Drug Distribution & Biotransformation PDF

Drug distribution and biotransformation Dr/ Amira Fawzy Taha  DRUG DISTRIBUTION After a drug enters the general circulation, it is distributed to various tissues. If the drug is high lipid soluble unionized less bound to pl...

Drug distribution and biotransformation Dr/ Amira Fawzy Taha  DRUG DISTRIBUTION After a drug enters the general circulation, it is distributed to various tissues. If the drug is high lipid soluble unionized less bound to plasma protein  Factors affecting drug distribution 1) The regional blood flow; the heart, liver, kidneys, brain and other highly perfused organs. 2) The physical and chemical properties of the drug: -Hydrophobic drugs (highly lipid-soluble) can dissolve in the lipid membranes of blood capillaries and, therefore, permeate the entire cell's surface. -By contrast, hydrophilic drugs (water-soluble drugs), which have either a non-uniform distribution of electrons or positive or negative charges, do not readily penetrate cell membranes, and therefore, must go through the slit junctions between capillary endothelial cells.  Factors affecting drug distribution 3) Selective accumulation of some drugs in particular tissues e.g., iodides are concentrated in the thyroid gland, tetracyclines in bones while chlorinated insecticides are accumulated in fats. 4) Special barrier: BBB 5) Binding of Drugs to Plasma Proteins: (albumin or α1-acid glycoprotein) The protein-bound drugs are pharmacologically inactive, non-diffusible and can't be metabolized or excreted The Free unbound drugs are pharmacologically active, diffusible and can be metabolized and excreted.  Factors affecting drug distribution The binding of drugs to plasma proteins is reversible and the two fractions exist in equilibrium; when the free part is metabolized or excreted, another part is released from plasma proteins. Thus, the bound fraction is considered a drug reservoir. Albumin for anionic drugs (weak acids). α1-acid glycoprotein for basic drugs.  Factors affecting drug distribution Clinical significance of plasma protein binding In patients with hepatic failure, renal disease or malnutrition, plasma proteins are low thus highly bound drugs should be given in less than normal doses. Drugs with higher affinities to plasma proteins can displace other drugs with lower affinities by competition. Therefore, plasma protein binding displacement is one of the most important sites of drug-drug interactions, e.g., displacement of warfarin by aspirin or sulfonamides.  Factors affecting drug distribution Clinical significance of plasma protein binding Plasma protein binding prolongs the half-life of the drug because the bound part is not metabolized or excreted and the drug tends to accumulate. Degree of binding to plasma proteins determines Vd, t½, and tissue penetration. High degree of binding may necessitate bolus injection, so the drug exerts its effect before massive combination with the plasma proteins. Ex: diazoxide in acute hypertensive crisis.  Factors affecting drug distribution 6)Tissue protein binding; Like plasma protein binding but it occurs in tissues and is a site for drug- drug interaction e.g. quinidine displaces digoxin from its tissue protein binding site as well as plasma protein binding.  REDISTRIBUTION Redistribution of the drug from its site of action into other tissues in which being inactive or stored. Redistribution may terminate the drug effect. Example: Single IV injection of anesthetic thiopental, a highly lipid-soluble drug, which reaches its maximal concentration in brain within a minute of its administration (blood flow to the brain is so high). After that, thiopental diffuse to muscle and adipose issue (highly lipophilic and perfused), where it is stored (depot), leaving the brain. Then the concentration in the brain and plasma falls and consciousness returns in 20-30 minutes → Ultra-short acting. However, repeated thiopental injection → saturate the storage sites and the plasma conc. rises, thereby the brain as well → prolonged duration of action arecovery requires several hours → Long-acting anesthetic.  DRUG BIOTRANSFORMATION The drug is eliminated through biotransformation and excretion. Drug Metabolism: is the chemical transformation which occurs to the drug inside the body in order to decrease its lipid solubility and alter its biological activity to be excreted by the kidney. Water-soluble drugs are readily excreted by the kidney.  DRUG BIOTRANSFORMATION Effects of metabolism on the biological activity of drugs: 1. An active lipid-soluble drug → inactive water-soluble metabolite. 2. An active drug → another active metabolite, e.g. Codeine is metabolized to morphine and diazepam to oxazepam. 3. An inactive (prodrug) → an active metabolite as in: Enalapril is metabolized to active enalaprilat. α-methyldopa is metabolized to α-methyl-norepinephrine Prednisone is metabolized to Prednisolone. Cortisone is metabolized to cortisol (hydrocortisone). Sulphasalazine is metabolized to 5-amino salicylic acid.  Organs responsible for biotransformation include: 1- Liver (main site). Hepatic microsomal enzymes or mixed functional oxidases: large family of isozymes called cytochrome P450 (CYP) found in the smooth endoplasmic reticulum of hepatocytes. Non-microsomal: drugs can be metabolized by enzymes that exist intracellular (cytosol, mitochondria) or extracellular (plasma). 2- Others: kidney, gut mucosa, lung, brain and skin. Types of Metabolic Reactions (Phases)  Types of Metabolic Reactions (Phases): (1) Phase I Reactions (Non- synthetic): Converts parent drug to more polar (ionized) metabolite(s) which subsequently undergo phase II to be easily excreted. Unlike products of phase II, the metabolites of phase I reactions may be still pharmacologically active. Phase- I reactions include: oxidation, reduction or hydrolysis. The aim of phase-I is the functionalization of the drug that means the formation of (hydrophilic) functional group on the surface of the drug as COOH, NH2 or OH group (by introducing a functional group or unmasking it).  Types of Metabolic Reactions (Phases): (1) Phase I Reactions (Non- synthetic): Oxidation: a. Aromatic hydroxylation of phenytoin (microsomal) b. Xanthine oxidase (XO) and monoamine oxidase (MAO) (non-microsomal) Reduction: occurs in both microsomal and non-microsomal enzyme systems Hydrolysis: occurs by non-microsomal enzymes. Hydrolysis of esters as procaine Hydrolysis of amides as lidocaine  Types of Metabolic Reactions (Phases): (2) Phase II Reactions (Synthetic or conjugation): Drugs “either directly or released from phase-I reactions” are coupled with an endogenous substance e.g., glucuronic acid, glycine, acetyl, methyl, inorganic sulfate, etc. to yield inactive water-soluble conjugates that are rapidly excreted in urine or bile. The coupled drugs are more polar and water soluble and, thus, easily excreted by kidney or bile. Notes: Some drugs are metabolized in a reversal manner: For example, isoniazid is first acetylated (Phase II reaction) and then hydrolyzed to iso- nicotinic acid (Phase I reaction).  Enterohepatic recirculation For some drugs that are excreted in bile, decoupling may occur by gut bacterial enzymes, so reabsorption of the uncoupled drug can occur from the intestine, and this is called enterohepatic circulation (recyclization) as with Estrogen and Piroxicam. Thanks