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Pharmacokinetic definitions
Agonist - Molecule that binds and activates the receptor Antagonist - Molecule that binds to the receptor, but no biological response is elicited (no efficacy). Dose-response curve - A graphical representation showing the effect of a drug (y-axis) relative to the concentration (x- axis). Shows the EC50, and the effect of other drugs/environmental factor have on the drug of interest. Shift to the R - decrease in potency, shift to L - increase in potency. Affinity - The tendency of a drug to bind to a receptor Efficacy - The tendency of a drug to activate a receptor, leading to a biological response. Potency - Measuring the strength of the drug relative to the drug's concentration and degree of efficacy. Drugs with high potency, are drugs with high efficacy at low concentrations. Determined by measuring the IC50. EC50 - 50% effective concentration. This is the dose required for an individual to experience 50% of the maximal effect. Measure to determine whether the drug is more potent than the other. ED50 -
50% effective dose. This is the dose required for 50% of the population to obtain a therapeutic effect. There are patient differences; factors such as age, amount of body tissue, renal function affect how well the drug works. Therapeutic Index - The difference between toxic dose and effective dose. If large, this means a high concentration of the drug would be required to have a dangerous effect. If small, very small difference, and so drug has the capacity to do more harm than good to the patient's body. Specificity - The capacity of a drug to cause a particular action in a population. Selectivity - The drugs ability to target only a selective population i.e. cell signalling pathway of one tissue vs many other types of tissues. Competitive antagonist - Compete with agonist at the same site of the receptor. Similar chemical structure, and can be overcome by increasing the agonist concentration (simulatable effect). Non-competitive antagonist - Binding to an allosteric site on the target tissue, changing the 3D structure, hence, changing the binding site for the agonist to bind. Irreversible antagonist - Covalent binding to the receptor site, this means they are so strongly bound, that they cannot come off. Insurmountable effect; no matter how much the agonist concentration is increased, no improvement Desensitisation - Repeated use of the drug causes the effect to be tapered off Immediate = tachyphylaxis
Phase 1 - solubility (oxidation, reduction, hydrolysis reaction) occurring by CYP450 enzymes Phase 2 - conjugation (increasing solubility) e.g. adding nitrate groups to the chemical structure of the drug NB: some drugs may only require Phase 2. Entero-hepatic - Drug is processed for several cycles before being allowed into enter systemic circulation. The drug re-enters the stomach as bile by hepatocyte recognition. From here it either gets excreted in the faeces or reabsorbed. Pharmaceutical interaction - Interactions occurring to the drug before it is even administered to the body. Chelating i.e. interaction with ions affecting solubility, chemical interactions affecting the environment e.g. pH, oxidation/reduction. Excretions - Hepatic-renal = main Sweating, breast milk, faecal = secondary Net excretion - (filtration (glomerulus) + excretion (PCT)) - re-absorption (DCT). This is dependant on the urine pH relative to the blood. Affects the neutrality of the drugs. Cmax - The maximal concentration of the drug in the body (peak absorption) Tmax - The maximal time taken to reach peak plasma concentration. Dependant on absorption. AUC -
Area under the curve. Relates to the blood/plasma clearance (used to work out the CL) Absorption rate - The amount absorbed from the administered site to measurement side per unit of time. A shows IV and B shows oral administration absorption rates. Elimination rate - The amount of the parent drug eliminated from the body per unit of time. Volume of distribution - Proportionality constant of the drug found in the plasma relative to the tissues Clearance - The volume of the drug cleared from the plasma per unit of time. Only deals with the plasma concentration NOT the concentration present in the tissues (elimination includes the tissues). Sum of all excretory organ activity, dependant on flow rate Half-life (t1/2) - The time taken for the concentration of the drug to halve. Half-life factor = 0. Bio-availability - Is the fraction of the dose which relates the systemic circulation as intact drug. Expressed as F. First Order - Change in concentration per unit of time, dependant on the concentration of the drug. Zero Order - Change in concentration per unit of time, independent of the concentration of the drug
Fetal trapping; more acidic - alkaline-based drugs get trapped. Consequences to the foetus; the need for owner consent and informed. Decreased gastric emptying What factors should be considered when patient is a neonate? - Allometric scaling; increased SA:V and low-fat content limited evidence for toxicity; no research on neonates GI - irregular peristalsis, but more rapid topical absorption. Greater water content; affecting hydrophilic drugs. Hepatic and renal function take several days to develop after birth. Question: What age is the animal no longer considered a neonate? What factors should be considered when patient is old? - Similar to neonate; like them have a greater water content and less proteins, especially albumin - increased the plasma concentration of the drug. Reduction in body mass. Increased lipid content gastric emptying reduced. What factors should be considered when patient is lactating? - Lipophilic drugs passed onto the neonate; lactating is secondary excretory organ. What factors should be considered when patient has hepatic/renal failure? - Clearance is no longer optimal. increase frequency of doses, but lower concentrations so the kidneys are able to handle the metabolism/excretion. Phase 1 and 2 affected. May be able to determine hepatic failure bu bile acid tests. For renal failure - measuring the metabolites in the urine. How are veterinary drugs regulated? - Data assessment and authorisation (EU medicine agency), decentralised (state individuals). Certification and quantification Prescribing, supply and dispensing
Testing, inspection and investigation Post authorisation What are SQPs? - Suitability Qualified Persons - specially trained non-vets to dispense drugs which do not require a clinical examination of the animal. Certificate given per course - SA, equine, farm and avian. Code of practice regulated by AMTRA - including modules about anatomy, physiology and basic disease challenges. POM-V - Veterinary can only prescribe a restricted drug (antibiotics) following the examination of the patient. Prescription can be sourced from the vet or online resources, but MUST be written and evidenced. These drugs need come from a registered premise. POM-VPS - Vet, SQP and any other qualified individual are able to prescribe a drug without a clinical examination of the patient. Drug still comes from a registered premise, and can be out-sourced as long as the owner as a written prescription. What factors are important to consider when prescribing the drug? - Provide the owner with the minimal amount, talk about the possibility of contraindications, tell them their options - the drug can be purchased elsewhere (ethical obligation). Make sure that the owner is competent at the administration and uses the drug for it's intended use. NFA-VPS - Non-food producing animals (doesn't include horses) - these are animals not intended to enter the food chain. Can be bought anyway - including pet shops, but the same advice must be given when owner is purchasing the drug. SAES -
Vets have NO authority (unless they have a licence from the Home Office, limited to research). Drugs have no recognised medical use and not lawfully accepted in premises. Schedule 2 examples - Morphine, pethidine, fentanyl, alfentanil, methadone, ketamine, amphetamines. Secobarbutal/quinabarbitone - these are the exemptions from safe custody Schedule 2 procedures - Most of these drugs belong to safe custody - kept locked up and secured 24/7. All encounters with the drug are recorded in a controlled drugs register. Good to have person collecting drug, ID recorded down in it too. prescriptions are only valid for 28 days, personally signed and minimal dose given. No repeats are given. Destruction protocol needs to have a witness, secretory of state (animal medicines inspectorate, RCVS practice standards scheme, a veterinary surgeon from another practice) and recorded down that the drug was destroyed. Prevents people trying to steal the scraps - e.g. fluid adding sand or cat litter so no longer viable. Schedule 3 examples - Buprenorphine, pentobarbital, benzodiazepine (some of these are exempt from safe custody - midazolam and tramadol) Schedule 3 procedure - These drugs are in safe custody but do not require a safe register to record the outtakes of the drug. written requisitions and prescriptions are only valid for 28 days, written only and no repeats. witnessed destruction only required by importers/exporters or manufacturers but not for the practice. Schedule 4 examples - Part I: Benzodiaepzines (diazepal) Part II: anabolic and androgenic steroids Schedule 4 procedures - Do not require safe custody, nor recording in register
written prescriptions only valid for 28 days and repeats are allowed witnessed destruction requirements for importers/exporters and manufacturers but not for the practice Schedule 5 examples - Pardale V (codeine/paracetamol) These are low strength drugs Schedule 5 procedure - No control regulations prescription can last for up to 6 months How long should any invoice for a scheduled drug be kept for? - 2 years Describe the process for drug discovery and development - Target identification and validation - finding the target receptor that needs to be altered for a therapeutic benefit i.e. gap in the market. May want the first vs best in class. Hit finding - testing chemicals > lead optimisation (narrow down successful drugs and synthesising them to become more potent, selective and metabolically stable) Proof of concept > exploratory development (involve animal trials looking for side effects, secondary effects i.e. drug to drug interactions, post-mortem analysis to measure TI, pharmacokinetic testing) Full development > clinical trials Registration Post-launch activities - SARs This whole process can take 5 to 11 years in veterinary medicine. Not as long as human medicine; often based on human research but translated over to animals. What does a patent allow a drug company to do? - Pay back the costs for drug development and discovery by restricting the drug access and distribution.
