Unit 2 Flashcards

Question

What can drugs distribute into?

Answer 1

Once absorbed from the site of administration drugs can distribute into: Plasma (if a drug has been given intravenously it will, of course, already be present in plasma) Extracellular fluid (ECF) - Interstitial fluid - Transcellular fluid Intracellular fluid (ICF)

Answer 2

Volume of distribution, Vd, is a measure of the volume of fluid required to contain the total amount of drug at its plasma concentration If the body was a compartment, the drug would be the same thoroughout.

Answer 3

Greater Vd is reflected by lower drug concentration. a) After injection the drug could just stay in the circulation b) The drug could distribute into extracellular fluid, reducing the plasma concentration c) The drug could distribute into total body water; if it does the concentration of drug in the plasma will be lower than if it had just distributed into the circulation and ECF

Answer 4

Vd = Q Dose (total amount of drug in the body; mg/kg) / Cp Plasma concentration (usually µg or ng/ml)

Answer 5

Vd VERY LOW (0.05 to 0.1 L/kg): Drug confined to the plasma compartment (large molecules) Vd LOW (0.2 L/kg): Drug confined to the plasma and interstitial space (highly polar molecules which penetrate membranes poorly) Vd INTERMEDIATE (0.6 L/kg): Drug enters total body water (crosses membranes) Vd VERY HIGH (>1 L/kg): Drug concentrates in fat or binds to a site within a tissue or cell TOTAL BODY WATER = APPROX 0.6 L/kg

Answer 6

1. It enables you to predict whether the drug selected for administration is likely to reach the target site at effective concentrations 2. The Vd can be used to determine the loading dose necessary to achieve a target plasma concentration

Answer 7

The ability of a drug to leave the circulation and enter interstitial fluid (and then to cross cell membranes) can be influenced by: - Size - Plasma protein binding - Endothelial cell barrier function - Ion trapping - Lipid solubility

Answer 8

Once a drug has entered the vascular compartment, it may circulate bound to plasma albumin and globulin The plasma protein bound and free drug in the circulation are in equilibrium Normally only the free drug crosses the endothelial cell barrier Drug + Plasma protein t = 0 total concentration t = n total concentration and unbound concentration

Answer 9

Drug binding to plasma protein occurs to a variable extent (from 0% to 99%) There are species difference in the extent to which a drug is plasma protein bound Displacement can occur if two extensively plasma protein-bound drugs are given together

Answer 10

Pharmacodynamics: The protein-bound fraction is pharmacologically inactive Pharmacokinetics: Only the free portion of a protein-bound drug will readily leave the circulation/be ultra-filtered in the kidney Toxicity: In a few individuals, the drug-protein complex may be recognised as 'foreign' i.e. behaves as an antigen, causing a hypersensitivity reaction on second exposure Interactions: Competition between drugs or endogenous compounds for protein binding can occur which may lead to unwanted effects

Answer 11

Drug can distribute in plasma, interstitial fluid or trancellular fluid (ECF compartments) and intracellular fluid (ICF) Volume of distribution can be calculated from plasma concentration, and used to predict this distribution Drug chemistry, particularly plasma protein binding, is the major determinant of drug distribution

Answer 12

Most drugs require metabolism prior to elimination from the body This converts drugs into more water-soluble compounds and aids their elimination Some drug metabolites are biologically active Some drugs are administered as inactive, pro-drugs and must be metabolised to an active form

Answer 13

The LIVER is the main site of drug metabolism Some drugs may be metabolised in other tissues e.g. PLASMA, wall of the GASTROINTESTINAL TRACT, LUNG and KIDNEY

Answer 14

Drugs metabolised in the liver must be able to cross the liver cell membrane to reach the microsomal enzymes The main enzymes involved in drug metabolism in the liver are the mitochondrial mixed function oxidase enzymes, otherwise known as cytochrome P-450 or CYP enzymes

Answer 15

Hepatic metabolism is normally biphasic PHASE 1: Convert lipophilic molecules into more polar molecules PHASE 2: Add a conjugating group to the molecule to increase polarity, decrease lipophilicity, and therefore aid drug excretion STEP BY STEP 1. Drug 2. Phase 1: oxidation, reduction, hydrolysis 3. Metabolite 4. Phase 2: Conjugation. Addition of e.g. glucuronic acid, glycine, sulphate, acetyl 5. Conjugate

Answer 16

Some drugs are extensively metabolised in the wall of the gastrointestinal tract or in the portal blood or in the liver before they reach the systemic circulation First pass metabolism affects the absorption of orally administered drugs

Answer 17

Liver cells transfer drugs or drug conjugates to bile They are delivered to the intestines where: - Conjugates are hydrolysed - The parent drug - Can be reabsorbed

Answer 18

The liver is the main site of drug metabolism Extrahepatic metabolism can occur in the plasma, wall of the gastrointestinal tract, lung and kidney Following conjugation, some drugs can be returned to the plasma as part of enterohepatic recycling.

Answer 19

Occurs primarily in the urine and bile Water soluble molecules tend to be excreted most efficiently as they are not reabsorbed (some are secreted into the renal tubule)

Answer 20

1. No filtration (proteins >70,000kD) 2. Partial filtration (drugs bound to plasma proteins; free drug is filtered) 3. Filtered then completely reabsorbed (e.g. glucose) 4. Filtered then completely reabsorbed from the tubules, partially excreted (most drugs) 5. Filtered then no reabsorption from the tubules (ionised, water soluble drugs; many drug metabolites) 6. Filtered then actively secreted into the tubule (some drugs and drug metabolites)

Answer 21

Filtered then actively secreted (some drugs) Secretion is an active, energy-dependent process involving transporter proteins in the cell membrane. The process is selective and saturable Note that there are transporter proteins for drugs in many other tissues including the intestinal epithelium Transporter proteins play a physiological role in moving endogenous substances into and out of cells (influx and efflux pumps). They are also important in regulating drug absorption and distribution.

Answer 22

The rate of excretion in the urine of drugs that are weak acids or weak bases depends on urine pH because this influences the proportion of unionised and ionised drug. In animals producing acidic urine (carnivores, concentrate fed herbivores) weak bases will be eliminated most efficiently In animals producing alkaline urine (herbivores on forage), weak acids will be eliminated most efficiently.

Answer 23

RENAL EXCRETION: - Main elimination process for polar (non-lipophilic) drugs - Most renal mechanisms (ultrafiltration, reabsorption) are passive - Species differences in drug clearance and half-life are usually minor. HEPATIC METABOLISM: - Main elimination process for lipophilic drugs - Enzyme driven, active processes - Species differences in drug clearance and half-life are usually marked

Answer 24

A wide range of pharmacokinetic parameters can be calculated from plasma (or urine) concentration-time data These provide useful QUANTITATIVE data on ADME Quantitative data are essential for: - A full understanding of drug absorption into, fate within, and elimination from the body - Design of dosage schedules for safe and effective clinical use

Answer 25

- Cmax - Tmax - AUC - Bioavailability (F) and Bioequivalence - Vd - Cl - T1/2 - First and zero-order processes

Answer 26

Plasma concentration rises, absorption > elimination Plasma concentration peaks and stabilises, absorption = elimination Plasma concentration falls, elimination > absorption

Answer 27

A drug with a narrow therapeutic index has a low safety margin, producing unwanted effects at doses close to those that produce the desired effect

Answer 28

Cmax, or maximum plasma concentration, refers to the peak concentration of a drug in the bloodstream after administration (shown as the peak in a plasma conc / time graph)

Answer 29

Tmax, or time to maximum plasma concentration, refers to the time it takes for a drug to reach its maximum concentration, or Cmax, in the bloodstream after administration. (shown as the x intercept at the peak on a plasma conc / time graph)

Answer 30

Provides an estimate of the amount of drug in the body over a period of time (e.g. 24hrs or the inter-dosing interval) and can be used to determine BIOAVAILABILITY

Answer 31

The fraction of the administered dose that reaches the systemic circulation in an active form It is expressed as a percentage of the total administered F = Area under curve (non vascular) / Area under curve (IV) x 100%

Answer 32

Two medicinal products containing the same drug but which have different formulations are bioequivalent only if the rate and extent of drug absorption is the same In practice this is when there are no significant differences between the AUC, Cmax and Tmax.

Answer 33

Units: ml/h (or mins) / kg The volume of blood {plasma} effectively cleared of drug by an eliminating organ per unit time E.g. renal clearance, which is determined by measuring drug concentrations in urine and plasma and the rate of urine flow % urinary excretion = the proportion of a drug dose that is excreted unchanged in the urine Note most drugs are metabolised to some extent. For the few that are not, the rate of renal clearance will be the main factor determining the duration of action

Answer 34

The time taken for the concentration of drug in the plasma to fall by 50% T1/2 is calculated from a log plasma concentration vs time curve

Answer 35

First-order pharmacokinetics refers to a type of pharmacokinetic process in which the rate of drug elimination is proportional to the concentration of the drug in the body. This means that a fixed proportion is removed per unit time. Most drugs are eliminated by first-order kinetics. There is an exponential decrease in drug concentration over time so a plot of plasma concentration against time is a curve. Therefore Half-life (T1/2) is independent of dose Elimination pathways are not saturated.

Answer 36

Relatively rare. Examples; salicylate (cat); phenytoin (man) There is a linear decrease in plasma drug concentration over time, i.e. the decline is not proportional to the drug concentration. Therefore a fixed amount of drug is removed per unit time T1/2 increases as the administered dose increases This is because of saturation of elimination pathways (usually hepatic enzymes or active secretion into the proximal convoluted tubule in the kidney). Therefore an increase in plasma drug concentration readily occurs with dose.

Answer 37

Cumulation to "steady state" with repeat drug dosing Administer series of doses at half-life intervals Peak and trough concentrations rise to attain a plateau after approx. 5 elimination half-lives

Answer 38

Use of almost all drug products is associated with side-effects A side-effect is an unwanted action caused by a drug used at a therapeutic dose Side-effects vary in severity and may be acute or chronic Adverse drug reaction is a term used to describe any unwanted event associated with use of a drug at therapeutic doses. This can also be referred to as drug toxicity. Side effect strengths: Limited significance --> debiliating --> disabling --> fatal.

Answer 39

The effective and safe clinical use of drugs depends on optimising dose schedules i.e. - The amount of drug given - and the dosing interval - and the duration of treatment - and the route of drug administration

Answer 40

1. Administer a series of doses (e.g. placebo, 1x, 2x, 4x, 8x, 16x) to groups of animals in cross-over or parallel design studies (DOSE TITRATION) 2. Pharmacokinetic (PK) and Pharmacodynamic (PD) in target species are established in separate studies and the results are then combined (PK-PD integration) 3. Establish PK and PD in a single study and model data in silicon (PK-PD MODELLING)

Answer 41

Variation in Pharmacokinetics may affect: - Therapeutic efficacy (increased or decreased) - Toxicity (increased or decreased) Therefore it may require: - Adjustment of dosing interval or dose

Answer 42

- Lipid solubility - Stability - Dose (first and zero order kinetics) - Acidic or basic nature and renal excretion - Chirality - Plasma protein binding - Effects on hepatic enzymes - Product formulation

Answer 43

The rate of excretion in the urine of drugs that are weak acids and bases depends on urine pH Animals producing acidic urine will eliminate basic drugs most efficiently Animals producing alkaline urine will eliminate acidic drugs most efficiently Administration of an alkalinising or acidifying agent will alter urine pH. Depending on the % urinary excretion, this approach can be used to speed up the rate of drug elimination from the body % urinary excretion is the percentage of drug excreted unchanged in the urine.

Answer 44

Drugs can compete for binding sites with endogenous compounds. If the concentration of an endogenous compound changes, it may affect the concentration of free drug in the plasma And If the increase in plasma concentration affects the rate of drug clearance, it will prolong the presence of active drug in the body.

Answer 45

Chiral drugs exist as enantiomers (a pair of compounds that are mirror images of one another) The pharmacokinetic properties of one enantiomer may differ from the other (they may also have different pharmacodynamic properties) One enantiomer may be converted to the other in the body (chiral inversion)

Answer 46

Salbutamol = S+ isomer inactive Ketamine = R- form causes hallucination and agitation DOPA = d-DOPA toxic ß-blockers = d- and l-enantiomers have different PK, particularly metabolism Verapamil = S- form 10-20 times greater potency than R+ form

Answer 47

Liver enzyme induction can be caused by repeated administration of some drugs - Examples: phenobarbitone and phenytoin (anti-epileptic drugs) Some drugs cause inhibition of liver enzymes - Examples: chloramphenicol (antibacterial drug) and cimetidine (reduces gastric acid secretion by inhibiting the actions of histamine at H2 receptors located on parietal cells)

Answer 48

Plasma drug concentrations will be decreased (enzyme induction) or increased (enzyme inhibition) Therapeutic efficacy may be lost (enzyme induction) or toxic effects may develop (enzyme inhibition). Dosing intervals may need to be adjusted

Answer 49

The formulation of a solution for intramuscular injection can be altered so that the aqueous solubility is reduced; this prolongs the duration of action of the drug (e.g. long-acting (depot) products that are given by intramuscular injection) Drugs that are broken down in acidic conditions can be protected by an enteric coating The particle size or structure of tablets can be altered so there is slow or sustained release.

Answer 50

Administering with food may cause the Cmax to increase, decrease or stay the same depending on the drug

Answer 51

Gastric or intestinal motility (e.g. increased motility decreases the time available for drug absorption) Splanchnic blood flow (e.g. reduced blood flow due to disease decreases drug absorption) Stability of drug (e.g. some drugs are unstable in gastric acid or are broken down by enzymes) Damage to, or loss of, the epithelial barrier (which can be caused by drugs or disease) reduces drug absorption

Answer 52

Dosing at the same time each day to avoid variation in factors such as metabolic rate or blood flow to the gastrointestinal tract which may affect drug pharmacokinetics

Answer 53

Pharmacokinetics may be altered by hepatic or renal disease and drug doses may need to be adjusted Effects of hepatic disease are difficult to predict but, in general, the dosing interval will need to be increased The higher the proportion of a drug dose that is excreted unchanged by the kidneys, the greater the effect of renal disease. Drug absorption and distribution may be affected by cardiac disease. Regional blood flow can vary in cardiovascular disease Infiltrative gut disease will reduce drug absorption Dehydration or acidosis can affect drug distribution e.g. poor absorption of drugs from a subcutaneous injection site where an individual is dehydrated.

Answer 54

E.g. in a stressed individual, the metabolic rate may increase speeding up active processes BUT drug distribution may be affected if the blood supply to the periphery is altered

Answer 55

Carprofen - given intra-operatively (as part of the pre-medication) or post-operatively at an oral dose of 4.0mg/kg to dogs undergoing surgery Pre-op Cmax = 11.0 µg/ml Pre-op AUC = 115 g/ml.h Post-op Cmax = 20.6 µg/ml Post-op AUC = 175 µg/ml.h

Answer 56

Reduced rate of renal excretion Reduced rate of hepatic metabolism Lower amount of plasma protein binding Greater absorption from the GIT (bioavailability) Possible increased permeability of the blood-brain barrier Increased volume of distribution

Answer 57

Some general decline in the efficiency of elimination mechanisms in the liver and kidney Changes are less specific than in neonates therefore it is not possible to generalise There are drug dependent differences and differences between individuals Adjustment to dosage schedules may be required More research is needed in animals

Answer 58

Many examples of differences observed in man Likely also to exist in animals. For example, gender differences in CYP isoenzymes have been reported in rats, affecting the rate of drug metabolism

Answer 59

Knowing the properties of a drug and its pharmacokinetics in the normal animal/human and how these may affect drug pharmacokinetics enables the adjustment of the dose or dosing interval - if necessary.

Answer 60

Therapeutic efficacy (increased or decreased) Toxicity (increased or decreased) Therefore it may require: Adjustment of dosing interval or dose

Answer 61

- Administration route - Food - Time of day - Disease - Physiological state - Gender - Species - Breed

Answer 62

- Absorption - Protein binding - Elimination (metabolism and excretion) - There can be marked species differences in the half life of a drug, and therefore in the inter-dosing interval required

Answer 63

There can be considerable variation in the bioavailability of drugs given orally due to differences in the anatomy of the gastrointestinal tract NB: other species dependent factors may contribute to observed differences in AUCs e.g. rapid metabolism Differences between monogastric and ruminant species can be particularly marked The rate and extent of percutaneous absorption can also vary between species due to differences in the structure of the skin

Answer 64

There is species variability in the extent of drug binding to plasma proteins. Differences in binding cannot be explained solely by variation in protein concentration and may be due to differences in protein composition and conformation

Answer 65

Differences between species are very common and may be qualitative or quantitative Qualitative: When a reaction is deficient in a particular species Quantitative: When there is a difference in the amount of enzyme present. This is very common and leads to major pharmacokinetic differences between species, notably in clearance and elimination half-life

Answer 66

A drug being used safely provided the dosing interval is increased E.g. in cats, aspirin is very slowly conjugated with glucuronic acid and the T1/2 is about 37.5hrs versus 8.5hrs in the dog A drug that can be used in one species not being safe to use in another E.g. in cats, paracetamol is metabolised by an alternative pathway to glucuronidation leading to the production of a toxic metabolite.

Answer 67

The relative importance of this route varies between species E.g. % of an I.V dose of carprofen eliminated by biliary secretion Dogs 70% Humans 30-35% (little recovered in faeces due to enterohepatic recycling)

Answer 68

Species differences in elimination half-life are the rule rather than the exception Differences can be profound and they are not easily predicted from the knowledge of the kinetics of related drugs or related animal species Do not extrapolate between species Half-life values are often longer in man than in other animal species

Answer 69

There are also species differences in metabolising enzyme found in other sites in the body E.g. plasma pseudocholinesterase (similar in structure to acetylcholinesterase) Low activity in pigs and ruminants Renal excretion in urine is less species dependent that drug metabolism as much of the process is passive

Answer 70

The rate of excretion of weak acids and bases in the urine depends on urine pH Animals producing acidic urine (carnivores, concentrate fed herbivores) will eliminate basic drugs most effectively Animals producing alkaline urine (herbivores on forage) will eliminate acidic drugs most efficiently

Answer 71

Exist as enantiomers which, structurally, are mirror images of one another Products containing chiral compounds are usually comprised of a mixture of enantiomers (e.g. salbutamol (Ventolin) is a 50:50 mixture of the R- and S+ enantiomers) Typically, only one enantiomer is biologically active (but the other may have unwanted effects) (e.g. S-ibuprofen is 100-fold more potent as COX1 inhibitor rather than R-ibuprofen) Two enantiomers may be eliminated from the body at different rates Chiral inversion in which one enantiomer is converted to the other (e.g. inactive R-ibuprofen can undergo chiral inversion by hepatic enzymes) may occur in one species but not in another

Answer 72

Drug half life Passage across the blood-brain (B-B) barrier Metabolism CYP isoenzyme activity

Answer 73

Passage across the blood-brain (B-B) barrier: - E.g. Avermectins (e.g. ivermectin) are more likely to accumulate in the CNS of collie dogs and related breeds causing toxicity - This is caused by a defect in the ABCB1 (also known as P-glycoprotein or MDR1) efflux transporter located on the blood-brain barrier due to a gene mutation in susceptible individuals

Answer 74

Breed difference in metabolism (of the COX-2 inhibitor, celecoxib) Two sub-populations, distinguished by their capacity to eliminate celecoxib (Extensive Metabolisers (EM) 45% Poor Metabolisers (PM) 53.5% and uncharacterised 1.65%) were identified in a population of 242 beagle dogs Hepatic microsomes from EM dogs metabolised celecoxib more rapidly than those PM dogs

Answer 75

E.g. lower activity of CYP2B11 in some dog breeds. Greyhounds recover slowly from the general anaesthetic propofol. This can be explained by a reduced rate of hydroxylation and therefore increased drug clearance time Mutations in CYP isoenzymes have also been noted in other domestic animal species

Answer 76

Species and breed differences in: - Pharmacokinetics - Pharmacodynamics When treating groups of animals: - There is likely to be variability in the dose received by individual animals when drugs are given in feed or in the water - The sickest and weakest animals may receive an inadequate dose When treating individual animals: - Owner compliance

Unit 2 Flashcards

(100 cards)