excretion

• Physicochemical properties (molecular size around 300, pKa, lipid solubility, sterioselectivity).
• Plasma concentration.
• Distribution and drug binding where Clr is inversely proportional to Vd, high excretion if in blood, plasma-bound drugs filtered less, urine pH, and active secretion.
• Blood flow influences GFR and active secretion.
• Biological factors.
  • Females typically have 10% less excretion than males.
  • Newborns have 30-40% less excretion compared to normal adults.
  • Altered GFR and tubular function occur with old age.
• Drug interactions.
  • Alteration of protein binding.
• Furesimide + Gentamicin increases Clearance & causes nephrotoxicity. pH adjustment.
  • Acidification with ammonium chloride or ascorbic acid increases excretion of basic drugs, while alkalinization with citrates, tartarates, or bicarbonates increases excretion of acidic drugs.
• Active secretion competition using Probencid+Penicillins.
• Forced diuresis using Mannitol.
• Disease states (renal dysfunction, uremia with impaired GFR, increased half-life).

Biliary Excretion Process

• Transporters in the hepatocyte's canalicular membrane actively secrete drugs and metabolites into bile.
• Involved transporters may include organic anion transporting polypeptides (OATPs), P-glycoprotein transport system, and multidrug resistance-associated proteins (Mrps).
• Stored in the gallbladder, drugs in bile enter the gastrointestinal tract and may be excreted via stools.

Enterohepatic Recycling

• A drug excreted in bile may be reabsorbed in the gastrointestinal tract.
• Drug conjugates may be hydrolyzed by gut bacteria, releasing the original drug back into circulation.
• Recycling continues until the drug undergoes metabolic changes in the liver, is excreted by the kidneys, or both.
• Extensive enterohepatic recycling prolongs the drug's presence in the body.
• Activated charcoal or anion exchange resins can interrupt enterohepatic cycling.
• Reduced bile flow from Cholestatic disease states influences drug elimination, increasing toxicity risk.

Drugs with Enterohepatic Circulation

• Examples include Ampicillin, Rifampicin, Estrogen, Morphine, Doxycycline, and Cefoperazone.

Fecal Excretion

• Orally administered drugs that are unabsorbed are excreted in feces.
• Examples include streptomycin, neomycin, and cholestyramine.

Pulmonary Excretion

• Gases and volatile substances, like general anesthetics, are excreted via the respiratory tract.
• No specialized transport systems are involved; simple diffusion across cell membranes predominates.
• The gas loss rate depends on respiration rate and pulmonary blood flow.
• Gas solubility in blood impacts the loss rate where nitrous oxide, being less soluble, excretes faster than ethanol, which excretes slowly due to high solubility.

Salivary Excretion pH and Compounds

• Saliva pH ranges from 5.8 to 8.4, allowing passive excretion of unionized lipid-soluble drugs. Bitter taste is an excretion indicator where basic drugs reduce saliva, causing mouth dryness.
• Compounds excreted include caffeine, phenytoin, and theophylline.

Mammary Excretion details

• Milk consists of lactic secretions rich in fats and proteins and it is important as excretion enters breast feeding infants.
• Milk pH varies from 6.4 to 7.6, therefore diffusion of free, unionized, and lipid-soluble drugs occurs passively.
• Highly plasma-bound drugs like diazepam are less secreted into milk.
• Though drug excretion in milk is less than 1%, potent drugs like barbiturates and morphine can induce toxicity.

Skin Excretion

• Drugs excreted through skin via sweat follow the pH partition hypothesis. Excretion of drugs through skin may lead to urticaria and dermatitis.
• Compounds excreted include benzoic acid, salicylic acid, alcohol, and heavy metals like lead, mercury, and arsenic.

Excretion Pathways, Transport Mechanisms, and Drugs Excreted

• Urine excretes free, hydrophilic, unchanged drugs/metabolites with MW < 300 via GF, ATS, and PTR.
• Bile excretes hydrophilic, unchanged drugs/metabolites/conjugates with MW > 500 via active secretion.
• Lungs excrete gaseous & volatile, blood & tissue insoluble drugs via passive diffusion.
• Saliva excretes free, unionized, lipophilic drugs via passive diffusion and active transport.
• Milk excretes free, unionized, lipophilic drugs (basic) via passive diffusion.
• Sweat excretes free, unionized lipophilic drugs via passive diffusion.

Clearance Calculation

• Clearance (CL) is the plasma volume from which a drug is removed per unit time.
• Clearance = Rate of elimination / plasma concentration.
• If drug X has a plasma concentration of 4mg/L and eliminates at 10mg/hr, its clearance is 2.5L/hr since (10mg/hr ÷ 4mg/L = 2.5L/hr).

Total Clearance

• obtained by summing individual clearances across all elimination routes.
• For a drug cleared through the kidneys, liver, and lungs: Cl(Total) = Cl(Renal) + Cl(Hepatic) + Cl(Others).

Clearance Quantitatively

• Clearance is the volume of blood cleared during time (min or hr).
• It is calculated as Cl = k * Vd, where k is elimination rate constant and Vd is apparent distribution volume.

Clearance Formula

• Clearance (CL) estimates the rate, while the formula is Cl = 0.693 x Vd / t1/2.

Area Under the Curve (AUC)

• The bigger the AUC, the smaller the Cl.
• After oral administration Cl = F* Dose/ AUC where F is oral availability.

Half-Life Definition

• Half-life is the time required to eliminate 50% of the drug in the body.
• Elimination half-life is the time for plasma concentration to reduce by half, with t1/2 determined by Vd and CL.
• Like clearance, half-life is constant for drugs that follow the first-order kinetics.
• Half-life is graphically determined via a blood level versus time plot or the relationship t1/2 = 0.693 x Vd / CL.

Factors Affecting Half-Life

• Both Vd and CL are needed to predict changes in half-life.
• Clearance is altered more than Vd by disease, age, and other variables.
• Half-life determines how quickly blood concentration rises or falls during continuous infusion or after stopping administration.

Clinical Significance of Reaching Steady State

• Drug effect close to steady-state is indistinguishable, therefore 3–4 half-lives of constant dosing are adequate.

Clinical Importance of Elimination Half-Life

• It is used to predict the time to reach steady-state levels during multiple dosing or continuous IV infusion. In addition, assists in determining dosing frequency where a steady state is reached.
• Steady state reaches when rate in (input) = rate out (output).
• The time to reach a steady state is dependent only on t1/2 of a drug, i.e., 4-5 t1/2.
• Drugs with short half-lives (2-4 hours) need frequent administration, while those with long half-lives (21-24 hours) require less frequent doses; digoxin with a 36 hour half-life is once daily, whereas aspirin needs frequent dosing.

Clinical Situations and Drug Half-Life

• An abnormality altering a drug's half-life may require adjustments in dosage.
• Patients with:
  • Diminished renal or hepatic blood flow (cardiogenic shock, heart failure, hemorrhage).
  • Decreased drug extraction ability from plasma (renal failure).
  • Decreased metabolism with concomitant drugs inhibiting metabolism, severe inflammation, or hepatic insufficiency (cirrhosis).
• These patients may require a decrease in dosage or less frequent dosing intervals. Increased blood flow and protein binding will necessitate larger or more frequent doses of drugs.