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ABSORPTION, DISTRIBUTION, BIOTRANSFORMATION (METABOLISATION) AND ELIMINATION OF DRUGS Assist. Prof. Dr. Heba ASKER Ankara Medipol University-Faculty of Pharmacy Department of Pharmacology ADME Absorption Distribution Metabolisation (Biotransformation)...

ABSORPTION, DISTRIBUTION, BIOTRANSFORMATION (METABOLISATION) AND ELIMINATION OF DRUGS Assist. Prof. Dr. Heba ASKER Ankara Medipol University-Faculty of Pharmacy Department of Pharmacology ADME Absorption Distribution Metabolisation (Biotransformation) Elimination (execretion) Absorption In order for drugs to affect a particular organ or tissue, they must reach that site of action in a certain concentration or amount. The stages of access to the site of action are absorption and distribution. Absorption: the passage of the drug into the systemic circulation (bloodstream) from the site of administration (e.g. the gastrointestinal tract into which drug enters after being swallowed orally).  The barrier that must be overcome for absorption varies according to the site of administration: gastrointestinal tract, oral and nasal cavity, tracheobronchial duct and peritoneum: first the epithelial layer of the mucous or serous membrane and then the endothelium of the blood vessels Intra-tissue administration (e.g. by injection): endothelium of capillaries in the tissue In intravenous administration: NO NO Absorption  Rate of absorption: the amount of drug absorbed per unit time. Factors affecting the rate of absorption: 1. Drug-related factors 2. Biological factors related to the place of administration 1. Drug-related factors A. Physicochemical properties of the drug molecule: a. Molecule size: the absorption rate of small molecule drugs is generally faster than that of large molecule drugs. In order to slow down the absorption rate and prolong the duration of action of some small molecule drugs, especially in IM injections, these molecules are converted into large esters (such as enanthate, decanoate, cypionate), e.g. some hormone preparations b. Lipophilicity: i.e. the rate at which the drug dissolves in fat (and therefore can pass through the fatty layer of the cell membrane) The concentration of drug dissolved in the lipid phase Lipid (fat)/water partition coefficient The concentration of drug dissolved in the water phase The greater this ratio of a drug, the greater the rate of diffusion through the cell membrane (diffusion) and therefore absorption Drugs exist in equilibrium in aqueous media in two states: ionised and non-ionised. Non-ionised part Lipophilic part B. Pharmaceutical form and solvent of the drug  Absorption of the drug administered in solid pharmaceutical forms is preceded by disintegration and dissolution of the drug in these forms  For liquid pharmaceutical drug forms: Absorption of the drug from solutions in which the drug molecules or ions are separated (free) in the solvent is more rapid than from suspensions or emulsions.  Sometimes, in order to slow absorption and prolong the duration of action, water-soluble drugs are converted into water-insoluble esters and prepared as suspensions in water or dissolved in vegetable oils (such as sesame oil and peanut oil, etc.)For example, procaine penicillin and benzathine penicillin administered intramuscularly and esters of some steroid hormones. C. Drug concentration: If the concentration of the drug at the site of administration is high, absorption is usually rapid. For example, a drug administered by injection into tissue in a volume of a few ml will be absorbed rapidly because the concentration will be high in the tissue, but when the same amount of drug is given orally in the same volume, absorption will be slower because it will be diluted in gastric or intestinal fluid. D. Pharmacological property of the drug: For example, vasoconstrictor drugs narrow the blood vessels when they are administered into the tissue, thereby reducing the blood flow and slowing down the absorption of their own and other drugs. The opposite can be said for vasodilator drugs. 2. Biological Factors Related To The Route Of Administration A. The rate of blood flow through the tissue or the wall of the body cavity (such as the gastrointestinal mucosa) where the drug is administered: For example, conditions such as shock, hypotension, congestive heart failure, arterial occlusion, etc. cause a decrease in blood flow at the site of drug administration and reduce the rate of absorption. B. The width and permeability of the absorbing surface: The wider the surface on which the drug is applied and the higher the permeability of this surface, the faster the absorption. e.g. absorption rate: mucosa of the small intestine > mucosa of the mouth, stomach and rectum > skin Passage Through Membranes In order for pharmacokinetic events such as absorption, distribution, biotransformation and excretion to occur, drug molecules must pass through certain layers of cells and enter the cell. The passage of drugs through cell layers occurs by the drug molecules passing through the cells forming those layers (transcellular); passing between cells (paracellular or intercellular) is less common. The structure that must be crossed to enter the cell and from there to pass outwards is the cytoplasmic membrane of the cell. Cell Membrane Crossing Mechanisms 1. Passive (simple) diffusion 2. Active transport 3. Facilitated diffusion 4. Other mechanisms: a. Pinocytosis b. Receptor-mediated endocytosis  Passive Diffusion The drug moves from the side of high concentration to the side of low concentration: a. No carrier molecule b. No energy required  Active Transport The drug molecule moves from the side of low concentration to the side of high concentration (against a concentration gradient or slope): a. Requires a transporter: the transporter molecule binds the molecule to be transported on one side of the membrane, passes with it through the membrane and releases the transported molecule on the other side. If a molecule is taken into the cell from outside by transporter-mediated transport, this is called uptake or influx; if a molecule is transferred from inside the cell to outside, this is called efflux. b. Requires energy. Active transport Facilitated Diffusion The drug moves from the side of high concentration to the side of low concentration. a. Requires a transporter b. No energy consumption required c. Much faster than passive diffusion Facilitated diffusion  Other Mechanisms Pinocytosis: plays a role in the entry of high molecular weight substances into the cell. They enter into a pit formed on the outer surface of the cell membrane, are completely surrounded by the surrounding membrane, and the vesicle breaks away from the membrane and enters the cytoplasm with the substance inside. Receptor-mediated endocytosis: large molecules (e.g. cyclosporine molecules combined with LDL) enter cells that have specific receptor proteins (such as the LDL receptor) on them that recognise them after binding with these receptors.  Ionisation of Drugs Most of the drugs are chemically weak acid or weak base organic substances The rate at which weak acids and bases ionise in aqueous media is related to the pH of the medium and the pKa of the drug. pKa = the pH value at which 50% of the drug molecules are ionised. pKa is a constant number for a given drug pKa= -log Ka Ka: Acidic ionisation (dissociation) constant for acids (Kb for basic drugs)  The pKa values of organic substances, like PH, are approximately between 0 and 14. It is close to 0 for strong acids and close to 14 for strong bases. Drugs with a strong base character (pKa values close to 14) are almost completely ionised in body fluids and therefore absorption is slow and difficult. For example, propantheline or guanethidine.  The rule: As the pH of the medium decreases, the proportion of the non- ionised fraction of weak acids (e.g. acetylsalicylic acid) increases and their absorption is facilitated accordingly. Conversely, a decrease in the pH value of the medium decreases the proportion of the non-ionised fraction of weak base drugs and therefore decreases their absorption rate.  Kinetics of Absorption Process  First order kinetics: Concentration-dependent kinetics the drug passes from the side of high concentration to the side of low concentration. e.g. Simple diffusion  Zero order kinetics: The passage of drugs across the membrane occurs with a constant rate (k), independent of concentration. This occurs in two cases: 1. If there is carrier saturation in active transport and facilitated diffusion 2. If the drug is administered in a special pharmaceutical form with a constant rate of release  Simple diffusion Passing rate Remaining amount Active transport Time TM= Transporter Maximum  Absorption Of Drugs From The Gastrointestinal Tract And Oral Bioavailability Oral Bioavailability: the rate and extent to which the active substance of an orally administered drug is absorbed from the pharmaceutical form and reaches its site of action in the body. Two important parameters: (i) absorption rate (ii) degree of absorption i.e. the percentage of the administered dose that is absorbed and reaches the systemic circulation  An important factor determining the bioavailability of orally administered drugs is the amount of drug that is absorbed from the gastrointestinal mucosa, passes into the portal blood circulation, passes through the liver, reaches the vena cava inferior and from there reaches the arterial blood circulation. The main absorption site of orally administered drugs is the small intestine. There are two reasons for this: 1. The small intestine mucosa of the small intestine is long tubular and provides a large absorption surface. 2. Long residence time of the drug in the small intestine.  Physicochemical Properties Affecting Absorption of Drugs from the Gastrointestinal Canal 1. Pharmaceutical form (solid, liquid): Two important physical events must occur in the lumen of the stomach and intestine before the absorption of drugs in solid pharmaceutical form: a. Disintegration of the pharmaceutical form (e.g. tablet) into small particles. b. Dissolution of the drug molecules within the particles in gastric and/or intestinal juice. Drugs in liquid pharmaceutical forms can be absorbed immediately without going through the above steps, unless they are in suspension or microcrystalline form. Absorption rate from the gastrointestinal tract according to pharmaceutical form: liquid > solid 2. Solubility of the drug in oil and water 3. Being in a state of salt: Resolution absorption 4. Particle size: particle size absorption Physiological Factors Affecting the Absorption of Drugs from the Gastrointestinal Canal 1. Stomach emptying time 2. Intestinal motility (peristaltic movements) 3. Passing blood flow  The Effect of Nutrients on Drug Absorption:  As a rule, taking medication on an empty or full stomach does not usually change the absorption degree (in this sense, bioavailability) of the drug; however, it may change the rate of absorption.  Sometimes food may interact with medicines. Therefore, it is recommended to take them on an empty stomach.  To take a medicine on an empty stomach: take the medicine half-one hour before or 2 hours after a meal.  Foods delay gastric emptying.  Acid and enzyme secretion of the stomach increases during the meal. Bioavailability of drugs that are not resistant to these secretions decreases when taken with food  The amount of fluid taken with the drug: taking the drug with plenty of water usually accelerates and increases absorption. Interaction with food and nutrients: Metal ions or protein breakdown products in food may form complexes with drug molecules, which may reduce or slow absorption.  Events Occurring Between Absorption Of The Drug From The Gastrointestinal Tract And Entry Into The Systemic Circulation First-pass elimination (presystemic elimination): drugs are absorbed through the gastrointestinal mucosa, enter the portal circulation through the capillaries of the mucosa and then pass through the sinusoids of the liver lobules, where they are metabolised by enzymes in mucosal epithelial cells or liver cells and converted into inactive metabolites. e.g. pravastatin, metformin, propranolol Unchanged forms and/or metabolism products (metabolites) of some drugs are excreted in bile Presystemic elimination  Drugs undergoing first pass elimination: o Lipophilic drugs o Have low systemic bioavailability when taken orally o Oral and parenteral doses are different  Enterohepatic Cycle: Some of the drugs captured by the liver cells while passing through the sinusoids in the liver lobules are metabolised and excreted in the bile. When the drug metabolites (conjugates) formed in the liver cell reach the small intestinal lumen in bile, they are hydrolysed by beta-glucuronidase and sulphatase enzymes. The free drug formed as a result of hydrolysis is absorbed from the small intestine and returns to the liver. Some of the drug passes into the systemic circulation and the remainder is reabsorbed into the bile. This gradually decreasing circulation of a part of the drug between the small intestine and the liver is called the enterohepatic cycle. This leads to prolonged duration of action of oral medicines. e.g. chloramphenicol, chlorpromazine, digitoxin and steroids ENTEROHEPATIC CYCLE  Distribution After absorption, the drug molecules entering the blood and circulating in the blood stream leave the vessel through capillaries in the tissues and first enter the interstitial fluid and are distributed in the tissues. Some drugs also pass into the cells from there. Then the drugs disperse into: 1. Plasma (half of the blood volume) Extracellular fluid 2. Interstitial fluid (CSF + fluids in other body cavities) 3. İntracellular fluid compartments  Usually by passive diffusion. The rate of distribution depends on the rate of blood flow through the organ or tissue. Heart, lungs, kidneys and liver Adipose tissue, skin, bones and skeletal muscles at rest  Distribution in Blood (Plasma) Drug molecules in the blood usually bind to plasma proteins at a rate that varies for each drug. The binding of drugs to plasma proteins is reversible. There is an equilibrium between the fraction of free drug passing into the interstitial fluid by passive diffusion and the fraction of free drug remaining in the plasma. The concentrations of these two fractions are usually equal when equilibrium occurs. Free drug molecules enter the tissue, drug molecules bound to plasma proteins act as drug storage or function. As the free drug molecules decrease in the plasma, the drug bound to plasma proteins is released into the plasma water, enters the tissue and the duration of action is prolonged.  Albumin: e.g. warfarin, tolbutamide, furosemide, digitoxin, diazepam. α1-acid glucoprotein: e.g. (dipyridamole, quinidine, imipramine, chlorpromazine and propranolol) P-lipoproteins: örn. cyclosporine beta globulin.  The binding of drug molecules to albumin is not selective; many drug molecules can bind to a certain point. If drugs that can bind to the same point are found together in the body at the same time, the drug with high affinity (interest) to the binding site removes the drug with low affinity from the binding site and releases it (competitive inhibition of binding).  Chronic liver diseases (such as cirrhosis), chronic renal failure and severe nutritional disorders increase the percentage of free drug in plasma by causing hypoalbuminemia or impairing the binding property of albumin, i.e. they decrease the binding rate. This situation requires dose reduction in acute drug treatment.  Rate of Distribution and Special Cases Related to Distribution It depends on four factors: i. The rate of diffusion: The more lipophilic, the less ionised and the smaller the molecule, the higher the diffusion rate from blood to tissue. ii. Tissue perfusion rate (the rate of blood flow through the tissue):Where the blood flow rate is high, diffusion is fast. iii. Affinity of the drug for tissue components iv. Binding to plasma proteins Passage of Drugs to the Central Nervous System The central nervous system is one of the organs through which much blood passes. However, the permeability of brain capillaries is different from that of capillaries in other tissues. ------------- There is a blood-brain barrier (BBB) on the wall of brain capillaries.  Blood-brain Barrier (BBB) 1. Tight junction between endothelial cells (no gap or pore). 2. Basement membrane beneath the endothelium in brain capillaries is perforated. 3. Capillaries are surrounded by a glia layer of astrocyte cells. 4. The membrane of the endothelium facing the lumen contains efflux (pumping back out of the cell) p-glycoprotein and similar proteins.  Ethyl alcohol, general anaesthetics (e.g. desflurane) and some highly lipophilic drugs (such as thiopental, other intravenous general anaesthetics and nicotine in tobacco smoke) enter the CNS very rapidly from the bloodstream. Factors That Relax The Blood-brain Barrier And Increase The Permeability Of Capillaries To Drugs Infection of the brain and meninges (encephalitis and meningitis) Radiotherapy Hypertonic solution (glucose, mannitol and urea solution) into the cerebral artery High concentration of alcohol Cytotoxic cancer drugs Glucocorticoid drugs, in turn, reduce the increased permeability Areas of the brain without BBB Chemoreceptor trigger zone and vomiting centre----- ????? Passage of Drugs to CSF CSF: cerebrospinal fluid, volume approximately 150 ml Lipophilic drugs pass by passive diffusion Some ionised drugs enter the CSF by active transport.  Sequestration and Storage in Tissue Sequestration: It is defined as the tight binding of drugs to certain intracellular or extracellular structures (e.g. protein, phospholipid and nucleoprotein molecules) in tissues and their storage there.  Leads to an unequal distribution of drugs between tissues.  May cause late onset of the therapeutic effect of the drug---- therefore a loading dose may be given at the beginning of treatment.  May cause prolonged therapeutic effect or side effects.  The number of sequestrated drugs is relatively small. Examples of sequestration events Barbiturates (e.g. thiopental): Highly fat-soluble substances, accumulate in lipid-rich structures in the body such as the CNS and adipose tissue Imipramine and some other antidepressant drugs that bind to the serotonin reuptake transporter protein of the cell membrane are stored in the lung. Tetracyclines chelate calcium in bone and accumulate in bones and teeth. Iodine accumulates in the thyroid gland, where it is found in much higher concentrations than in plasma. Redistribution When highly lipid-soluble (lipophilic) drugs are administered by inhalation (e.g. volatile liquid and gaseous general anaesthetics) or i.v. (e.g. thiopental), they initially accumulate in high concentrations in the brain and other organs with a high blood supply (such as the heart and kidneys). Meanwhile, their distribution into a tissue such as adipose tissue, which can retain lipid-soluble substances but through which blood flows slowly and in small amounts, is very low. Within a few hours, however, since the drug in the circulating blood is sufficiently available to this tissue, the drug accumulates more in the adipose tissue, which constitutes a larger volume compared to organs such as the brain, heart and kidneys. This leads to a short distance from the site of action (the brain for the above- mentioned drugs) and a rapid termination of the effect. Ion Trap The tendency of a drug to concentrate in body compartments where it is more ionised. The equilibrium concentration of a drug distributed in two compartments separated by a passively diffusible membrane is not equal in each compartment if there is a pH difference. The drug concentrates more in the compartment where it can be more ionised (polar). This is called the ion trap phenomenon. Acidic drugs are concentrated on the side with a higher pH. Basic drugs are concentrated on the side with a lower pH. In which cases is this feature used?  Virtual Distribution Volume The volume of fluid in which it is possible for the total amount of drug present in the body at a given moment after drug administration to be distributed at a concentration equal to the drug concentration (C) measured in plasma at that moment is defined as the virtual volume of distribution (vd) of that drug. Vd = Amount of the drug in the body/C It is used to calculate the amount of drug that needs to be given to achieve a given plasma concentration. Biotransformation (Metabolisation) of Drugs Biotransformation: Drugs undergo chemical changes in the body under the action of enzymes. ineffective. Sometimes drugs are biotransformed into more effective and/or more toxic compounds. This is called Bioactivation For example, the conversion of codeine to morphine, conversion of methyl alcohol to formaldehyde and formic acid  Pro-Drug Sometimes, an ineffective compound is rendered effective by biotransformation in the body. Such compounds are called prodrugs or precursor drugs. Examples: Corticosteroid drugs cortisone and prednisone: ---------- Are ineffective when applied locally to the skin ---------- When administered systemically, they act in the liver after conversion to hydrocortisone and prednisolone, respectively. P-carotenes are inactive precursors of vitamin A (provitamin A). Converted to active vitamin A in the body.  The compounds into which the drug is transformed as a result of biotransformation are called metabolites of that drug Some biotransforming enzymes have polymorphisms. Polymorphs of the same enzyme have different activities. The type, amount or activity of the enzyme in the individual is largely genetically determined and due to this situation, the activity of biotransforming enzymes and therefore the rate and rate of inactivation of drugs may show significant differences between individuals. However, certain drugs and environmental factors (such as smoking, alcohol, certain nutrients and polluted air) may also be responsible for differences in enzyme activity between individuals by inducing or inhibiting drug metabolising enzymes. Locations of Biotransforming Enzymes Liver Lungs Kidneys Gastrointestinal mucosa Blood Bacteria in the intestinal flora Enzymatic Events Types Oxidation: especially Cytochrome P450 microsomal enzymes (CYPs): e.g. CYPlA2, CYP2C9, CYP2C19, CYP2D6, CYP3A4. Reduction: e.g. conversion of aldehydes to alcohols and saturation of double bonds Cleavage: the removal of a group from a drug molecule or the splitting of a drug molecule (such as esters and ethers) into two smaller constituent molecules Conjugation: e.g. conjugation with glucuronic acid, glutathione and sulphate Enzyme Substrates mediating Biotransfomation for CYPIA2 Antidepressants (imipramine, clomipramine), clozapine, xanthines (caffeine, theophylline), olanzapine, polycyclic aromatic hydrocarbons, paracetamol, propranolol, (R)warfarin CYP2C9 Fenitoin, fluvastatin, lozartan, irbesartan, oral antidiabetic agents (glipizide, glibenclamide, tolbutamide), non-steroidal anti-inflammatory analgesics (diclofenac, flurbiprofen, ibuprofen, indomethacin, naproxen, piroxicam), (S)varfarin CYP2C19 Antidepressants (amitriptyline, imipramine, clomipramine), diazepam, proton pump inhibitors (lansoprazole, omeprazole), propranolol, (S)mefenitoin CYP2D6 Tricyclic antiarrhythmics (mexiletine, propafenone), various antidepressants (amitriptyline, fluoxetine, fluvoxamine, imipramine, clomipramine, maprotiline, trazodone, venlafaxine), beta-blockers (metoprolol, propranolol, timolol), neuroleptics (haloperidol, thioridazine), opioid analgesics (dextromethorphan, codeine, tramadol), nicotine, debrisoquine CYP3A4 Antiandrogens (finasteride, flutamide), antiarrhythmics (amiodarone, dizopyramide, quinidine, lidocaine), antihistamines (astemizole, loratadine" terfenadine), antineoplastics (cyclophosphamide, doxorubicin, etoposide, ifosfamide, paclitaxel, vinblastine, vincristine), azole antifungals (itraconazole, ketoconazole, miconazole), benzodiazepines (alprazolam, midazolam, triazolam), erythromycins (erythomycin, clarithromycin), glucocorticoids (dexamethasone, methylprednisolone, prednisolone, prednisone), hypolipidaemic drugs (atorvastatin, lovastatin, simvastatin), calcium channel blockers (amlodipine, nimodipine, nifedipine, nicardipine, nimodipine, nitrendipine, nizoldipine, verapamil), indinavir and other HIV protease inhibitors, cyclosporine, tamoxifen, testosterone, warfarin, zolpidem Enzyme Enzyme Inducers Inhibitors CYPlA2 Cigarette smoke, char-grilled meat, Fluvoxamine, firafillin, galangin, cimetidine, ciprofloxacin omeprazole, polycyclic aromatic hydrocarbons, phenytoin CYP2C9 Barbiturates, phenytoin, rifampin Amiodarone, fluconazole, fluoxetine, fluvoxamine, fluvoxamine, isoniazid, co-trimoxazole, metronidazole, simethidine, sulfafenazole, ticlopidine, tylenic aside, voriconazole CYP2C19 Carbamezapine, rifampin, prednisone Fluconazole, fluoxetine, fluvoxamine, proton pump inhibitors (omeprazole, lansoprazole, pantoprazole, rabeprazole), ticlopidine CYP2D6 Unknown Amiodarone, antidepressants (fluoxetine, paroxetine, sertraline), quinidine, mibefradil. neuroleptics (haloperidol. thioridazine), classical antihistamines (diphenhydramine, chlorpheniramine, clemastine, hydroxyzine, promethazine, tripelenamine), cimetidine, terbinafine, methoxalene CYP3A4 Aminoglutethimide, barbiturates, Antidepressants (fluvoxamine. nefazodone), azole dexamethasone, phenytoin, antifungals (ketoconazole, miconazole, oxiconazole), grizeofulvin, carbamazepine, phenytoin, erythromycin, clarithromycin, some pioglitazone, rifampicin, rifabutin corticosteroids (methylprednisolone, prednisolone, prednisone), grapefruit juice, red wine, isoniazid, calcium Elimination of drugs (excretion) Excretion of drugs or their metabolites from the body occurs mainly in 3 ways: 1. Into the urine via the kidneys. 2. Into bile by liver cells. 3. Through the lungs (excretion of gases and volatile liquids). 1. Elimination through the kidneys The most common way of excretion of medicines. It happens in 3 ways: A. Glomerular filtration B. Tubular secretion C. Tubular reabsorption  A. Glomerular filtration It is a passive diffusion event that occurs very rapidly. Molecules with a molecular weight of less than 20 kilo daltons are filtered through the glomeruli and excreted into the tubular lumen Albumin and other large molecule proteins and associated drugs are not filtered Since the molecular weight of most of the drugs is below 1000, the free drug fraction undergoes glomerular filtration, except for the bound drug fraction in plasma. The glomerular filtration rate of the kidneys is 130 ml/min  B. Tubular secretion  It is in the proximal tubules and the drug is excreted into the tubular lumen by active transport mechanism  Tubulus cells have two different types of transporter molecules specific for acidic and basic drugs and their metabolites.  Examples of acidic drugs excreted in this way: Penicillins, cephalosporins, salicylates  Examples of basic drugs excreted in this way: morphine, histamine, dopamine, serotonin C. Tubular reabsorption It is a reabsorption (reabsorption) event that negatively affects drug excretion and tries to reduce drug excretion. Generally, the drug is reabsorbed (reabsorbed) from the tubular lumen to the capillaries by passive diffusion in the capillary network around the tubules.  Renal Clearance Clearance: in general, the volume of virtual plasma (ml) that is completely cleared of a given drug or substance per unit time (per minute).------ml/min Clearance is an indicator of the rate of drug elimination Renal clearance: the virtual volume of plasma cleared of an unmetabolised (unchanged-active) drug in one minute by renal excretion. Elimination half-life (t1/2): Time required for the amount of drug in the body to decrease by half Elimination half-life is inversely proportional to clearance The larger the virtual volume of distribution (Vd) or the smaller the clearance, the longer the residence time of a drug in the body Renal clearance of glucose is zero because it is completely reabsorbed  Increasing Excretion By Changing The Ph Of Urine Alkalisation of urine: In poisoning with weak acid drugs such as salicylate and phenobarbital, sodium bicarbonate is administered intravenously and renal excretion of these drugs is increased by ion trap mechanism (used in cases of poisoning). Acidification of urine in poisoning with weak base drugs is not used due to serious complications of metabolic acidosis that may occur.  2. Excretion into Bile from the Liver Drugs and the products of their metabolism (especially conjugation products) are partially secreted by liver cells into bile, which is then excreted into the small intestine and excreted in faeces Sometimes the inactive drug conjugate is hydrolysed in the intestine by digestive enzymes, especially enzymes secreted by microflora, and the released drug molecules can be reabsorbed (enterohepatic cycle/loop) It occurs by passive diffusion or active transport. Hepatic clearance: the virtual volume of plasma cleared per unit time (1 min) of a drug metabolised in the liver by excretion into the bile. a parameter indicating the rate of elimination 3. Excretion Through The Lungs Gases and volatile substances diffuse into the alveolar cavity from the blood passing through the perialveolar capillaries by crossing the alveolar membrane. It is a passive diffusion event e.g. general anaesthetics (halothane, isoflurane) Execretion Through Other Locations Drugs and their metabolites can be excreted in the secretion of all exocrine glands such as salivary glands, lacrimal glands, mucous glands of the respiratory tract, mucous glands of the gastrointestinal tract, glands of the genital tract and mammary glands in lactating women. Excretion by Secretion in Milk By passive diffusion. Some medicines are contraindicated, i.e. prohibited, in breastfeeding women because of their high excretion in milk. Diazepam and other benzodiazepines, barbiturates, barbiturates, antihistamines, phenytoin or cannabis can pass too much of these drugs in the milk to sedate a nursing baby. The mother's intake of lithium salt, iodine preparations, antithyroid drugs, atropine, caffeine and high doses of aspirin can also cause side effects in the breastfed baby.  Breastfed infants of mothers who use morphine or heroin can become dependent on morphine or heroine and withdrawal of the drug can cause withdrawal symptoms in the infant Glycosides and antihypertensive drugs (except reserpine) do not pass into the milk to such an extent that they have a marked pharmacological effect in infants. Estrogenic drugs are excreted in milk and breastfed infants of mothers taking them may develop gynaecomastia (breast enlargement)