ADME and Toxicity

Aim of drug treatment To obtain a drug concentration at the target sit which is effective for the appropriate amount of time while minimising side effects. Pharmacokinetics Drugs effect over time and what the body does to drugs. Bloodstream A drug is absorbed only when it has entered this. Skin, cornea and mucous membranes Examples of topical administration. Topical Most often used for local effect because most drugs are poorly absorbed though unbroken skin. GI tract Where drug enters when administered through enteral routes. Sublingual, rectal and oral Categories of enteral administration. Sublingual Administered as sprays, pastes and dissolvable tablets direct from oral cavity. Sublingual Elicits rapid response and useful when a drug is unstable at gastric pH or when rapidly metabolised by liver. Suppositories Rectal method of administration. Rectal Elicits local or systemic effect and useful if patient is vomiting, post-OP or an epileptic child. Oral Most absorption occurs in the intestines and balance must be achieved between H2O and lipid solubility. Fatty food and CO2 Examples given of factors that influence the ability of drugs to exit the stomach. Fatty food Decreases stomach emptying therefore takes longer to feel effects of alcohol. CO2 Increases stomach emptying therefore feel effects of alcohol quicker. Ca2+ Binds to tetracycline and prevents absorption Parenteral Taken into the body or administered in a manner other than through the digestive tract. Intravenous Fasted and most certain method of administration providing 100% absorption. Bolus Intravenous administration all at once. Infusion Intravenous administration over time. Heat/massage Can increase absorption from subcutaneous and intramuscular administration. Faster Absorption of subcutaneous and intramuscular compared to oral. Diffusion through tissue and local blood flow Factors that affect the effect of subcutaneous and intramuscular administration. Inhalation Results in significant absorption through the lung. Volatile aesthetics Often administered via inhalation. Inhalation Easily adjust plasma concentration and responsible for absorption and elimination. Local and system Effects of inhalation. Bronchodilators e.g. salbutamol Example of inhalation eliciting local effects. Reaches 100% absorption. IV injection 1/3 Distribution How much of the drug makes it to its target. Simple diffusion Higher concentrations migrate towards lower concentrations. Carrier transport Against a concentration gradient - drug is carried across. Body fat Acts like a storage warehouse, low blood supply prevents migration and action. Albumin Main plasma protein that drugs bind to which prevent drugs effect. Thyroid drugs Condition for which protein binding is relevant. Aspirin Can displace valium through competing for binding sites causing an increased therapeutic effect from valium. Blood brain barrier A mechanism that prevents certain molecule from entering the brain but allows others to cross Water soluble Class of drug prevented from entering the brain by the blood brain barrier and fetus by the placental barrier. Meningitis and encephalitis Disease that weaken the blood brain barrier making it more permeable which allows drugs to enter the brain that would otherwise not. Placental barrier Many layers of tissue which prevent many drugs and chemical reaching the foetus from the mother. Small MW or lipophilic drugs Chemical characteristics that make drugs more susceptible to reaching the foetus. Vd Parameter used to measure how much a drug moves around the body Small Relative Vd value for drugs bound to plasma proteins. Water soluble Form that drugs must be in order to leave the body. Liver Where the majority of metabolism's enzymatic reactions take place. CYP450s Enzymes involved in Phase 1 reactions. Conjugations Phase 2 reactions to add size. Bioactivation Where phase 1 metabolites of drugs are toxic. Prodrug An inactive drug that is converted into a metabolite that provides the therapeutic effect. Induction When a compound increases liver enzymes. Competitive blocking Where drugs bind to enzymes and prevent them from working. Induction Increased rate of metabolism of drugs due to an increase in CYP enzymes. Decreased Smoking effect on the stimulant effects from coffee. CYP3A Metabolises approximately 70% of all medications including ethanol, paracetamol and volatile aesthetics. GSH, UDPGA and SO3 The 3 major conjugation systems. GSH Livers major defence against free radicals and toxic metabolites of drugs. Glutathione GSH stands for UDPGA Glucuronide UDPGA and SO3 Conjugate a wide range of chemicals that have OH or NH groups. F Bioavailability Bioavilability The amount of the original drug which gets into the blood stream and is expressed as a percentage or fraction. First pass metabolism 2/3 Drug metabolism in the liver that reduces the amount of drug available to be absorbed into the blood stream. Kidney Organ primarily responsible for drug excretion. Water soluble These drugs pass through the kidney 'filter' and can be excreted in the urine. Lipid soluble These drugs are further metabolised by CUP450 enzymes in the kidney. Lungs and gall bladder Other organs involved in excreting drugs. Gases and other volatile substances What the lungs are primarily responsible for excreting. Nitrous oxide and ethanol Examples of drugs excreted through the lungs. Bile Stored in the gall bladder and drugs can be secreted into it for excretion. Bile acids and bilirubin Regulated by gall bladder. Jaundice Caused by an accumulation of bile acids and bilirubin. Breast milk Where fat soluble drugs and chemicals can accumulate including caffeine, ethanol and nicotine. Half life The time required for the plasma levels of a drug to fall to half of the original value. Steady state concentration The point where drug accumulation equals drug elimination. Loading dose A priming dose given to bring plasma levels up quickly. CYP2E1 Metabolises paracetamol to NAPQI NAPQI Toxic metabolite of paracetamol. Liver injury Effect of NAPQI accumulation. Ethanol and acetone Potent inducers of CYP2E1. 21 Number of standard drinks a week to induce CYP2E1. GSH Can act on NAPQI so it can be excreted. CCl4 and Disulfiram Inhibitors of CYP2E1. Disulfiram Drug given to people to deter them from drinking. CCl4 Industrial solvent contained within fire extinguishers and destroys CYP2E1 enzyme in the metabolic process. CCl3 Free radical produced by the metabolism of CCl4 by CYP2E1. Increased hepatotoxicity Effect of CYP2E1 inducers and CCl4 interactions. Decreased hepatotoxicity Effect of CYP2E1 inhibitors and CCl4 interactions. Acetaldehyde Build up results in nausea, vomiting and hypotension. ADH For which ethanol has the highest affinity for out of all alcohols. ADH Metabolises antifreeze (ethylene glycol) into toxic glycoaldehyde. Ethanol Prevents glycoaldehyde from being produced because it has a higher affinity for ADH. 3/3