Pharmicokinetics Flashcards
What are the disadvantages of IV injection?
Irreversible Skill require to administer Infusion require apparatus Inconvenient for the patient Risk of infection/embolism High initial conc
What are the advantages of IV injection?
Speed
Control
Accuracy (helpful for drugs with a narrow therapeutic window)
What determines the rate of absorption of intramuscular and subcutaneous injections?
Local concentration and blood flow
Also if the drug precipitates then the local conc remains constant as long as solid remains
What are the advantages of subcutaneous injection?
Slow prolonged, constant absorption (in effect an infusion)
Long term administration
Certainty that drug is taken
What are the disadvantages of subcutaneous injection?
Rate of entry into general circulation can be inconsistent and unpredictable
Can be painful
If precipitates can be slowly absorbed
What is the rate of transdermal absorption determined by?
The lipid/water partition coefficient
What are the advantages of transdermal administration?
Avoids first pass metabolism in the liver
Can give steady state absorption for long periods of time
What is the first pass effect?
The term used to describe the fact that many drugs absorbed by the stomach will pass through the liver and eliminated
What are the advantages and disadvantages of administration sublingually/buccally?
Adv
Rapid onset
Avoids first pass metabolism
Dis
Taste
Accumulation of saliva
Small surface area
What are the advantages and disadvantages of oral administration of a drug?
Adv
Self administration
Cheap
Effects can be spread over a long period of time
Dis Slow Variable Digestion Vomitting/diarrhoea First pass effect
What affects the rate of absorption of drugs across gut epithelium?
Low degree of ionisation
High lipid/water partition coefficient (of non ionised form)
Small atomic or molecular radius of water soluble substances
What determines the degree of ionisation of a drug?
The pH of the environment and the pKa value of a drug
What kind of drugs are absorbed well in the stomach?
Acids, whereas weak bases can trapped
What kind of drugs are absorbed well in the small intestine?
Bases are absorbed well
What can cause low bioavailability of a drug?
High degree of ionisation
Digestion
Metabolism
First-pass effect
What can cause variability in bioavailability?
Vomiting and diarrhoea
Food in gut can slow transit time to the intestine and can impair absorption
High fat meals can increase the rate of absorption with poor water solubility
What are the main areas a drug can distribute within?
Blood ECF ICF Fat Other (CSF, peritoneum, sivonial fluid and fetus)
What is the equation that gives total plasma concentration?
C = C(free) + C (bound)
What protein do most neutral and weakly acidic drugs bind to in the blood? Why?
Albumin
Each drug has multiple binding site and makes up 50% of total plasma conc
Which protein do most weak bases bind to?
α2-acid-glycoprotein
Each molecule has a single high affinity site
What are the important consequences of drug binding to plasma protein?
Increases the amount of drug that can be transported in the blood
Only free drug can cross capillary walls so binding to plasma protein affects the rate at which drug enters interstitial fluid
Binding affects rate at which drug is eliminated
Percentage bound can change in presence of other drugs (could result in toxic levels)
What are the volumes of different bodily compartments?
Total - 42L
/ \
Extracellular - 14L Intracellular - 28L
/ \
Plasma - 3L Interstitial - 11L
What is the formula for the volume of distribution?
Vd = Total amount of drug in the body / plasma conc
How does binding affect the apparent volume of distribution?
High degree of protein bound = Vd is lower than actual volume
How does sequestration of drug in fat deposits affect the apparent volume of distribution?
Binding/sequestration can reduce plasma conc = High Vd
What are the was in which drugs can pass through capillary walls?
Tight junctions form pores = drugs of less the 30 angstrums can cross rapidly
Large drugs can move by transcytosis
How can drugs bypass the BBB if they aren’t lipid soluble? When is this used?
Intrathecal administration, directly into the CSF allows administration of drugs to the meningeal surfaces of the brain?
Used to treat infectious meningitis and CNS leukemia
What do P-glycoproteins do? What is their role?
Actively transport drugs out of cells
Play an important role in excreting toxic substances from cells in order to prevent build up
How are drugs removed from their site of action?
Metabolism
Excretion
Storage (in fat)
What enzymes are involved in the inactivation of drugs? Which is the most common?
CYP enzymes in hepatocytes and in the wall of the intestines
Cytochrome P450
What are the common features of CYP enzymes?
Low substrate specificity
High solubility in lipids
What kind of reactions does cytochrome P450 catalyse?
Phase 1 reactions:
- Oxidation
- Hydrolysis
- Hydroxylation
What are the Phase II reactions involved in drug metabolism? What is the role of these reactions?
The attachment of a chemical group
These chemical groups make the molecule more polar and this more excretable via the kidney
What class of enzyme catalyse Phase II reactions in drug metabolism?
Transferases
What is the process of aspirin metabolism in the liver?
Aspirin -> Salicyclic acid -> Excreted
Pro-drug
What is the metabolic pathway of diazepam?
Diazepam (active)
N-demethylation
Desmethyldiazepam (active)
Aliphatic hydroxylation
Oxazepam (active)
Glucuronide conjugation
Oxazepam glucuronide (inactive)
What are phase II conjugations often followed by?
Secretion of modified drug into bile by relatively non-specific transporters (including P-glycoprotein)
What are examples of drugs that can enter the enterohepatic circulation?
Digitoxin and diethylstiboestrol
What is the single most important source of variability in drug response? What can cause this?
Drug metabolism
Can be... Poorly developed in neonates Reduced in age Sex dependent Depressed by chronic hepatitis or cirrhosis Cause by genetic variation Altered by drug interactions
What are inducers of drug metabolism?
Drugs that on repeated administration induce CYPs either by enhancing synthesis or inhibiting degradation
Give some examples of drug inducers.
Phenobarbitone
Phenytoin
Ethanol and smoking
What can inducers cause? When can this cause complications?
Can cause tolerance
Can cause complication in multi-drug therapy
Which drugs can inhibit CYP enzymes? How is inhibition achieved?
Erythromycin and imidazole containing drugs
Inhibition involves complexing the cytochrome heme-iron
Why are drugs that inhibit CYP enzymes helpful?
They can dramatically slow down the elimination of a second drug
What are the two ways by which reabsorption can be reduced?
By making the drug more polar
Changing the pH of the urine (eg bicarbonate can be administered)
What are the two transport mechanisms used by drugs? What are the features of both of these?
Anion transport
Cation transport
Saturable and substrates will compete with one another if they utilise the same mechanism
Why might drug excretion via a route that is quantitatively small be clinically significant?
May be useful for assessing drug exposure
Eg hair and drugs of abuse
What is zero order elimination?
When the rate of elimination is constant and independent of plasma conc of drug (enzyme are saturated)
What is first order elimination?
When the rate of elimination varies proportionally with the plasma conc of a drug
What is equation used to quantify a saturable process? When can this equation be simplified?
The Michaelis-Menton equation
u = V(max)xS / S+K(m)
When S«Km
u=V(max)xS / K(m)
What is clearance? How can it be calculated from a graph?
The rate of elimination / Plasma conc
Clearance = Dose (iv) / AUC
How can F be calculated?
F = AUC(oral)/AUC(iv) x D(iv)/D(oral)
What is Vd equal to?
Clearance / ke
How can clearance be calculated in a constant infusion model?
Clearance = dose rate / C(ss)
What equation give the rate of approach to steady state?
Cp = Cp(ss) (1 - e^-ke.t)
How can Vd be calculated from the terminal section of a constant infusion graph?
V(d) = ( Clearance x AUC(end) ) / C(ss)
What rate of elimination will give the faster approach to steady state?
A fast one
What is the criteria needed for the use of oral drugs in order to give a prolonged effective Cp?
t(1/2) > 4 hrs
What are the two equations used to give C(max) and C(min)?
C(min) = C(max) x e^-k(e).τ
D x F = Vd( C(max) - C(min) )
How is C(av.ss) calculated?
AUC = C(av.ss) x τ
DF/T = CL x C(av.ss)
When can multiple oral dosing be taken to the same as IV infusion?
When 3τ < t(1/2)
When should a loading dose be uses?
If the rate of elimination is very slow
Name two examples of drugs that show zero order elimination
Alcohol
Phenytoin
What is the role of general anaesthetics?
Used to render patients unaware of, and unresponsive to, painful stimulation during surgical procedures
What are the three kinds of general anaesthetics?
IV
Volatile inhalants
Inorganic gases
What is a factor that affects the potency of general anaesthetics?
Lipid solubility (oil:gas partition coefficient)
What are the effects of general anaesthetics?
Loss of conscious experience Loss of memory Loss of motor reflexes Loss of response to painful stimulation Changes in CV and respiratory performance
What are the well defined stages of general anaesthetic action?
Conscious but drowsy
Surgical anaesthesion
Medullary paralysis and death
What are the two stages of general anaesthetic excretion and what causes this?
Initial fast phase
Slower phase
This is due to initial high conc in high flow tissues (eg the brain) which then drops as it redistributes (not due to elimination)
What are the phases during/after general anaesthetic action?
During injection - high arterial conc/high blood flow tissues
Fast redistribution phase - drug moves out of high flow tissues and into low flow tissues
Intermediate phase - Drug diffuses out of all lean tissues but is still diffusing into fat
Terminal phase - accumulated in fat and is being eliminated slowly
What can occur if a large dose or repeated doses of general anaesthetic are given?
Cp after fast distribution may exceed level needed for anaesthesia (recovery is greatly delayed)
Propofol?
General anaesthetic used IV as it is metabolised more rapidly than older GAs
Primary target is GABA(A) receptor - produces prolongation of GABAergic IPSPs
Etomidate?
General anaesthetic used IV as it is metabolised more rapidly than older GAs
Primary target is GABA(A) receptor - produces prolongation of GABAergic IPSPs
How are inhalation anaesthetics eliminated?
Via the lungs
What is the determining factor for how long it will take an inhalation anaesthetic will take to reach equilibrium?
If it is more soluble then it will take longer to reach equilibrium
Nitrous oxide?
Inhalant anaesthetic used as a GA
Had a low C(blood):C(gas) and fast induction/recovery
Why do GA redistribute so well in the fat?
~20% body vol
Many GAs are 100x more soluble in fat than water
What was the first theory of general anaesthetic action? Who proposed it?
Lipid theory - narcosis commences when any chemically indifferent substance has attained a certain conc in the lipids of the cells
Overton and Meyer (1937)
What is the evidence in support of lipid theory?
Anaesthetic potency correlates well with lipid solubility
What is the evidence against lipid theory? Who showed this?
Firefly luciferase is inhibited by a variety of anaesthetics at clinically relevant concentrations and order of potencies
Was shown by Frank and Lieb (1984)
What the two proposed actions of general anaesthetics used to explain lipid theory? What is the evidence for each?
Membrane expansion - Pressure reversal demonstrated in tadpoles. This is proposed to prevent channels functioning
Increased membrane fluidity - Temp changes of 1-2*C cause similar changes in fluidity
What is the cut off effect? What is this theory consistent with?
The fact that increasing chain length will increase potency up until a limit.
The theory that GAs work through binding to a hydrophobic pocket
What are the most likely protein targets for general anaesthetics?
GABA(A) and glycine receptors which are potentiated by anaesthetics
K+ Channels
NMDA receptors
What is the proposed model of the protein theory of GA action?
GAs bind to preformed cavities causing little change in structure
They stabilise conformations that contain the binding site
What is the primary target of propofol and etomidate? Which part is thought to play a crucial role?
GABA(A) receptor
β-subunit plays a crucial role (etomidate is more effective on β2 or 3)
What is the β3 N265M knock out?
Mutation found in transmembrane 2 of the GABA(A) receptor that shows reduced effectiveness of Propofol
Also the channel showed reduced IPSPs in the presence of propofol
Halothane
Inhalation anaesthetic
Medium induction/ recovery
Where are inhalation general anaesthetics thought to act? Why is this?
Upon the α subunit of the GABA(A) receptor
-Effects of halothane and isoflurane are blocked by S270W
Two pore domain K+ channels
-Potentiation is blocked by M159A
Thiopental
General anaesthetic barbiturate
High lipid solubility
TREK1 KO mouse
Mice lacking the TREK1 K+ channel
Show reduced responsiveness to Halothane - suggests halothane acts at TREK1 K+ channels
Mutations in TM3/4 of the NMDA receptor
Caused a reduction in alcohols ability to inhibit these channels
