Pharmacology

• Pharmacokinetics determines what the body does to the drug, absorption, distribution, metabolism and excretion. (ADME)

   

  Pharmacodynamics is what the drug does to the body. Its effects (intensity, time course, mechanisms of action and side effects). Also relates to the relationship of the drug concentration at the effect site
• 1.      One compartment model

  -          Gives us an understanding of how a drug moves through the body.

  -          Not directly relevant for clinical practice

  -          Assumption that after absorption the drug distributes quickly and evenly throughout the body
• 1.      Two compartment model

  -          How a drug moves between two compartments: central (blood, well supplied organs) and peripheral (tissues and organs with a slow blood flow e.g. muscle and fat)

  -          Distribution is quick in the central compartment then slower in peripheral

  -          Over time the drug equilibrates between the compartments

  -          The key difference between this and the one-compartment model is that drugs don't distribute instantly throughout the entire body
• 1.      Multicompartment model

  -          A central compartment and multiple peripheral compartments

  -          Drug moves from central to peripheral and between peripherals at different rates

  The drug is eventually eliminated from the central compartment (through processes like metabolism or excretion), but some drug might still be slowly releasing from the peripheral compartments back into the bloodstream.
• An open model in pharmacokinetics refers to a system where the drug enters the body, moves through it, and is eventually eliminated i.e. the drug is not recirculated into the body. Elimination occurs from the central compartment

   

  A closed model describes a drug that is re-circulated by enterohepatic re-circulation (Drug released into GIT via bile then reabsorbed into plasma)
• Zero order means the rate at which drug concentration changes is constant and independent of drug concentration i.e. elimination is constant
• First order means that the rate of drug elimination changes and is proportional to drug concentration. Drug concentration decays exponentially
• Factors effecting movement of drugs between compartments:

  -          Molecular size of the drug

  -          Degree of ionisation (non-ionised drugs are more lipophilic so pass through phospholipid bilayers more easily)

  -          Lipid solubility of ionised and non-iodised forms

  -          Protein binding

  -          Location of movement (e.g. intercellular gaps in capillaries, blood brain barrier tight junctions, size of gap)
• Drugs move across membranes by:

  ·       Passive transfer

  -          Depends on lipid solubility and concentration gradient.

  -          There are aqueous pores for small hydrophilic molecules

  ·       Carrier mediated transport across membranes

  o   Facilitated diffusion by membrane bound carrier

  -          Down a concentration gradient but faster

  o   Active transport

  -          Against a concentration gradient

  ð  Membranes may be saturated or be blocked by competitive inhibition
• The blood brain barrier is made up of tight junctions between capillary endothelial cells which do not allow for passive transport of dissolved substances in the plasma to the brain. Membrane transporters can block the entry of drugs unless there is facilitated diffusion by a membrane bound carrier or active transport
• Ion trapping:

  Most drugs are weak ions or bases. Drugs cross membranes in their non-ionised form but the local pH of an environment may form an ion-trap e.g. gastric pH (can cause gastric ulcers), foetal pH (slightly lower than mothers, must be considered when doing pregnant animals), milk pH and urine pH.

   

  The Henderson-Hasselbalch equation states that the degree of ionisation depends on the pH and pKa of the drug. (pKa is the pH at which 50% of the drug is ionised)
• Absorption is passage from the site of administration to the blood steam. Is dependant of solubility, physiochemical properties, site of administration and bioavailability (the proportion of a drug that enters the bloodstream when introduced into the body and is available to have an active effect. Worked out from area under an absorption curve)
• Parenteral absorption is dosing where the GIT is bypassed:

  -          Intravenous: most rapid onset but must be administered at a given, usually slow, rate)

  -          Intramuscular: there is a delay in onset and onset may vary between muscle groups

  -          Subcutaneous: less painful than IM, but onset time is usually not dissimilar
• Parenteral administration generally achieves systemic levels faster but oral administration is often the only option for an owner . If an animal is inappetent or vomiting then parenteral is advantageous.

  -          Special considerations for oral admin in ruminants

  -          Some drugs can only be given by specific routes
• Factors to be considered when administering oral drugs:

  -          Will the drug be absorbed in the stomach or small intestine

  -          The speed of gastric emptying

  -          Presence of food

  -          First pass effect
• The first pass effect refers to the removal of a percentage of a drug as it passes through the liver via the portal vein before it reaches the systemic circulation and effect site. This can be circumvented by rectal or sublingual administration.
• Distribution is defined as The movement of a drug across membranes via blood flow to different organs. Certain drugs distribute by reversibly binding to plasma proteins (usually albumin). A bound drug does not move through membranes unless there is carrier mediated transport. Free drug concentration may be increased by hypoalbuminemia, uraemia or displacement by same/other drug.
• The volume of distribution (Vd) is a theoretical volume that relates the amount of drug in the body to the concentration of the drug in the blood (plasma). It doesn't correspond to any specific anatomical volume, but rather reflects how the drug disperses between the blood (central compartment) and other tissues (peripheral compartments).
• Elimination is the biotransformation and elimination of a drug. Rate and type of elimination can depend on physicochemical properties, lipid solubility (Lipid solubility enhances access to sites of metabolism whilst Water solubility enhances possibility of renal excretion) and polarity
• Biotransformation is the chemical modification made to a chemical compound. It specifically describes how the body metabolizes drugs and other substances. Occurs mainly in the liver but also in the plasma (pseudocholinesterases hydrolyse a number of drugs like atropine), kidney, gut and lungs
• Biotransformation involves various enzymatic reactions that alter the structure of drugs, making them more water-soluble. Phases:

  Phase 1: hydrolysis, reduction or oxidation

  Phase 2: conjugation (acetylation, to amino acids)- may occur directly to the parent drug or to the product of a phase 1 reaction
• enzymes in Phase 1 oxidation reactions and how drugs can affect them:

  Phase 1 oxidation reactions occur mainly due to hepatic microsomal enzymes (mixed function oxidases). Some drugs can inhibit or induce these enzymes:

  Inducers: Enhance their own metabolism and that of other drugs e.g. phenobarbital, diazepam

  Inhibitors: Reduce their own rate of metabolism and that of some other drugs e.g. ketoconazole.
• There are some species differences in phase 2 oxidation reactions.

  Cats are deficient in glucuronyl transferase which gives them a limited ability to perform glucuronidation (hence why paracetamol is toxic to them)

  Dogs have limited capacity to perform acetylation
• possible outcomes for glucuronide conjugates:

  -          Excreted in bile

  -          Hydrolysis in the gut

  -          Reabsorption of active drug

  -          Enterohepatic recirculation
• Excretion is the removal of drug or drug products from the body.

   

  The kidney is the main organ, but drugs must be water soluble. There is dependency on good GFR and active transport mechanisms. Drugs may be reabsorbed if they are lipid soluble or ionised.

   

  Other routes such as the biliary system, skin and pulmonary system are less common
• the main factors which need to be considered in order to construct dosing regimens:

  quantify elimination by establishing drug half life (time taken for the plasma drug concentration to fall by 50%). If the drug is of first order kinetics then this is predictable and independent of the dose. Zero order drugs are less predictable.

   

  Then establish clearance to establish the dose size needed.

   

  We must also consider the steady state where levels of drug remain stable in the body within therapeutic range.
• Factors affecting drug half-life:

  • Effects on access to sites of biotransformation or elimination

  • Interaction with other drugs eg cyclosporin/ketoconazole

  • Physiological/pathological states e.g. kidney or liver issues
• Steady state can be maintained by 3 methods:

  1.      Intravenous continuous infusion (expensive, time consuming and requires hospitalisation)

  2.      Loading dose followed by a regular dose at fixed intervals- reduces time taken to establish steady state

  3. Fixed interval dosing which takes about 5 half lives to achieve steady state
• Pharmacodynamics Describe what the drug does to the body: drug action (interaction of drug with receptor) and drug effect (subsequent chain of events caused by the drug/receptor interaction.
• A drug receptor is a macromolecular structure with which a drug reacts. Their interaction is the ‘drug action’. A receptor may be a protein (e.g. muscarinic receptor), an enzyme, a nucleic acid or something less specific
• An agonist is a drug which binds to a physiological receptor and mimics the effect of its endogenous ligand

  A full agonist can achieve maximal response even if not all the receptors it targets are occupied

  A partial agonist is incapable of achieving maximal response even if ALL its receptors are occupied
• Affinity is the tendency of the ligand (drug) to bind to a receptor
• Efficacy describes how good a drug is at eliciting a response i.e. a partial agonist has less efficacy than a full agonist
• Potency is a relative term which is used to compare two drugs. It compares the concentration required to elicit the same response.

   

  Drugs can have the same efficacy but differing potencies. We use EC50 to measure potency (the concentration at which 50% of maximal response is produced.
• Antagonists can have affinity but they have no intrinsic activity. This means they can block the effect of an agonist either competitively (effect is surmountable by increasing agonist) or non-competitively (antagonism cannot be overcome by increasing agonist)

   

  Antagonists can be at the level of the receptor or:

  -          Chemical antagonists

  -          Pharmacokinetic antagonisms (e.g. increased metabolism)

  -          Physiological antagonism (e.g. opposing actions)
• law of mass action affects drug/receptor interaction:

  By increasing amounts of drug and/or receptor, the reaction is driven forwards

   

  More drug or a bigger available gradient means a greater reaction is achievable

   

  However occupation of receptors doesn’t always result in activation
• Selectivity defines the capacity to preferentially produce one particular effect (often drugs produce more than one effect)

   

  Specificity is absolute selectivity (only acting on one receptor type)
• The therapeutic index is the ratio of the dose giving an undesirable effect over the dose required to give the desired effect.

  i.e. the area of clinical effect between the minimum effective concentration boundary and the toxic concentration boundary (anything beyond that is the danger zone)
• Ligand gated ion channel receptors – the ion channel is at the cell surface and allows for ions to move directly through a membrane
• G protein coupled receptors span a membrane with an extracellular amino terminus and an intracellular carboxy terminus. Different drugs can serve the same mechanisms on GPCRs but they have differing effects by their nature and duration.