Pharmacokinetics PP - Lecturer.pptx

Pharmacokinetics DWA 2024 Learning Outcomes LO3 Understand the anatomical and physiological principles underpinning pharmacokinetics 3a Outline the stages of pharmacokinetics LO4 Understand the principles of pharmacodynamics 4a State the patient factors that influence the action of veterin...

Pharmacokinetics DWA 2024 Learning Outcomes LO3 Understand the anatomical and physiological principles underpinning pharmacokinetics 3a Outline the stages of pharmacokinetics LO4 Understand the principles of pharmacodynamics 4a State the patient factors that influence the action of veterinary medicines Starter Task (5 mins) Define pharmacokinetics What are the four stages involved in pharmacokinetics? Define pharmacodynamics Starter Task Define pharmacokinetics - The affect that the body has on a drug What are the four stages involved in pharmacokinetics? - Absorption, Distribution, Metabolism, Excretion Define pharmacodynamics - The affect a drug has on the body Recap: Functions of the Liver (5 mins) How many can you remember? Recap: Functions of the Liver Carbohydrate metabolism = glycogen storage = released during low bg Protein metabolism – forms plasma proteins including fibrinogen, albumin and prothrombin. Performs the transamination of proteins (converting less useful proteins in to form that may be more useful in tissue building and repair). Also, deamination, where it converts excess amino acids to urea, so they can be excreted. Fat metabolism – Converts fatty acids to phospholipids for building cell walls and cholesterol in bile salts. Bile formation Exhausted erythrocyte breakdown (haemoglobin is excreted as bilirubin) Erythropoiesis Vitamin and iron storage Body temperature regulation Detoxification of harmful substances Pharmacokinetics Refers to the movement of drugs in to, through, and out of the body Is divided in to 4 stages: 1. Absorption 2. Distribution 3. Metabolism 4. Excretion Pharmacokinetics Absorpti Distributi Metaboli Excretion on on sm https://youtu.be/NKV5iaUVBUI 1. Absorption The journey of the drug from administration into systemic circulation Effects the speed and concentration that a drug reaches its location of effect (e.g., plasma) Each route of administration will alter the absorption As an example: An oral medication has to pass through the stomach acid, digestive enzymes of the small intestines and liver processing. This will significantly diminish the amount of drug available to make it to the blood stream. A medication administered intravenously will bypass all of these processes, meaning that all of the drug enters the blood stream The amount of the medication that is absorbed into circulation is known as its bioavailability Bioavailability The bioavailability of a drug refers to the fraction of an administered dose of unchanged drug that reaches systemic circulation. e.g., drugs administered IV have 100% bioavailability, compared with drugs administered orally having far less. What affects the rate of absorption? Form of drug e.g., aqueous solution more rapidly absorbed than oily solutions, suspensions or solids Route of administration (no absorption for IV administrations) Physical and chemical characteristics of the drug Blood flow at the administration site 2. Distribution How the substance is spread through the body The goal of distribution is to achieve the effective drug concentration To be effective a drug must reach its destination and not be protein-bound The protein principally responsible for the movement/distribution of protein-bound drugs is albumin Where distribution of a drug is more difficult to achieve, loading doses may be used to reach the required drug concentration sooner, rather than relying on accumulation What affects distribution? Characteristics of the medication (molecule size, binding capabilities) Patient hydration status Patient plasma protein concentration (albumin can be affected by renal and hepatic function) Patient body condition score Regional blood flow Lipid solubility of drug (drugs that are lipid soluble will be widely distributed) Whether drug becomes protein-bound Physical boundaries e.g., the blood-brain barrier What affects distribution? Another example… In renal dysfunction, uraemia decreases the ability of acidic drugs (e.g., diazepam) to bind to proteins, which will result in more ‘free’ medication available to act on the patient's physiology. This results in the same dose of medication having a more profound effect on the patient, including increased undesired effects such as respiratory depression. 3. Metabolism Most drugs undergo some form of metabolic conversion before excretion to render the drug more soluble so that excretion is easier Drug metabolism is carried out by enzymes, including those from the kidneys, lungs and in plasma The major site of drug metabolism is the liver Not all drugs undergo metabolism. Metabolism in the Liver The majority of drug metabolism occurs in the liver. Usually, this process deactivates the drug and converts it to a form that can be excreted from the body. The health of the liver can have a significant impact on both the efficacy of medicines and the risk of toxicity. It is dark red in colour due to the high volume of blood flow going through it. The cells of the liver are called hepatocytes. First Pass Metabolism Drugs absorbed via the gastrointestinal tract will travel through the hepatic portal system to the liver The liver will metabolise the drug, decreasing the amount that makes it into systemic circulation This is why oral medications often have a higher recommended dose than parenterally administered medicines Prodrugs Most medications will be inactivated by metabolism in the liver, but some depend on this to become effective These are called prodrugs, and examples include ACE inhibitors (enalapril) and codeine Enzyme inducers and inhibitors Metabolism of medication can also be impacted by certain medicines. Cytochrome enzymes in the liver are involved in drug metabolism (CYP450). Enzyme inducers (e.g., phenobarbital and rifampicin) increase the number of cytochrome enzymes, which will then increase the rate of drug metabolism. Enzyme inhibitors (e.g., cimetidine, diltiazem) reduce the number of cytochrome enzymes, therefore decreasing the rate of drug metabolism. What affects metabolism? The liver has a limited capability for drug metabolism, which is how they can still enter circulation at a therapeutically effective dose. Liver enzymes can be affected by the drug, decreasing its ability to metabolise it. This will potentially result in increased effects from the drug (including side effects). Some substances will enhance the enzymes effect, reducing the overall efficacy of a drug. Hepatic dysfunction and the neonatal and geriatric life stages are all likely to display a reduced ability of the liver to cope with medication, which is why reduced doses and careful monitoring is often advised. A – young patient B – geriatric patient Drug metabolism in cats Cats are suspected of having a glucuronidation deficiency when compared to dogs Glucuronidation is a detoxification pathway that is used for the metabolism of some drug types This means that cats will take much longer to metabolise and excrete drugs such as propofol, carprofen, aspirin and paracetamol than dogs would. Some half-life comparisons: Aspirin – Dogs 8.6 hours, cats 37.6 hours Carprofen – Dogs 10 hours, cats 20 hours Glucuronidation is not the only manner of metabolising drugs, so this is not the case for all, just those detoxified this way 4. Excretion Lowering of plasma drug concentration = clearance Achieved by: excretion of unaltered drug, or metabolism followed by excretion Principle organ: Kidney (removes water soluble material from the body) Liver also involved: Eliminates metabolised drugs in bile Drugs may also be excreted via sweat glands, mammary and salivary glands and the lungs What affects excretion? Renal disease may reduce the body’s ability to excrete metabolites or the unchanged drug For this reason, patients with renal dysfunction may require reduced doses, or certain medications being avoided entirely SPCs will give guidance on the suitability of a medicines use in cases of hepatic or renal disease Drug Excretion Pharmacokinetics: Factors that influence the duration and action of medicines Species Cats have much slower hepatic drug metabolism than many other species Age Fetal, newborn and geriatric animals have limited/reduced capacity to metabolise drugs Sex In rats females metabolise drugs more slowly than males Weight / body condition Adittional fat tissue results in increases of distribution space, lowering the serum concentrations of fat soluble medications Underlying medical conditions (Hydration / excretory system function) Renal disease Kidneys responsible for excretion Reduced dosages needed Hepatic disease Liver responsible for metabolism Reduced dosages needed Circulatory disease / Shock Reduced circulating blood volume Absorption from s/c and i/m administration will be slower than normal How does pharmacokinetics impact upon us administering medicines? Each individual is likely to respond to medication in a slightly different way This may mean that, depending on the considerations on the previous slides, doses have to be adjusted to suit the patient. Problems associated with having to do this include a delay in achieving the desired therapeutic effect, and the risk of having adverse reactions. A good understanding of pharmacokinetics and its impact can help vets to select suitable doses and methods of administration straight away. This is the principle behind therapeutic drug monitoring. Pharmacokinetics: Intravascular vs Extravascular Administration (20 mins) Create a comparison table comparing these administration routes, to include: Bioavailability Onset of action Dose size Risk of adverse reaction Risk to patient Review Summarise the 4 stages of pharmacokinetics on a flash card Learning Journal Complete a learning journal entry detailing the following: How confident are you describing the 4 stages of pharmacokinetics When we have an elderly, overweight, mildly dehydrated canine patient in for treatment, what concerns do we have regarding medication administration and why?