ISHIK UNIVERSITY FACULTY OF DENTISTRY Pharmacology Fall 2015 Dr. Esra Tariq Bayrakdar Pharmacist (M.Sc.)

Drug Distribution Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium(extracellular fluid) and/or the cells of the tissues. The delivery of a drug from the plasma to the extracellular fluid primarily depends on blood flow, capillary permeability, the degree of binding of the drug to plasma and tissue proteins, and the relative hydrophobicity of the drug.

Drug Distribution Blood flow Capillary permeability Capillary structure To enter the brain, drugs must pass through the endothelial cells of the capillaries ofthe CNS or be actively transported. lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS Drug structure: lipid-soluble drugs readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells. Ionized or polar drugs generally fail to enter the CNS because they are unable to pass through the endothelial cells of the CNS

Volume of Distribution It is sometimes useful to compare the distribution of a drug with the volumes of the water compartments in the body. The volume of distribution is a hypothetical volume of fluid into which a drug is dispersed.

Binding of drugs to plasma proteins Binding is relatively nonselective as to chemical structure and takes place at sites on the protein to which endogenous compounds Plasma albumin is the major drug-binding protein and may act as a drug reservoir; that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma.

Kt : Dissociation constant =k2/k1 Only drugs which did not bind to plasma proteins are diffused between membranes. Binding to proteins affect the drug activity (Binded form= Inactive) It affects the drugs distribution for a compartment to another. (The passif diffusion and glomeruler filtration are affected but the active transport is not affected from this case) The binding is reversible with weak bonds (Va der Waals, Ionic bonds) D + Albumin ↔ Drug-albumin complex Kt : Dissociation constant =k2/k1

Drugs Bind to Plasma Proteins in High Level The drugs that bind to albumin are generally lipophilic and weak acids (diazepam, aspirin) Drugs that bind to the α1 acid glycoprotein are generally base form (lidocain, Prazocin) There are limited binding points on the proteins that bind drugs, therefore when the concentration increased there could be a saturation. But in therapeutical concentrations this is not likely to happen.

Aspirin, predisolone, valproic acid drugs binding saturation percent in therapeutic concentration is between 50-60%. Therefore these when their concentrations increased, the toxic effect is possible.

Competition for Binding between Drugs Class I drugs: If the dose of drug is less than the binding capacity of albumin, then the dose/capacity ratio is low. The binding sites are in excess of the available drug, and the bound-drug fraction is high. This is the case for Class I drugs, which include the majority of clinically useful agents.

Competition for Binding between Drugs Class II drugs: These drugs are given in doses that greatly exceed the number of albumin binding sites. The dose/capacity ratio is high, and a relatively high proportion of the drug exists in the free state, not bound to albumin. Clinical importance of drug displacement: This assignment of drug classification assumes importance when a patient taking a Class I drug, such as warfarin, is given a Class II drug, such as a sulfonamide antibiotic.

Binding of drugs to plasma proteins Binding is relatively nonselective as to chemical structure and takes place at sites on the protein to which endogenous compounds Plasma albumin is the major drug-binding protein and may act as a drug reservoir; that is, as the concentration of the free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma.

Drug Metabolism The chemical outeraction of drug in the body. Water soluble drugs are excreted unchanged in the liver. While lipid soluble drugs after filtration from glomeruler are largely reabsorbed from renal tubules and re-enter circulation. Drug metabolism generally produce substance which are more water soluble and polar than the compound.

Major organ for metabolism of drug is liver. Metabolism of drug also occur in kidney, intestine,and even in skin. Lipid soluble drugs are metabolised in liver. First Pass Metabolism: Is metabolism of drug during its passage from its site of administration into systemic circulation. Drugs given sublingually : Angisid (Nitroglycerin) ..

Biotransformation (Drug metabolism) may lead to : 1. Conversion of pharmacologically active drug to pharmacologically inactive drug. Most of drugs are inactivated during metabolism. Ex. Oxidation of barbiturate, phenytoin Hydrolysis of acetylcholine, Conjugation of salicylate 2. May lead to conversion of pharmacologically active drug to another active compound, Long duration of action Ex. Codein to morphine Digitoxin to digoxin 3. Raw Drugs (Co-Drugs)are inactive and metabolised to active form by metabolism. Ex. Levodopa to Dopamine Enalapril to enalaprilate Sulfasalazine to 5-aminosalicylic acid

Metabolism(Biotransformation) After absorption, drugs could go under three possible fates: Excreted unchanged Metabolised by enzymes (microsomal, non-microsomal) Spontaneously changed into other substances because of appropriate pH of body fluids. Metabolism makes lipid soluble drug compounds change to lipid insoluble substances, so they are not reabsorbed in the renal tubules and are excreted.

2) Phase-II Conjugation Reactions Glucuronide conjugation (aspirin) Glycine conjugation (salicylates) Glutathione conjugation(Paracetamol) Acetylation(sulfonamides) Methylation (adrenaline) Sulfate conjugation (chloramphenicol) Riboucleoside/nucleotide synthesis: activation of purine and pyrimidine antimetabolite in CA therapy. 1) (Phase-I Reactions) Oxidation (alcohol, Diazepam) Reduction(warfarin,Prednisolone) Hydrolysis(Lidocaine) METABOLITE DRUG PHASE-II EXCRETION PHASE-I

Factors Effect Drug Metabolism Age Gender Disease Nutrition and diet Drug-Drug interaction

Enzyme Induction Many drugs interact with DNA and increase the synthesis of microsomal enzyme proteins. As a result, rate of metabolism of inducing drug itself and/or other drugs is increased. Drugs causing liver enzyme induction: Carbamazepine X oral contraceptives  Leading to failure of contraception. Barbiturates X Steroids

Consequences of Enzyme Induction Decrease intensity and duration of action of drugs that inactivated by metabolism. Increase the intensity of drugs that are activated by metabolism. Tolerance occur if the drug induces its own metabolism. Metabolism of endogenous substances. Ex. Phenibarbital induces metabolism of bivaluridin.

Enzyme Inhibition One drug may inhibit metabolism of other drugs if it utilizes the same enzyme. Ex. Cimetidine inhibits the metabolsim of propranolol (activity of propranolol is increased but it is not metabolised) Chloramphenicol and warfarin  Chloramphenicol increased the effect of warfarin by decreasing metabolism..Bleeding risk

Drug Excretion The major organ for excretion is Kidney Drugs also excreted from lungs, biliary system, milk, saliva and sweating.

Renal Excretion : The amount of the drugs and their metabolites in the urine are determined by 3 processes: 1. Filtration of the drug through glomerular. 2. Renal tubular secretion of drug. 3. Renal tubular reabsorption of drugs.

Renal Filtration : Most of the lipid soluble and water soluble drugs with MW less than 500 are filtrated through glomerular, and drugs which bound to plasma proteins will not be excreted except in diseases. Filtration of drugs are decreased by the age of 60 !!! In elderly people the dose of drugs should be adjusted.

Renal Tubular Secretion RTS of drugs occur via active transport system. One drug may competitively inhibit tubular secretion of other drugs. Ex. Probencid inhibits tubular secretion of pencillins.Can be used to prolong the duration of action of short acting penicillins. Cefepime X Probenecid

Renal tubular reabsorption, depends on pH of urine which determines the degree of ionization of both acidic and basic drugs. The degree of ionization of many drugs weak acids or weak bases is pH dependent, and this markedly influences their renal excretion. The ion-trapping effect means that a basic drug is more rapidly excreted in an acid urine which favours the charged form and thus inhibits reabsorption. Conversely, acidic drugs are most rapidly excreted if the urine is alkaline. Urinary alkalinisation is used to accelerate the excretion of salicylate in treating selected cases of aspirin overdose.

Excretion of Drugs Through Lungs General anesthetic drugs, alcohol and paraldehyde are excreted through the lung (exptiration). The excretion of drug through the lungs can be recognised by odor of the drug.

Excretion Through The Biliary System The main factor the affects biliary excretion are: MW of drug more than 300 Presence of polar compound (water soluble) Drugs which are metabolised by glucronidation. Drugs metabolised by oxidation, reduction, hydrolysis, and conjugation.

Amoxicilline, Indomethacin : Are drugs excreted unchanged in bile Amoxicilline, Indomethacin : Are drugs excreted unchanged in bile. If the biliary excreted the drug is reabsorbed again from intestine, the phenomena is called Intrahepatic Circulation. If the drug is metabolised by glucronide conjugation and excreted to bile, then it is hydrolysed by bacterial flora in intestine to form free drug which absorbed again (estrogen, Morphine) In the absence of the bacterial flora the drug excreted through faeces.

Excretion Of Drug Through Faeces Unabsorbable drugs and drugs which are excreted through bile or saliva may be excreted through faeces.

Excretion Through Saliva Some drugs are excreted by saliva : Potassium iodine ,expectorant are excreted through saliva. Excretion of metronidazole through saliva is important for treatment of ulcerative gingivitis.

Excretion Through Milk The pH of milk is acidic , most of basic drugs are excreted through milk (morphine) The excreted drug in milk may affect the baby Morphine may cause respiratory depression.