Pharmacokinetics Flashcards
What is the process of Pharmacokinetics?
Dose administered - drug in bloodstream - drug in tissues- drug metabolised or excreted
OR
- Drug binding at site of action
- toxicity or efficacy
What is the therapeutic range?
- aims to keep concentration of drug in the plasma within a certain range
- minimum toxic concentration . above this = toxicity
- Min therapeutic concentration = below = no beneficial effect
How do drugs move across membranes?
- Through passive diffusion
- small molecules move faster
-solubility in the lipid bilayer - Inside - lipid bilayer = hydrophobic (not too much tho!)
- Facilitated Transport (carrier mediated)
- Passive
- Bidirectional
- Relies upon conc gradient
- slc (solute carrier) = Organic Anion/Cation Transporters
- Active transport
- If drug is a substrate for transporter/carrier which pumps drugs back into lumen
- ATP-driven pumps
(ABC superfamily like P-glycoprotein - Can also occur in the kidney, brain`
What is the effect of pH in the stomach/intestine for weak acids?
- Many drugs are weak acids
- Charged drugs do not cross membranes
- Low PH = h+ = high, EQUILIBRIUM GOES TOWARDS HA
- VERY little ionised = lots absorbed
- High pH, H+ = low. More ionised, less absorbed
- Charged ions do not pass the membrane
What is the effect of pH in the stomach/intestine for weak bases?
Low pH= High H+ = equilibrium goes towards BH+
- Lots ionised
- Little absorbed
- High pH , less ionised , more absorbed
What is the effect of pH in the kidney?
Weak bases
- Charged drugs do not cross membranes
- At low pH , [H+] is high, equilibrium goes towards BH+
- Lots ionised = little absorbed
= At high pH [H+] is low
- Less ionised = more absorbed
What are the principles of Pharmacokinetics ?
- Absorption from the site of administration
- Distribution within the body
- Metabolism
- Excretion
How is the rate of absorption into systemic circulation modified?
- site of administration
- drug formation
What is the definition of absorption?
- The transfer of drug from the site of administration to the systemic circulation
What is Bioavailability (F)?
F = Quantity of drug reaching systemic circulation as intact drug/ Quantity of drug administered (i.e. does)
What is bioequivalence?
- If the drug preparation contains the same active ingredient
AND - When the rates and extents of bioavailability of the active ingredient in the two products are not significantly different.
What factors affect absorption from the gut?
- Gastric emptying ( taking meds on an empty stomach)
- Gastrointestinal motility
- Blood flow
- Particle size and formulation
- Physiochemical factors e.g. solubility, molecular weight, binding to calcium (esp. in milk) or fat in food
- Metabolism ( enzyme-catalysed reactions)
What is the first pass effect?
- When drugs are metabolised by enzymes in the gut wall or liver
What may metabolism in the gut or liver lead to?
- Activation of pro drug- one that is converted to an active form by enzymes in the liver
OR
-Inactivation - when a drug converted to inactive metabolites.
What are the routes of absorption from the GI tract?
- Mouth,Rectal - avoids first pass metabolism
– Sub-lingual
– Buccal - Oral
- Duodenal
What is the sub-lingual (glyceryl trinitrate) route of administration?
- undergoes first pass metabolism
- Needs a quick response (does not go into stomach)
- given as a spray or tablet under tongue
- given for angina
What are sub-cutaneous routes of adminstrations (Examples)?
- Local anaesthetics, that act locally
- Can be given with vasoconstrictor to delay systemic absorption
What are intra-muscular depot preparations?
- Contraceptives
- Gradual release, sustained concentrations
- Convenience
What are examples of rectal adminstered drugs?
Anti-epileptic drugs
- Diazepam for epilepsy when there is continuous fittings
What are examples of topic drugs?
- Anti-inflammatories
- Ibuprofen, avoids irritation to stomach
- Corticosteroids, avoid systemic side effects
What are examples of intra-articular anti-inflammatories?
- Corticosteroids, direct to target, avoids systemic side effects.
What is the effect of plasma protein binding on distribution?
- Can slow down the elimination of the drug
How are drugs distributed?
- Different drugs distributed in different ways
- Lipid soluble/water soluble drugs have a smaller distribution in the body = slower elimination in the body.
What is the volume of distribution (Vd)?
The volume of plasma that would contain the total body content of the drug at a concentration equal to that of plasma.
- concentration = mass/ volume
What is the common rule of Vd for lipid-soluble drugs?
- The plasma concentration can be very small even though there is still a lot of drug in the body.
What is the estimate Vd of large hydrophilic drugs (heparin, insulin)?
Plasma ~3.5L/70kg
What is the estimate Vd for small hydrophilic drugs(e.g. gentamicin, theophylline) ?
Plasma + extracellular Vd ~ 14L/70 kg
What is the estimate Vd for moderately lipid soluble drugs (E.g. ethanol, phenytoin)
Total body water ~ 14L/70 kg
What is the estimate Vd for very lipid soluble drugs (e.g. morphine, cannabis)?
Concentrated in tissues/fat
Vd > 40 L/70 kg
A novel drug has been discovered for the treatment of epilepsy in adults. The Vd is 12L. Will it be useful for epilepsy? Yes/No, why?
- No , 12 L suggests that drug is hydrophilic. Drug needs to get inside of the brain and needs to be lipid soluble. Lipophilic Vd> 40L
What is elimination?
The removal of the original drug from the bloodstream.
- Either by metabolism to a different chemical structure
- Or by excretion in kidney, breath, skin and hepatobiliary system
Where are drugs metabolised?
- Usually in the liver, but also the gut , plasma and lungs
What is Phase 1 of drug metabolism?
- often catalysed by cytochrome P450 enzymes (CYP). Important for non-polar drugs.
- Oxidation, Hydroxylation, Dealkylation, Deamination, Hydrolysis
What is Phase 2 of drug metabolism?
- Increases drug solubility in water and therefore excretion in the kidney
What happens when two drugs are given together and metabolised by the same enzyme?
One may inhibit the metabolism of the other.
What happens if a drug is taken in the presence of an inhibitor of cytP450?
Its metabolism would be reduced
What happens when CytP450 is induced?
The amount of enzyme increases- metabolism of drug is also increased.
What does metabolism in the liver depend on?
- Perfusion
- Plasma protein binding
- Secretion into bile
- Presence and activity of transporters and enzymes
- Low extraction ratio <0.3
- High extraction ratio > 0.7
What is renal elimination?
- When blood is filtered at the glomerulus
- Nutrients are then reabsorbed and lipid soluble drugs can diffuse back into the blood
- Some drugs actively secreted from blood to urine
What factors affect renal elimination?
- Plasma protein binding can slow elimination
- Drugs can compete for transporters
What is renal clearance?
The efficiency of elimination , i.e. the ratio of the rate of elimination to the plasma concentration.
What is the equation for renal clearance?
renal clearance = rate of elimination into urine mg/h / plasma concentration (mg/L)
What is the equation for rate of elimination?
Rate of elimination = volume/time X conc (urine)
What is the equation of hepatic clearance?
rate of elimination via liver (mg/h) / plasma concentration (mg/L)
What is the definition of plasma clearance?
- The volume of plasma from which all the drug molecules would need to be removed per unit time to achieve the overall rate of elimination of drug from the body.
- Total CL = renal CL + hepatic CL
What is the half life of a drug?
The time taken for the concentration to decrease by half.
Under what circumstances is the half life constant ?
plasma = fluid in a bucket (single compartment)
inflow = absorption of fluid into the body
outflow = removal of fluid through filtration in the kidneys
volume of fluid in the bucket is constant
Why is the half life for other drugs not constant?
- The drug is redistributed into fat or tissues
- The elimination mechanism becomes saturated
