Pharmacokinetics 3

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  • Created by: LBCW0502
  • Created on: 29-01-18 12:57
What is distribution?
Refers to the reversible transfer of drug from one location to another within the body (requires measurements in tissues which is difficult)
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What can the rate and extent of distribution be derived from?
Blood or plasma
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Which factors determine the distribution pattern of a drug over time?
Ability to cross tissue membranes, extent binding in blood/tissues, partitioning into lipid/adipose tissue
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What does tissue concentration depend on?
Physico-chemical properties of drug (e.g. lipid solubility, crossing blood/brain barrier, blood flow)
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Describe distribution following an IV bolus
Rapidly places drug in blood
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What is the distribution phase?
The time period in which drug in all tissues comes to equilibrium with that in plasma (characterised by volume of distribution, V)
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What are the assumptions for the one compartment model?
The drug in blood is in rapid equilibrium with drug in extra vascular tissues. Drug concentration may not equal in each tissue or fluid (assume that they are proportional to the concentration of drug in the blood at all times) - not exact/reasonable
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What are the assumptions for the one compartment model (rapid mixing)?
Drug is mixed instantaneously in blood or plasma. Actual time taken for mixing is usually very short (within minutes) - in comparison with normal sampling times it is insignificant (don't sample fast enough to see drug mixing in blood)
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Describe the assumption of distribution being a first order kinetics
Linear model. Rate of change of drug concentration is directly proportional to drug concentration remaining to undertake process (if we double the dose, the concentration will double at each time point
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Is first order kinetics an assumption of a linear model?
Yes (not a one compartment model)
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Give an example of a zero order pharmacokinetic model
Phenytoin
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Give an example of a first order pharmacokinetic model
Digoxin
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What is passive diffusion?
Molecules move down a concentration gradient due to kinetic energy of molecules. Characterised by absence of competition between molecules and lack saturation
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What is a carrier mediated system?
Characterised by saturability, specificity and competition inhibition
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What is passive facilitated diffusion (e.g. glucose transport)?
Glucose moves down a concentration gradient as a passive process. At high plasma glucose concentration the rate of transport of glucose reaches a maximum
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What is active transport?
Net movement of a drug against a concentration gradient (can be large). Maintenance of gradient requires metabolic energy e.g. angiotension-converting enzyme inhibitors via the dipeptide transport system
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What is perfusion?
Distribution can be rate-limited by perfusion/permeability. Some tissue membranes have no barrier to distribution (lipophilic). Well perfused tissues take up a drug more (extravasation)
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How does permeability-rate limitation arise?
Due to polar drugs diffusing across tightly knit lipoidal membranes (differences in ease of entry are a function of both lipid-water partition coefficient and degree of ionisation)
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Do most weak acids and bases exist in solution as an equilibrium between unionised and ionised drugs?
Yes
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Describe the pH partition hypothesis
Only unionised/non-polar (lipophilic) drugs penetrate tissue cell membrane. Increased accumulation of drug on side of membrane where pH favours ionised form. At equilibrium the concentration of unionised species is equal on both sides
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Is the unionised form assumed to be lipophilic enough to transverse membranes?
Yes
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What is the Henderson-Hasselbalch equation?
pH = pKa + log 10 (ionised/unionised)
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At which values are very weak acids such as phenytoin unionised?
At all pH values (pKa > 7.5)
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Is drug distribution rapid for weak acids with pKa > 7.5?
Yes
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Acids with which pKa values are subject to dramatic changes in rate of transport with change in pH?
3.0 - 7.5
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A base must have which pKa values to be transported independent of pH?
pKa
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Bases with which pH values are transported dependent upon pH?
5-11
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Which bases are in an ionised form with low transport?
Bases with a low pH (of gastric fluids/strong bases)
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Why does thiopental enter the brain more rapidly than it does in muscle tissue (opposite for penicillin)?
Thiopental is lipophilic and is able to cross the blood-brain barrier
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What is the most important plasma protein?
Albumin
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Describe features of protein binding
Many drugs bound to plasma and tissue proteins. Dynamic process affects free drug concentration. Only free (non-bound) drug is pharmacologically active
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Give examples of drugs which are highly protein bound
Phenytoin (90%) and warfarin (99%). Small concentration of free drug in plasma
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Is it true that only unbound drug fraction is able to bind to target site?
Yes (active). E.g. 100% unbound (Li), 20% unbound (Quinidine), 3-10% (Methadone), 2% unbound (Oxazepam), 0.5% unbound Warfarin
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What are the conditions for altered binding when albumin is decreased?
Liver cirrhosis, serious burns to the body, pregnancy (higher dose/concentration of free drug)
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What are the conditions for altered binding when a1-acid glycoprotein is increased?
Myocardial infarction, surgery, Crohn's disease, trauma to body and rheumatoid arthritis (lower dose/concentration of free drug)
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Describe the features of tissue binding
Fraction of drug in body located in plasma depends on binding to plasma/tissue. Drug with high affinity for plasma proteins/located in tissue if tissue has greater affinity for plasma (methadone). Distribution of plasma-protein bound drug restricted
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Can alcohol distribute equally into total body water?
Yes
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Give an example of a drug where the distribution of plasma-protein bound drugs is restricted to plasma and extracellular fluid
Warfarin
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What is multiple equilibria?
Occurs in plasma where drug can bind to various proteins. Acidic drugs bind to albumin. Basic drugs bind to a1-acid glycoprotein. Within tissue binding can also occur. There may be partition into adipose tissue (fat)
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Distribution of drugs into tissue depends on which factors?
Blood flow to tissues, partition co-efficient of drug between blood and tissue, degree of ionisation of drug at plasma pH, molecular size of drug, extent binding to plasma/tissue proteins
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What is volume of distribution (Vd)?
Proportionality constant that relates the amount of drug in the body to the drug concentration in blood/plasma. Mathematical 'fudge' factor where amount 'A' of drug in the body related to 'C' concentration in plasma
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Is V a physiological volume?
No. Never less than blood or plasma volume but it can be larger than total body water volume for some drugs
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Which physiological fluid compartments can a drug distribute into?
Plasma/interstitial volume (extracellular) and intracellular
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What is the total body water?
42 L (tissue/fluids outside bloodstream comprise main water compartment = 37 L)
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What is apparent volume of distribution (V)?
A reflection of the amount of drug left in the blood after all the drug has been absorbed. The concentration in plasma after distribution of dose administered is complete (extent of tissue distribution)
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Does V indicate the location of the drug?
No
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What does a low value for V indicate?
A small volume of distribution. Drug is held in the bloodstream
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What does a large value for V indicate?
Large volume of distribution. Very little drug remains in the bloodstream
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What is V measured in?
L or L/kg
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Which equation is used to described V?
V = Ab / Cp (amount of drug present in the body/plasma concentration of drug)
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Is apparent V a function of pKa of the drug?
Yes (lipid vs solubility). Also indicates extent to which plasma and tissue binding occurs (fu = Cu/C)
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How is the degree binding expressed?
As a ratio bound-to-total drug concentration (ratio limit 0-1.0 where 0.9 is highly bound). Binding is a function of affinity of the protein for the drug
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What is the rate of presentation?
Q.CA (product of blood flow and arterial blood concentration)
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What is the net rate of extravastation?
The difference between rates of presentation and leaving where CV is emergent venous concentration ((Q.CA-CV))
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Blood and tissue can be view as how many compartments?
One compartment (if no impediment to movement into tissue) - then CV is in equilibrium with CT
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How do you calculate the amount of drug in plasma?
Vp x Cp
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How do you calculate the amount of drug in the body?
V x C
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How do you calculate the fraction of drug in plasma?
Vp / V
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What does V> 4 L indicate?
Drug present in tissues or fluids outside the department. Actual sites cannot be determined from this value
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What is Vc?
The central compartment (all drugs initially distribute into bloodstream/central compartment)
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What is Vt?
Peripheral compartment (tissues)
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If the drug rapidly equilibrates within tissue compartment, then which compartment model is used?
One-compartment model which uses apparent volume of distribution
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How do you calculate the apparent volume of distribution for intravenous bolus dose?
V = D/C(O) (dose assuming absorption complete/initial drug concentration in blood)
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What is the dose administered measured in?
mg or micrograms
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What is the concentration of drug present measured in?
mg/L or nanograms/mL
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How do you calculate concentration?
Dose/V (able to rearrange to calculate V)
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What does a large V indicate (e.g. nortriptyline)?
Preferentially distributed in tissues, not found in large concentration in blood, must be lipophilic drug
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Give examples of drugs linking to apparent V
Gentamicin, phenytoin, phenobarbital, diazepam, digoxin
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What is the value of V determined mainly by?
Perfusion and protein binding
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What are the V values for flurosemide, ethanol and digoxin?
15 L (highly protein bound), 35 L (distributed in body fluids), 450 L (extensively distributed and bound in extravascular tissues)
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What is a loading dose?
(Vd)(Cp)/(S)(F) or LD = Vd x Cp
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What is the salt factor?
1.0 (unless stated)
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Card 2

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What can the rate and extent of distribution be derived from?

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Blood or plasma

Card 3

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Which factors determine the distribution pattern of a drug over time?

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Preview of the front of card 3

Card 4

Front

What does tissue concentration depend on?

Back

Preview of the front of card 4

Card 5

Front

Describe distribution following an IV bolus

Back

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