Pharmacokinetics Revision Notes PDF

[Pharmacokinetics] - How drug concentration moves through the body - Motion - Drug concentration changing - What body does to the drug - ADME (Absorption, Distribution, Metabolism, Excretion) Absorption and Distribution are [ENTERING] Metabolism and Excretion are [LEAVING] [Absorpt...

[Pharmacokinetics] - How drug concentration moves through the body - Motion - Drug concentration changing - What body does to the drug - ADME (Absorption, Distribution, Metabolism, Excretion) Absorption and Distribution are [ENTERING] Metabolism and Excretion are [LEAVING] [Absorption] - Before entering the systemic circulation and depends on route of administration. - Substance entering the blood, systemic circulation. Factors affecting absorption; - Weight - Age - Diet - Hepatic and liver function - Other medication - Surgery - Route of administration - Gut content - Medical conditions such as a stoma Site of administration to blood stream. Cross biological membrane / cell membranes. Bulk of cell membrane is primarily lipid; lipid soluble drugs pass easily. Dose, molecular size (smaller the better) lipid and water solubility all affect distribution of drugs. Oral needs to be absorbed by gut; bioavailability reduced. Oral \> needs to cross cell membrane of intestine \> to get to portal circulation \> liver and then systemic circulation. What affects treatment affective? - Compliance with meds in general - Stomach fluid (PH) - Acidity (low PH) - Food - Gut content; empty or full stomach. - Diarrhoea - Molecule size also affects this (large ones struggle) - Older people Most drugs absorbed in small intestine. PH how this further affects - uncharged molecules i.e. ionised molecules are more lipid soluble. *From circulation \> goes to liver, this is called 1^st^ pass metabolism.* Non-ionised lipid soluble; ionised = water soluble. If ionised less solubility and less absorbed. Most drugs are done by passive diffusion in absorption process - the process by which molecules diffuse from a region of higher concentration to a region of lower concentration. It is the most important mechanism for passage of drugs through membranes. What affects absorption? - Route - Age - Diet - Other meds - Other conditions - Gut content - Blood flow. - Permeability of capillaries for drug molecules, e.g. lipid soluble, can easily pass membrane as membranes contain fatty acid. [Route of Administration ] *Question -- compare routes of administration and effect of 1^st^ pass metabolism, also how route of administration may effect therapeutic window?* - IV - 100% bioavailability unchanged, bypass of 1^st^ pass metabolism, straight to circulation. - Oral - most barriers to cross, 1^st^ pass metabolism takes place where it is greatly reduced before reaching systemic circulation. - Rectal administration -- only 30% goes to hepatic portal vein. - IM / sub-cut - slower absorption rate, not full bioavailability. Compartmentalisation and high concentration. High blood flow so fast absorption, skips first pass metabolism, absorbed at site, can be delayed in depots, good bioavailability. - Sublingual - they dissolve however you end up swallowing some of this. - Inhalation -- rapid and used for compartmentalisation. - Dose range of drug that medication is effective with minimal adverse effects, displays plasma concentration levels. Different drugs have different windows, for example, rapid absorption would require more doses to keep therapeutic window at a steady state. - Repeat doses are given and plasma concentration builds up, it reaches a steady state. This is when the drug is most therapeutic as long as regular doses are given. The time taken to reach the steady state is 5x's the half-life of a drug. Drugs with a shorter half-life will take less time to reach a steady state. *Explain the differences that would likely occur in the absorption of drugs if given by intravenous, intramuscular, oral or rectal administration. Explain which properties of the drug would be relevant to this;* Intravenous administration has a 100% bioavailability, therefore bypasses first pass metabolism. Intramuscular administration has a high blood flow which leads to fast absorption, also skips first pass metabolism and is absorbed at the site. It has good bioavailability but not 100% as with intravenous, however its absorption can be delayed with depot injections. Rectal medications have reduced absorptive surfaces, therefore only 30% of the drug goes into the hepatic portal vein, and also bypass first pass metabolism. Oral administrated medications go through first pass metabolism, they're the most common form of medications however have the most complications; repeated doses are required in order for a steady state to be achieved and absorption of the medications take time. *Peak plasma concentration rate* is reached when drug absorption rate = clearance rate. [Bioavailability:] - \% of drug that makes it to systemic circulation unchanged. - Oral drugs are not 100% bioavailable. - This is important to know when transferring drugs from oral to IV as can accidentally double doses. [Distribution:] Dispersion of a substance through tissues of the body and fluid, after in systemic circulation it can then be distributed from one place to another. This starts in the vascular space (blood/plasma) and then goes to extravascular space (fat/muscles). Through the blood and body water, to various tissues and site of action. Plasma (water compartment) or body tissues (fat compartments), lipid soluble seem to have a higher volume of distribution. Plasma proteins - made in liver. Not needed for drug binding, albumin (a plasma protein) are large and act like sponges to the drug. Meaning no drugs available sometimes to act on the receptors, until more drug is added, when the plasma sites are completely protein saturated. Distribution controls how long the drug acts, accounts for most side effects produced. VD = ratio between total drug in body to amount of drug in plasma. VD used to calculate loading doses. What affects distribution? - Blood flow rate - Depending on amount of blood organ receives - Drug reservoirs (think of albumin) - Permeability of capillaries for transfer (however, lipid soluble don't need transport systems to carry across). [Metabolism]: (Biotransformation) irreversible transformation of Drug A (parent compound) by enzymes into Drug B (daughter compound) make it more active or polar in order to eliminate/excrete it; done by the LIVER. First Pass Metabolism; a process in which a drug administered by mouth is absorbed from the gastrointestinal tract and transported via the hepatic portal vein to the liver, before it reaches the rest of the body, where it is metabolised. As a result, in some cases only a small proportion of the active drug reaches the systemic circulation and its intended target tissue. This first pass through the liver thus greatly reduces the bioavailability of the drug. First-pass metabolism can be bypassed by giving the drug via sublingual or buccal routes. If liver impairment, less of drug metabolised by 1^st^ pass and risk of toxicity increases, would not get inactivation of active drug. [Biotransformation:] - Process of metabolising drugs in the body. - It occurs mainly in the liver and is therefore often called *hepatic metabolism*. - Some drugs are activated by this hepatic metabolism -- these are called *pro-drugs*. - Drug metabolism is split into two phases in the liver. - An example of phase one metabolism is *oxidation*. - An example of phase two metabolism is *conjugation*. Liver - "Hepatic" liver removes some drug before systemic circulation. 75% of metabolism in the liver, kidneys and adipose also do a bit. Liver alter drugs in 2 x main ways; *Phase 1* - To make less pharmacologically active. Oxidation, reduction, hydrolysis -- catabolic reaction; phase 1 reactions. Pro drugs, these become more active -- gets metabolised into something more active than less. *Phase 2* - Altered to make more soluble. Conjugation, anabolic reaction, makes lipid soluble drugs attach to water soluble component, e.g. sulphate or glucuronide, to allow it to filter through the nephron and stay in, allowing it to get lost in the urine. *Enzyme induction* - part of this is cytochrome p450, enzyme pathway in metabolism of drugs, some drugs stimulate liver to create enzymes. Circulatory disorder, e.g. cardiovascular disorder also affects this. Acidosis also affects, drugs would be less likely to ionise and be more lipid soluble, as it is filtered into nephrons, it then comes out. So alkaline drugs are lost more rapidly, acidic drugs would be lost more slowly. Drugs can interact with stomach acid. Liver disease, may avoid lipid soluble drugs as can not be conjugated and excreted, causing build up in the liver. Also drugs that have high 1^st^ pass metabolism, if liver has liver disease, can cause high concentration build up. Cytochrome p450 active to inactive drug. Biotransformation in the liver. Factors that may effect metabolism; - Age - Genetics - Gastric acid (PH) - Gastric emptying - Nutritional status - Problems with blood flow - Liver disease [Excretion:] The removal of substances from the body, done by the *KIDNEYS: Renal* Factors preventing drugs reaching the systemic circulation/blood; - The properties of the drug - Physiological factors - Blood flow rate - Permeability of capillaries *Alterations due to liver or renal impairment* Volume of distribution; amount of drug in the body divided by plasma concentration of the drug. Excreted 70% of renal, biliary, faeces, hair, sweat etc Some drugs unchanged in excretion, only certain ones such as antibiotics. [Pharmacodynamics] ***"Study of how drugs produce the effects to the body"*** - The impact the drug has on the body - How powerful is the drug - What's the concentration? - Potency - Drug receptor interactions Receptors; recognition proteins, think lock and key. Ligands; any substance, endogenous or exogenous that can bind to a receptor. Agonist; a drug that binds to a receptor and elicits a response. Antagonist; a drug that binds to a receptor and produces no response thus blocking the receptor. G-Protein; a protein coupled to some receptors that transduces the response of the receptor becoming activated by GTP. Endogenous; if made in the body; neurotransmitters, hormones, cytokines. Exogenous; from outside the body, e.g. drugs. 4 Target Molecules: RICE Receptors are proteins either inside a cell or on its surface which receive a signal. In normal physiology, this is a chemical signal where a protein-ligand binds to a protein receptor. The ligand is a chemical messenger released by one cell to signal either itself or a different cell. Ion channels are protein molecules that span across the cell membrane allowing the passage of ions from one side of the membrane to the other. They have an aqueous pore, which becomes accessible to ions after a conformational change in the protein structure that causes the ion channel to open. Carrier molecules are a secreted protein which binds to drugs, carrying them to cell transporters, where they are moved into the cell and can be blocked leading to an accumulation of a substance. Enzymes can be inhibited leading to a reduction in product and an increase in substrate; they are biological catalysts that increase the rate of chemical reactions in the body. They are integral to many normal physiological functions. Many drugs target enzymes to prevent them from carrying out their normal function. [4 main types of receptors:] KING located in cells which transform information; - Kinase linked receptor - ION channel - Nuclear receptor - G-protein coupled receptors Ligand gated ion channel receptors/ionotropic receptor; receptors, ion channels, carrier molecules, enzymes. G protein/coupled receptor; when a ligand binds to this receptor, it signals the G-Protein, also called the 2^nd^ messenger system, biological response within seconds, e.g. adrenaline stimulates and binds to receptors, but drugs like propranolol for example will inhibit this and reduce the effect (antagonist). Nuclear receptors; found in nucleus, switch gene on/off, steroid hormone receptors, for example, take longest to exert action; hours or days to exert an effect. Kinase-linked receptors; kinase transfers phosphate between amino acids in different proteins, signalling a pathway; domino effect, ligand knocks over 1^st^ domino and so on, slow and take hours to have effect e.g insulin receptor. [Synapses:] Communication unit of the nervous system is the neuron. It consists of a cell body and a nucleus, both needed for the synthesis of cellular chemicals. Pre-synaptic cell terminal is in close contact with the post-synaptic cell which is either the dendrite of another neuron or could be muscle cell or gland. [Half-life of drugs:] Half-life (t ½); the time taken (required) to reduce the plasma concentration of a drug to half of its original value. The half-life is useful in; - Duration of action after a single dose - Determining how often a drug should be given - Determining when a drug will exhibit its pharmacological effect and reach steady state - Determining how long it will take for a drug level to fall *Look how liver affects this* - In the case of renal failure, drug excretion will be impaired, and consequently, the peak initial concentration and excretion rate of a given drug will increase. Hepatic disease also affects the half-life of a given drug due to impaired metabolism. Because the liver inactivates active metabolites at a slower rate, the body will take a more extended period to remove the drug from circulation. [Therapeutic Window and Steady State:] The range of plasma drug concentration in which medicine has its best effect. Therapeutic window is a measure of the safety of a drug. Wants a drug with wide therapeutic window, dose range between desired effect and toxicity, ideally. Shows min dose to max toxicity. Dose range of drug that medication is effective with minimal adverse effects, displays plasma concentration levels. Different drugs have different windows, for example, rapid absorption would require more doses to keep therapeutic window at a steady state. Repeat doses are given and plasma concentration builds up, it reaches a steady state. This is when the drug is most therapeutic as long as regular doses are given. The time taken to reach the steady state is 5x's the half-life of a drug. Drugs with a shorter half-life will take less time to reach a steady state. Steady State; rate going in same as rate going out. If above steady state then TOXICITY. Therapeutic index; reflects the relative safety of a drug, compares the amount of a drug required to induce a therapeutic response to the amount that would cause toxic effect. [Excipients:] - Non-drug parts of the medicine included to make the medicine more effective and convenient. - Oral - flavouring, bulk, stability, solid form for liquid drugs, enteric coating, delayed release preps. - IM - oil for delayed release depot injections. - Inhalation - propellant gas. [Tolerance:] Tolerance -- decreased response to the same dose of drug that occurs with repeated administration. Many reasons pharmacokinetic and pharmacodynamic; - Reduced absorption - Increased elimination - Reduces receptor sensitivity (enzyme induction) - Reduced production of endogenous analogues -- for example with repeated use of opiate drugs, the production of endorphins will be reduced. - Increased production of endogenous antagonists. For example, some sedative drugs will cause an increase in the production of stimulatory neurotransmitters such as noradrenaline. In some cases the use of a drug may produce an increased response on subsequent exposure. If the drug was effective in the past this could increase the placebo effect produced by the drug. [Blood-Brain Barrier:] - Membrane between the circulating blood and the brain. - Special compartment - 3 aspects to this; blood brain barrier, foetus, and gonads. - Permeability low in this system. Glial cell is something that makes up part of NS but not a neuron, it is a supporting cell. Astrocytes project pseudopodia onto brain capillaries, further reducing permeability. - Tight endothelium, active transport systems, glial cells / astrocytes -- making it less permeable and pumping things out of CNS into body. - Physical -- folds of the glial cells make capillaries less permeable. - Active transport systems removing substances from the brain. - Maintains a stable internal environment in the brain. - Many drugs will have limited access into the brain. What characteristics of drugs will affect their entry into these special compartments? - Size -- smaller drugs penetrate more easily. - Better penetration with very lipid soluable drugs. - Some drugs actively transported out. - Active transport system can be affected by other substances, e.g. the herb St. John's Wort. [MECC is the strategy from PHE:] I would utilise the Making Every Contact Count approach (M.E.C.C). This approach is to behaviour change that utilises day to day interactions that people and organisations have with other people to encourage changes in behaviour that have a positive effect on the health and wellbeing of individuals, communities and populations. Through health promotion with my patient during my consultations, I would empower and encourage them, to make a positive change to their physical and mental health, e.g, smoking cessation, healthy diet and exercise, and exploring ways to help improve mental health. The MECC approach details the importance of a holistic approach to health care and those professionals can utilise any contact/interaction with a patient, however short, to explore other factors that can influence their health or wellbeing. In consultation with a patient who has Botox, they disclose that they would like to reduce alcohol intake and stop smoking as these break down Botox and negatively impact upon healing following treatments; as well as other detrimental health concerns. The benefits greatly outweigh the risks; I would refer to local services for smoking cessation and discuss the health benefits of reducing alcohol intake. Through encouragement I help my patient to make healthier choices which would improve their wellbeing and mental health without directly telling them what to do. As an INP, I am there to assist and guide my patient to make informed choices which would promote healthy living. I would raise the issue of lifestyle changes after a conversation about their lifestyle choices and current health situation. I listen to my patient, respond appropriately and sign post them to appropriate services where they would get the required support and guidance from; this allows my patient to be in control and to take action. I remain impartial and display empathy at the issues we are discussing. I advise my patient of the NHS smoking cessation programme and local alcohol support services through Wigan council. We make a plan going forward, collaboratively, and book a further appointment to review my patient's progress and to discuss any issues they may have experienced. I relate to the Behaviour Change Model and advise how my patient can stay healthy by eliciting some behavioural changes when trying to stop smoking; we discuss smoking alternatives such as patches and chewing gum. When discussing alcohol reduction I highlight the weekly/monthly health benefits that this would achieve. I use the Health Belief Model; my patient feels that a cancer can be avoided should they stop smoking and they feel positive that switching to a smoking substitute will help them to stop smoking which will reduce their chances of developing cancer. At this point I would offer my patient leaflets with further information and advice, appropriate to what we have discussed. Behaviour Change Model: Prochaska and Di Clements: Biopsychosocial [Public Health:] - Helping people to stay healthy and protecting them from threats to their health - The science and art of preventing disease, prolonging life and promoting health through the organised efforts of society - Eliciting behaviour change - Health protection: protecting peoples health e.g food poisoning - Health Improvement: e.g quit smoking - Healthcare public health: effective health services, easily accessible etc - Wellbeing - Health inequalities - Social determinants of health [Public Health England:] - To keep people safe - To prevent poor health - To narrow the health gap - To support a strong economy 10 key priority areas of PHE; - Smoke-free society - Healthier diets, healthier weight - Cleaner air - Better mental health - Best start in life - Effective responses to major incidents - Reduced risk from antimicrobial resistance - Predictive prevention - Enhanced data and surveillance capabilities - New national science campus [Health Belief Model:] - Feels that a negative health condition (e.g. HIV) can be avoided - Has a positive expectation that by taking a recommended action they will avoid a negative health condition (e.g. using condoms will be effective at preventing HIV) - Believes that they can successfully take a recommended health action (e.g. can use condoms comfortably and with confidence) [Cycle of Change Model:] - Perceived susceptibility - Perceived severity - Perceived benefits - Perceived barriers.  [Drug of Choice -- Flucloxacillin ] Flucloxacillin is a narrow-spectrum penicillin (beta-lactam antibiotic) with antibacterial activity. Used for the treatment of bacterial infection caused by susceptible, usually gram-positive organisms. Used in cellulitis of the face post aesthetic injectables (my scope). Like other beta-lactam antibiotics, Flucloxacillin is an agonist to the nuclear receptor PXR that regulates the expression of cytochrome P450 (CYP) enzymes and acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up major components of the cell wall of gram-positive bacteria. Flucloxacillin binds to and inactivates penicillin binding proteins (PBP's) located to the inner membrane of the bacterial cell wall; inhibits protein synthesis by binding to the 50s subunit of the bacterial ribosome within the cell cytoplasm. Inactivation of PBP's interferes with the cross-linkage of peptidoglycan chains necessary for bacterial cell wall strength and rigidity. This interrupts bacterial cell wall synthesis and results in the weakening of the bacterial cell wall, eventually causing cell lysis. Therefore, ceasing the spread of infection for the patient being treated, resulting in the patient and the wound infection healing. Flucloxacillin is stable against hydrolysis by a variety of beta-lactamases, including penicillin axes, and cephalosporinases and extended spectrum beta-lactamases. Flucloxacillin is not to be used in patients who are allergic to penicillin. Common side effects of oral Flucloxacillin are gastrointestinal disorders with less common side effects being eosinophilia. [Special Population; Elderly ] *Explain how pharmacokinetics would be altered in this case.* Pharmacokinetics can be altered in the elderly, due to many factors. There are changes in the gastrointestinal tract which result in reduced acid secretion in the stomach which have an impact on absorption rates. The stomach has slower motility therefore the stomach is slower to empty and there is a reduction in total surface area for absorption; a reduction in first pass effect. Body composition changes with age therefore distribution is affected, there is reduced muscle and less fat, there is less body water which changes the volume of distribution of drugs. Water soluble drugs result in an increase in plasma concentration and increase in pharmacological effects. There is a reduction in the size of the liver and reduction in blood flow. This results in reduced metabolism capacity and increase in toxicity as the drug can remain in the body for longer and with repeated dosing. There is a reduction in renal clearance and reduction in eGFR due to the liver size decreasing with age. The biggest change is GFR rate which is the rate of which fluid is filtered from kidney nephrons and by the age of 80 there is a reduction of 50%. Medication given to the acutely unwell dehydrated patient can cause increased toxicity, elderly patients have diminished chances of managing side effects. The drug is also excreted more slowly. It is necessary to reduce drug doses in the elderly to prevent toxicities, adopting a start low go slow approach; starting at a low dose and titrate to a therapeutic level.