6. Kinetics Flashcards
Dynamics is … whereas kinetics is …
- what the drug does to the body
- what the body does to the drug
4 stages of pharmacokinetics
- absorption
- distribution
- metabolism
- excretion
Why do we need to calculate pharmacokinetics parameters?
- to ensure dosage regimen results in correct plasma concentration in all patients
- irrespective of disease state, capacity to eliminate, route of administration, age and other drug therapy
Order of ADME process and where they occur
- site of administration
- absorption to plasma
- distribution from plasma to tissues and back
- from plasma to urine and faeces is metabolism and excretion
Define ‘absorption’
transfer of an exogenous compound e.g the drug from site of administration into systemic circulation
Processes in absorption
- crossing cell membranes by -
- passive diffusion down conc gradient
- active transport (esp. GI tract)
In general, … compounds cross cell membranes easier
Explain
- lipid-soluble
- more rapidly absorbed
- but must be in solution and degree of ionisation is important
- the more unionised, the more is absorbed
The more unionised lipid-soluble drug, the more …
absorbed
Explain absoption in stomach for oral route of drugs action
- not important site of absorption - most orally administered drugs not absorbed here
- mainly weak acids and small amounts of aspirin, NSAIDS and alcohol that are
- very low pH (1-2)
- role of gastric empyting controls delivery of compounds to small intestine and higher rate of absorption here
What orally administered drugs are absorbed in the stomach?
- not much
- weak acids
- small amounts of aspirin, NSAIDS and alcohol
Why is not much absorbed in the stomach?
- high acidity
- drug ionisation state is changed and not in a position to be absorbed
Does stomach acid destroy drugs?
- no
- just prevents stomach from absorbing it
- weak acids can be ionised and absorbed
How often does gastric emptying occur?
What’s the basic process?
- every 2hrs
- sphincter muscle changes and relaxes
What happens to orally administered drugs in the small intestine?
- absorption site of most exogenous compounds
- preferally weak bases - like most drugs
- large, highly permeable, vascularized surface area
- pH ranges from 6 in the duodenum and 7.4 in the terminal ileum
- enterocytes in the epithelium contain drug-metabolising enzymes and transporters
List factors that affect gaatrointestinal absorption
- gut motility
- gut pH
- physico-chemical interactions
- particle size and formulation
How does gut motility affect gastrointestinal absorption?
- major effect
- generally decreased motility leads to decreased absorption
- also, excessively rapid movement reduces absorption
How does gut pH affect gastrointestinal absorption?
- poor absorption of strong acids and bases
How does physico-chemical interactions affect gastrointestinal absorption?
- tetracycline binds to Ca rich foods
- bile-acid-binding resins may bind to other drugs
How does particle size and formulation affect gastrointestinal absorption?
- pharmaceutical preparations are formulated to produce desired absorption characteristics
- slow or fast release particles
- resistant coating
Gastrointestinal absorption factors also impact …
bioavailability
- the proportion of administered dose which enters systemic circulation
Can you change gut pH?
yes
with diet
Define ‘bioavailability’
- fraction of administered dose which enters systemic circulation
Define ‘first pass metabolism’
- metabolism which occurs in the intestine and liver before drug reaches systemic circulation
What is the parameter for absorption?
- area under the curve
- used to estimate bioavailability
- use trapezoidal rule and equation
conc 0 + conc 1divided by 2 times time1-0
If a time concentration graph starts with a high concentration at 0 time, what does this show?
- IV administration
- no increase as drug absorbs into systemic circulation
For an IV dose, bioavailability is …
Compare to an extra-vascular dose
- 1
- less than 1
Limitations of bioavailability
- doesn’t consider inter and intra individual variations in enzyme activity, gastric pH and intestinal motility
- doesn’t consider rate of absorption
2 other parameters of absorption that aren’t bioavailability
- Cmax
- Tmax
Cmax and Tmax are good because…
they’re the easiest PK parameters to calculate
- just look at the time by Cp graph
How to work out Cmax and Tmax?
- at the peak of the graph
- Tmax is where it is on the X-axis
- Cmax is where it is on the Y-axis
Define ‘Tmax’
- time at which Cmax is reached
- usually in hours
Define ‘Cmax’
- maximum conc of compound after administration
- in mg/ml or ng/ml
Explain reasons for sublingual administration
- required for fast/rapid response
- utilises venous drainage from mouth into superior vena cava and top of the heart
- avoids first pass metabolism
- e.g glycerine trinitrate in diabetes
Explain rectal/vaginal route
- bypasses GI/hepatic first pass effects
- rich blood supply
- absorption may be rapid/extensive but depends on drug formulation
- pH 7-8
- drainage in rectum 2/3 systemic (middle and inferior rectal vein) and one third portal (superior rectal vein)
Main advantages of rectal/vaginal route
- useful when drug causes vomiting and nausea
- or if patient is already vomiting and GI system is compromised post op
Advantages of injection administration
- predictable, rapid action
- altenative for drugs that are irritant by other methods
- iv infusion for ill, hospitalised patients
Disadvantages of injection administration
- difficult/painful
- risk of infection
- cost and safety
- immediate adverse effects
What are subcutaenous/intramuscular injection?
- faster systemic effect than oral or local
- like local anaesthetics
List enteral routes of drug administration
- oral
- sublingual
- rectal
- vaginal
List parenteral routes of administration
- intravenous
- intramuscular
- subcutaneous
- transdermal
- inhaled
- intrathecal
- other
Absorption is essential in all drug administrations except …
IV
3 most important ways drugs cross cell membranes
- passive diffusion through lipid
- diffusion through aqueous channel
- carrier mediated transport
Explain passive diffusion of drugs
- lipid solubility important determinant
- non-polar/un-ionised susbstances dissolve in lipid
- ionised species have low lipid solubility
- many drugs are weak acids or bases and exist iin both ionised and un-ionised forms
- ratio of ionised to un-ionised determined by pH
Weak acids are proton … and bases are …
donator
acceptor
Degree of ionisation changes with respect to … dependent on …
- pH of solution
- pKa of drug
pKa measures …
strength of acid/base
When pH of solution equals the pKa …
50% of the drug is ionised
Explain absorption in terms of changing pH and pKa
- in low pH, more H+
- more unionised acid but more ionised base (BaseH+)
- in high pH, more OH-
- more ionised acid but unionised base
Ionised species have low …
lipid solubility
Explain pH partioning
- acidic drugs accumulate in basic fluid compartments and vice versa
- plasma is more neutral (6-7)
- acid in plasma becomes ionised and is trapped, can’t get back
- basic drugs get trapped in stomach, becomes charged and can’t get back to plasma
Aspirin is a … acid with pKa of around …
What does this mean?
- weak, 3.5
- in the stomach, mostly un-ionised and can pass through the lipid membrane
Is pH partition the main determinant of drug absorption?
- no
- enormous absorptive surface area of villi and microvilli in ileum compared with much smaller surface area of overriding importance
Distribution depends on …
- ability of drug to cross cell membranes (on physiochemical properties)
- blood flow to individual tissues
- extent of plasma protein binding
Once equilibrium has been reached between systemic circulation and a tissue, what happens?
- elimination processes that lower the blood concentration lead to a parallel decrease in tissue conc
- half life in plasma equals elimination half life in tissue
Define ‘drug distribtuion’
reversible transfer of drug from one location to another in the body
For more drugs, distribution is what movement?
passive diffusion of un-ionised form across cell membrane
When does distribution stop?
when equilibrium between plasma and tissue is reached
How does blood flow to tissues effect drug distribtuion?
- tissues that are well perfused like lungs and liver get drug rapidly
- poorly perfused like fat, muscle, skin take longer
Factors affecting the rate of distribution
- membrane permeability
- blood perfusion
How does membrane permeability affect rate of distribution?
- drugs perfuse faster through highly permeable renal capillaries
Factors which affect extent of distribution
- lipid solubility
- pH-pKa
- plasma protein binding
- tissue binding
Where are the factors that affect distribution opposite?
- highly impermeable capillaries in brain
Which drugs tend to stay in the systemic circulation rather than distribute to tissues?
- drugs with high molecular weight
- drugs with high degree of binding to plasma proteins
2 examples of key drug binding proteins in plasma
- albumin
- alpha 1 acid glycoprotein (AAG)
How is albumin a key drug binding protein?
- where produced?
What does it bind?
Levels in body?
- produced in liver to bind mostly acidic and some neutral drugs
- decreased in malnutrition and cirrhosis but normally 3.5-5 g/dL
How is alpha 1 acid glycoprotein a key drug binding protein?
- where produced?
What does it bind?
Levels in body?
- liver
- binds mostly basic and some neutral drugs
- acute phase protein elevated in some diseases like cancer in inflammation but normally 0.4-1.1 mg/mL
Some drugs are 1% or 99% plasma protein bound. Are these active?
only the free/unboound drug is pharmacologically active
The amount of drug that is bound to plasma protein depends on what?
- conc of free drug
- affinity of its binding sites
- conc of protein
What does the free drug and plasma protein form?
drug-plasma protein complex
Extensive plasma protein binding means what?
- slows drug action and elimination
- slower acting and prolonged therapeutic effects
How do tissues bind drugs?
- either due to composition (lipid-soluble drugs accumulate in fat)
- or via binding to cellular components (proteins, pigments, minerals)
Explain how tetracyclines bind tissue
- antibiotic example
- accumulate slowly in bones and teeth
- high affinity for calcium
- can’t be used in children for this reason
Explain how chloroquine binds to tissue
- antimalarial drug
- high affinity for melanin and taken up by retina (rich in melanin granules)
- accounts for ocular toxicity
Give and explain the distribution parameter
- volume of distribution
- a dilution factor which represents the relationship between amount of conc in body and plasma concentration
- can be called apparent as may exceed total physiological volume for some compounds
- expresssed in volume, sometimes weight
How to calculate volume of distribution
- easiest after IV bolus but can be done in individual tissues
- V = dose/plasma conc at time 0
Define Vd/volume of distribution
- the distribution of drug between plasma and rest of body after oral/paranteral dose
When do drugs have a low Vd?
- if drugs confined to plasma compartment
When do drugs have a high Vd?
- accumulate outside the plasma like being stored in fat
If a drug with large Vd has been given in overdose what can be done>
- readily removed by dialysis
- but dialysis only removed free drug from plasma
Total blood volume is …
0.08L/kgT
Total body water is …
0.57L/kg
Vd of heparin
0.05 -0.1 L/kg
Vd of warfarin
0.1-0.2 L/kg
Vd of phenytoin
0.7-0.9 L/kg
Vd of paracetamol
1-2 L/kg
Vd of morphine
2-5 L/kg
Chloroquine Vd?
200 L/kg
How do calculate Vd using plasma volume of drug?
Vd = Vp + Vt (fu/fut)
Vp is plasma volume of drug
Vt - apparent tissue volume of drug
fu - fraction unbound in plasma
fut - fraction unbound in tissue
Volume of distribution is used to calculate what?
drug dose
Vd is dose/?
[drug] plasma
Plasma concentration of drug dictates what?
- ability of a drug to reach its target organ in effective concentration
- therefore defines dose
Plasma concentration is affected by Vd of a drug.
Low Vd means?
High Vd means?
- confined to plasma so high plasma concentration
- accumulated in peripheral tissues so low plasma concentration
Often the desired duration of drug therapy exceeds that achievable of one dose so what happens?
- multiple doses needed to maintain drug plasma concentration within limits of efficacy and toxicity
- initial dose required (loading dose) and subsequent dosing frequency depends on volume of distribtuion
What is phenytoin sodium?
- a common antiepileptic
- acts to suppress abnormal brain activity in seizure by reducing electrical conductance among brain cells
- stabilizes inactive state of voltage-gated sodium channels
- also treatment option in trigeminal neuralgia if carbamazepine or other first-line treatment doesn’t work
Binding to plasma proteins is specific/non-specific and competitive/non-competitive
Explain
- non-specific and competitive
- means plasma proteins bind to different drugs and these drugs compete for binding sites on plasma proteins
- displacement of one drug may have serious consequences however e.g if warfarin is replaced with tolbutamide produces haemorrhage risk, but tolbutamide can be displaced by salicylates and risk of hypoglycaemia
What drugs are distributed through body water?
- lipid soluble drugs which readily cross cell membranes
- e.g phenytoin, ethanol
- Vd of around 41.5L
What kind of drugs are distributed in extracellular compartment?
- low lipid solublity
- e.g gentamicin
- Vd of around 16L
Drugs confined to plasma compartment are …
too large to cross capillary wall easily
- e.g heparin
- Vd of around 3.5L
Define ‘interstitial fluid’
- same as tissue fluid
- solution that bathes and surrounds the cells of multicellular animals
