PHAR2: Introduction - pharmacokinetics Flashcards
With regard to pharmacokinetics, how is absorption defined?
as the passage of a drug from the site of administration into the plasma
Define bioavailability
Fraction of the initial dose that gains access to the systemic circulation.
Overall, absorption deals with the ______ for drug transfer into the systemic circulation, whereas bioavailability deals with the _______ of drug transfer into the systemic circulation
process
outcome
What are the five main methods of drug administration?
- Intra-venous
- Oral
- Inhalational
- Dermal (percutaneous)
- Sub-lingual
What is the bioavailability for intra-venous?
100%
What are the two ways molecules move around the body from the initial site of administration?
- Bulk flow transfer (in the bloodstream)
- Diffusional transfer (i.e. molecule by molecule across short distances)
For intravenous what is the method of delivery to the intended site of action?
Bulk flow
Except for intra-venous administration, what do all other methods of administration have to do?
diffuse across at least one lipid membrane
What are the different mechanisms by which drugs can cross the lipid membrane
- Diffusion through lipid membrane
- Diffusion through aqueous pores
- Carrier proteins
- Pinocytosis
Why do most drugs not cross the lipid membrane by diffusion through aqueous pores?
Most pores are 0.5nm in diameter, most drugs are larger than this
Which method do most drugs cross the lipid membrane?
- diffusing across lipid membranes
- carrier mediated transport
Describe carrier mediate transport
which involves a transmembrane protein, which can bind drug molecules on one side of the membrane and then transfer them across to the other side of the membrane.
What do drugs need to be in order to cross the lipid bilayer by diffusion?
Drugs need to be suitably lipid soluble to do this
What determines: drug absorption from the gut or drug penetration into tissues or drug elimination in the kidneys?
lipid solubility
For oral administration of the drug, which barriers need to be crossed?
a) small intestine microvilli
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect
For inhalation of the drug, which barriers need to be crossed?
a) alveoli/bronchi
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect
For intra-nasal administration of the drug, which barriers need to be crossed?
a) mucous membranes of nasal sinus
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect
Why will drugs exist in both ionised and unionised states?
Most drugs are either WEAK ACIDS or WEAK BASES
Is aspirin a weak acid or base?
weak acid
Is morphine a weak acid or base?
weak base
At physiological pH (7.4), how would aspirin and morphine act?
Aspirin would be more likely to donate protons (H+) and morphine to accept protons (H+)
Which of the ionised or unionised forms of aspirin and morphine going to be more lipid soluble?
Unionised/non-polar = more lipid soluble
Lipid membrane = non polar
Therefore like for like -> more lipid soluble
What is a huge determinant of absorption of drugs across lipid membranes?
pH of the tissue
Weak acids will be more unionised in What type of environments?
Acidic
Weak bases will be more unionised in what type of environments?
Alkaline
What does dissociation constant mean?
quantitative measure of the strength of acid in a solution
How do you determine the ratio of ionised to unionised drug?
By the dissociation constant (pKa) and the pH in that particular part of the body
How are weak bases represented?
B + H+ BH+
How are weak acids represented?
A A- H+
What does dissociation involve?
Loss of a proton
What is the dissociation constant determined by?
The Henderson-Hasselbalch equation
What is the Henderson-Hasselbalch equation for weak bases?
pKa = pH + log [BH+]/[B]
What is the Henderson-Hasselbalch equation for weak acids?
pKa = pH + log [AH]/[A-]
Does the pKa of the drug change as it passes through the body?
No
Why does the body compartment have a significant impact on the amount of ionised versus unionised drug in that particular compartment?
The pH of the body compartment will change, therefore ratio of ionised to unionised drug will change
How do you rearrange the Henderson-Hasselbalch equation to calculation the ratio between ionised and unionised acid
antilog[pKa-pH]=[AH]/[A-]
How do you rearrange the Henderson-Hasselbalch equation to calculation the ratio between ionised and unionised base
antilog[pKa-pH]=[BH+]/[B]
If the pH and pKa are the same then what does that mean about the ratio between ionised and unionised drug ratio?
50% 50%
If the pKa of Aspirin is 3.5, if the urine pH is 8, then work out the ratio of the ionized and unionized forms of aspirin
0.00003
If the pKa of Morphine is 8, if the urine pH is 8, then work out the ratio of the ionized and unionized forms of morphine
1
If the pKa of Morphine is 8, if the blood pH is 7.4, then work out the ratio of the ionized and unionized forms of morphine
3.98
If the unionised:ionised drug ratio is high, what does this mean about the delivery of the drug?
a significant proportion of the drug (the unionised portion) should easily cross the lipid membranes of one body compartment and thus gain access to other body compartments.
If the unionised:ionised drug ratio is very low, what does this mean about the delivery of the drug?
a very significant proportion of the drug will struggle to diffuse across the lipid membranes of the body compartment and will remain ‘trapped’ in these compartments
What is known as the pH partition hypothesis?
The proportion of drug in any body compartment is dependent on pH. It also results in the phenomenon of ‘ion trapping’ – acidic drugs tending to become ‘trapped’ in compartments with high pH and basic drugs tending to become ‘trapped’ in body compartments with low pH.
What is ion trapping?
Acidic drugs tending to become ‘trapped’ in compartments with basic pH and basic drugs tending to become ‘trapped’ in body compartments with acidic pH
What are carrier transport systems are present to regulate?
The entrance and exit of physiologically important molecules across lipid membranes
How may less lipid soluble drugs access tissues?
Via protein carriers: the carrier protein binds to one of more molecule(s) and transports the molecule to the other side of the membrane
In terms of pharmacokinetics, what are the most important carrier systems relating to drug action?
Renal tubule
Biliary tract
Blood brain barrier
Gastrointestinal tract
What are these carrier systems important for? Renal tubule Biliary tract Blood brain barrier Gastrointestinal tract
These particular carrier systems are therefore responsible for drug access to the bloodstream (absorption from the gastro-intestinal tract), for drug access to certain tissues (absorption across the blood brain barrier) and excretion of drugs from the body (excretion from the kidney of the gastro-intestinal tract).
What are the two major advantages of administering drugs for local effects?
1) You can deliver the drug directly to the intended site of action
2) You can administer a high local concentration without worrying about systemic effects
It is very rare that a drug effect can be completely _______. Why is this?
Localised
Most tissues receive a good blood supply – as a result, if the drug is lipid soluble at all, some of it will diffuse into the tissue blood supply from where it can exert a systemic effect.
What are the factors that affect tissue distribution?
Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation
What % of cardiac output do the: liver, heart, brain, kidneys, muscle
Liver 27% Kidneys 22% Muscles 20% Brain 14% Heart 4%
Once drugs reach the systemic circulation, what do most of them will bind to?
Plasma proteins: with some drugs, they can be up to 99% bound to proteins
The amount of drug that is bound depends on three factors, what are they?
1) The free drug concentration
2) The affinity for the protein binding sites
3) The plasma protein concentration
What is the most important plasma protein?
Albumin: which is particularly good at binding acidic drugs
What is the concentration of albumin in the blood?
0.6mmol/l
How many binding sites does albumin have?
two
What is the binding capacity of albumin alone?
1.2mmol/l
Why is it important that the binding capacity of albumin is 1.2mmol/l?
The plasma concentration required for a clinical effect for nearly all drugs is considerably less than 1.2mmol/l. The consequence of this is that the plasma proteins are NEVER saturated with drugs.
Since, plasma proteins are never saturated with Differences in the extent of plasma protein binding for individual drugs is largely due to what?
The particular affinity for the protein binding sites for that particular drug
What binds particularly well to albumin?
Acidic drugs: therefore they tend to be more heavily plasma protein bound
If a drug is bound to plasma proteins, what can it not do?
It is unable to leave the blood until it dissociates from the protein
Describe what continuous capillary structure is like
Most of the capillaries in the body have the continuous structure – endothelial cells aligned in single file with small gap junctions between the cells. If drugs are very lipid soluble then they can diffuse across the endothelial cell and access the tissue.
Describe what blood brain barrier capillary structure is like
If drugs are less lipid soluble, then (unless they are very small and can pass through gap junctions), they will need to be transported into the tissue via carrier proteins. The ‘blood brain barrier’ refers to the capillary structure in the brain, where there is a ‘continuous’ structure, but with the addition of tight junctions between endothelial cells. This makes the brain the most difficult tissue in the body for drugs to gain access to – which makes sense, when you consider the critical physiological role of the brain.
Describe what fenestrated capillary structure is
an example of a tissue with this capillary structure is the glomerulus of the kidney. The kidney is a key tissue involved in excretion of chemicals including a large number of drugs. Fenestrations are circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs. This allows for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs.
Describe what discontinuous capillary structure is
an example of a tissue with this capillary structure is the liver. The 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. A 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 the most important factor that can influence drug localisation to tissues?
Body fat
Will the ionised or unionised drug localise in body fat?
Unionised
What factors will determine whether the non-ionised drug will accumulate in the body fat?
1) Blood flow to the body fat is very low – approximately 2% of the cardiac output. As a result, at any given moment in time, only small amounts of the non-ionised drug is being delivered to the body fat.
2) The lipid solubility of the drug. E.g. Morphine can access the brain, which suggests it is fairly lipid soluble. However, its oil/water partition coefficient (i.e how well it dissolves in fat versus how well it dissolves in water) is 1.
What happens to drug in the body fat that has a high oil/water coefficient?
It will slowly leak back into the bloodstream. (due to the poor blood flow to this tissue and the preference of the drug for the body fat versus the aqueous blood)
What is oil/water coefficient?
The ratio of drug that can dissolve in oil vs water
Give an example of a drug that has a very high oil/water coefficient
General anaesthetics (5000)
In order for drugs to be effectively excreted, is it better if it’s more or less lipid soluble and why?
Not lipid soluble, meaning the drug would be more effectively retained in the blood (drugs would not diffuse out of the blood into tissues) and more of the drug would be delivered to the various excretion sites.
Although it is better for excretion for drugs to not be lipid soluble, why is it better for therapeutic reasons for the drug to be lipid soluble?
In terms of therapeutic effectiveness, we WANT drugs to be lipid soluble, so that they can easily access tissues to produce their effects.
How are drugs designed, to be lipid or non-lipid soluble?
We tend to design relatively lipid soluble drugs. It is then up to the body to alter the drug to make it less lipid soluble and easier to excrete.
What does the process of metabolism involve?
Conversion of drugs (usually quite lipid soluble) to metabolites (usually less lipid soluble and easier to excrete).
What is the major metastatic tissue?
Liver
What are the main enzymes responsible for drug metabolism?
Cytochrome P450 enzyme
What are the two types of biochemical reactions?
Phase 1 – main aim is to introduce a reactive group to the drug
Phase 2 – main aim is to add a conjugate to the reactive group
Both stages together act to decrease lipid solubility which then aids excretion and elimination.
Name the three processes by which phase 1 metabolism can occur?
- Oxidation
- Reduction
- Hydrolysis
What is the most common phase 1 metabolism process?
Oxidation
What do all oxidation reactions start with?
A hydroxylation step, utilising the cytochrome P450 system
What is the aim of a hydroxylation step?
To incorporate oxygen into non-activated hydrocarbons.
End result of phase 1 metabolism is to produce metabolites with functional groups that do what?
Serve as a point of attack for the conjugating systems of phase 2
Phase 1 reactions will often produce what type of metabolites?
Pharmacologically active drug metabolites
What are pro-drugs?
The parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite - In this case, metabolism is required for the pharmacological effect.
Name the different types of phase 2 reactions
Glutathione conjugation
Glucuronidation
Acetylation
Sulfation
What are the predominant form of phase 2 enzymes?
Transferases to transfer the substituent group onto the phase 1 metabolite
What is a particular problem for orally administered drugs?
First pass hepatic metabolism
Why is first pass hepatic metabolism a problem for orally administered drugs?
Orally administered drugs are predominantly absorbed from the small intestine and enter the hepatic portal blood supply where they will first pass through the liver before they reach the systemic circulation. At this point, the drug can be heavily metabolised and as a result, little active drug will reach the systemic circulation
What is a solution to first pass hepatic metabolism?
administer a larger dose of drug to ensure enough drug reaches the systemic circulation
What is the problem with increasing the dosage for all individuals to overcome the problem of first pass hepatic metabolism?
the extent of first pass metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies. As a result, drug effects and side effects are difficult to predict.
Name the routes of excretion of drugs
- Lungs
- Breast milk
- Sweat
- Urine
- Bile
- Faeces?
What are the 3 major routes for drug excretion via the kidney?
1) Glomerular filtration
2) Active tubular secretion (or reabsorption)
3) Passive diffusion across tubular epithelium
Why does excretion of different drugs vary so greatly?
The extent to which drugs use the three excretion processes differs enormously
What size is the limit for Glomerular filtration?
Drug molecules of molecular weight less than 20,000 to diffuse into the glomerular filtrate
What molecules will have a quicker rate of excretion as a result of glomerular filtration
Small drugs of less than 20,000 molecular weight
What is the most important method for drug excretion in the kidney?
Active tubular secretion
What % of the renal plasma is filtered at the glomerulus?
20%
The remaining 80% of the renal plasma passes onto where?
the blood supply to the proximal tubule
Why is active tubular secretion more important than glomerular filtration?
- More drug is delivered to the proximal tubule than the glomerulus
- Within the proximal tubule capillary endothelial cells there are two active transport carrier systems
What is the difference between the two active transport carrier systems in proximal tubule capillary endothelial cells? (&one similarity)
One is very effective at transporting acidic drugs and one is very effective at transporting basic drugs.
Both are quite capable of transporting drugs against a concentration gradient.
What percentage of the water from the glomerular filtrate is reabsorbed?
What else is reabsorbed?
99%
If drugs are particularly lipid soluble, then they will also be reabsorbed, passively diffusing across the tubule back into the blood
What factors will influence the extend of reabsorption?
1) Drug metabolism – phase 2 metabolites tend to be considerably more water soluble than the parent drug and are therefore less well reabsorbed
2) Urine pH – this can vary from 4.5-8. Based on the pH partition hypothesis mentioned above, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH
You are taking Drug A as an analgesic – it is a weak acid. The urine pH suddenly increases from 6.5 to 8. Will the drug effect be prolonged or reduced over the next few hours?
Explain
Reduced
Drug A is a weak acid. If the urine pH increases to 8, then Drug A will become more ionised in the alkaline environment. This will decrease the lipid solubility of Drug A. As a result, less of the drug will be reabsorbed in the kidney tubule, and more will be excreted. The drug effect will be reduced due to this more effective excretion.
What system is particularly useful at removing phase 2 glucuronide metabolites?
Biliary excretion
How do liver cells transport some drugs from plasma to bile?
Primarily via transporters similar to those in the kidney
What happens to drugs transported to the bile?
They are then excreted into the intestines and will be eliminated in the faeces
What is enterohepatic recycling?
Recycling of a drug via the hepatic system that can significantly prolong the effects of a drug
Explain the 5 steps of glucuronide recycling
1) A glucuronide metabolite is transported into the bile.
2) The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
3) Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
4) Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
5) The molecule returns to the liver where a proportion will be re-metabolised, but a proportion may escape into the systemic circulation to continue to have effects on the body.
What are the four parts determining the time course of drug action?
Absorption
Distribution
Metabolism
Excretion
