Pharmacokinetics Flashcards
What factors are involved in pharmacokinetics?
- Absorption
- Distribution
- Metabolism
- Excretion
What is absorption?
passage of a drug from the site of administration into the plasma
What is bioavailability?
the fraction of the initial dose that gains access to the systemic circulation
What is the difference between absorption and bioavailability?
- Absorption deal with process for drug transfer into the systemic circulation
- Bioavailability deals with outcome of drug transfer into systemic circulation (ie how much)
What determines absorption and bioavailability?
Site of administration
When will you have the best absorption and bioavailability?
Intravenous administration - process for drug passage is injecting full dose straight into circulation - outcome if the full dose is administered straight into the circulation is that the bioavailability must be 100%
What are other forms of drug administration.?
- Oral
- Inhalational
- Dermal (Percutaneous)
- Intra-nasal
- and many more
When might bioavailability in each case be less than 100%
Need to transfer across at least one lipid membrane (not injected straight into blood stream)
How can drugs move around the body as?
- Bulk flow transfer (i.e. in the bloodstream)
2. Diffusional transfer (i.e. molecule by molecule across short distances)
What is pinocytosis? When is it used?
- Small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug
- Vesicle then release the chemical on the other side of the membrane
e. g insulin access to brain rarely used to transport drugs
Is diffusion used often?
Diffusion across aqueous pores i.e. the gaps between epithelial/endothelial cells that make up the membrane, is also not a major route for movement of drugs across membrane
Why is diffusion not used that often?
- pores are less than 0.5nm in diameters
- very few drugs this small
- little movement of drugs across this aqueous route
How do most drugs move across membranes by diffusing across lipid membranes?
- diffusing across lipid membrane
2. Carrier mediated transport
What is carrier mediated transport?
- involves a transmembrane protein
- which can bind drug molecules on one side of the membrane
- then transfer them across to the other side of the membrane
When can drugs diffuse across lipid membranes?
drugs need to be suitably lipid soluble to do this
Are drugs usually more water soluble or lipid soluble? Why is this the case?
- more water soluble than lipid soluble
- mostly given orally and need to be water soluble to dissolve in aqueous environment of GI tract so that available for for absorption
What type of chemicals are most drugs?
- Weak acids
- Weak bases
- Exist in. ionised or unionised forms
What form is aspirin usually in? What does it do in its ionised state?
weak acid - in ionised state donate protons H+
What form is morphine usually in? What does it do in its ionised state?
weak base: in its ionised state accept protons: I.e. B(morphine)H+
When are drugs more likely to diffuse across plasma membranes?
unionised form of drugs retains more lipid solubility and is more likely to diffuse across plasma membranes
What does whether a drug is ionised or not depends on?
- the dissociation constant (pKa) for that drug and
2. the pH in that particular part of the body
What happens if the pKa pf the drugs and pH of the tissue are equal?
drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised
What is the pKa of aspirin?
Weak acid, 3.5
What happens to aspirin in a pH of 3.5?
equally dissociated between the two forms
What happens to aspirin (and weak acids) when the pH decreases?
unionised form starts to dominate
What happens to aspirin (and weak acids) when the pH increases?
ionised form starts to dominate
What is pKa of morphine?
Weak base, 8.0
What happens to morphine when the pH is 8.0?
equally dissociated between the two forms
What happens to morphine (and weak bases) when the pH decreases?
ionised form starts to dominate
What happens to morphine (and weak bases) when the pH increases?
unionised form starts to dominate
Where is low pH?
Stomach
Where is higher pH?
Blood and urine
How come the weak bases don’t get trapped in the stomach and. weak acids aren’t trapped in the blood?
- Weak base poorly absorbed from the stomach due to the low pH leading to a high drug ionisation
- Once drug reaches the small intestine be able to access a huge number of transport proteins that will enable absorption from the gastrointestinal tract
- A weak acid could potentially be absorbed from the stomach in its unionised state - then become more ionised at physiological pH and potentially become ‘trapped’ in the blood.
- Most tissues possess transport proteins that could potentially move the ionised drug from the blood into the tissue.
Where are the most important carrier systems relating to drug action found?
1) Renal tubule
2) Biliary tract
3) Blood brain barrier
4) Gastrointestinal tract
How are these carrier systems responsible for drug access?
- absorption from the gastro-intestinal tract (bloodstream)
- drug access to certain tissues (absorption across the blood brain barrier)
- excretion of drugs from the body (excretion from the kidney of the gastro-intestinal tract).
What does the the amount of drug exposed to different tissues depend on?
- Regional blood flow
- Plasma protein binding
- Capillary permeability
- Tissue localisation
At rest how much cardiac output does the liver receive?
27%
At rest how much cardiac output does the heart receive?
4%
At rest how much cardiac output does the brain receive?
14%
At rest how much cardiac output does the kidneys receive?
22%
At rest how much cardiac output does the muscles receive?
20%
When is more. drug distributed to tissues?
- more drug distributed to those tissues that receive most blood flow
- distribution of blood to tissues increases or decreases depending on circumstance e.g during exercise more blood will be diverted to the muscles
- after a large meal more blood will be diverted to the stomach and intestines
What is plasma protein binding?
- Once drugs reach systemic circulation common for them to bind to plasma protein - some drugs
- Can be up to 99% bound to proteins - the most important plasma protein with regard albumin (binds to acidic drugs)
What does the amount of drug bound depend on?
- The free drug concentration
- The affinity for the protein binding sites
- The plasma protein concentration
What is the binding capacity of albumin?
- Conc in blood is approx: 0.6mmol/l
- Each albumin protein has two binding sites - so the binding capacity of albumin alone is 1.2mmol/l
What is the plasma concentration required for a clinical effect for nearly all drugs? Why is this good for albumin?
- considerably less than 1.2mmol/l
- plasma proteins are NEVER saturated with drugs
What is the differences in the extent of plasma protein binding for individual drugs?
largely due to the particular affinity for the protein binding sites for that particular drug
What bind particularly well to albumin?
acidic drugs bind particularly well to albumin and therefore tend to be more heavily plasma protein bound
When can drugs actually diffuse out of blood and access tissues?
ONLY FREE DRUG - Any drug that is bound to plasma proteins CANNOT leave the blood until it dissociates from the protein
What are most of the capillaries in the body?
‘continuous’ structure: endothelial cells aligned in single file with small gap junctions between the cells
When can drugs diffuse across the endothelial cell and access the tissue?
Very lipid soluble
What happens if drugs are less lipid soluble?
(unless they are very small and can pass through gap junctions), they will need to be transported into the tissue via carrier proteins
What is the blood brain barrier?
- capillary structure in the brain,
- ‘continuous’ structure with tight junctions between endothelial cells
- Drugs hard to gain access
What is discontinuous capillary structure?
- big gaps between capillary endothelial cells
- allows for drugs to easily diffuse out of the bloodstream and access the liver tissue
What is an example of discontinuous capillary structure?
liver is one of the key metabolic tissues in the body and deals with metabolism of a huge variety of chemicals including the majority of drugs
What is fenestrated capillary structure?
- Fenestrations: circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs
- Allows forsmall drugs to pass from blood to kidney tubules which will enhance excretion of these drugs
What is an example of fenestrated capillary structure?
- glomerulus of the kidney
- kidney is a key tissue involved in excretion of chemicals including a large number of drugs
What is the. difference between blood and brain in water and fat content?
- Blood higher water content
2. Brain higher fat content
What does this mean for the equilibrium of delta9-THS very lipid soluble drugs?
- equilibrium is going to be more heavily weighted towards retention in the brain
- arger proportion of delta9-THC is going to be ‘localised’ in the brain compared with the water soluble drug
What does this mean for the equilibrium of very water soluble drugs?
-equilibrium is going to be more heavily weighted towards retention in the plasma
