PHAR 2: Intro to Pharma - Pharmacokinetics Flashcards
What is pharmacokinetics?
- pharmacokinetics deals with what the body does to the drug
List some of the main pharmacokinetic factors
- absorption
- distribution
- metabolism
- excretion
Observe the learning outcomes of this session
Describe absorption with regard to pharmacokinetics
- With regard to pharmacokinetics, absorption can be defined as the passage of a drug from the site of administration into the plasma.
What is bioavailability?
What is other concept is it linked with?
- Bioavailability is defined as the fraction of the initial dose that reaches the systemic circulation
- it is linked with absorption
What does the site of administration influence?
- has a very big influence on the absorption and bioavailability of a drug
Give some examples of forms of drug administration
- A drug administered by the intra-venous route (where the entire dose is injected straight into the circulation) will have a bioavailability of 100%, by definition.
- Oral
- Inhalational
- Dermal (Percutaneous)
- Sub-lingual
In each case, the bioavailability is likely to be less than 100%.
What are the two ways drug molecules can move around the body from the initial site of administration?
- Bulk flow transfer
- i.e. in the bloodstream - Diffusional transfer
- i.e. molecule by molecule across short distances
Which methods of administration use bulk flow transfer and which use diffusional?
- With regard to the intravenous route, the drug is injected straight into the bloodstream, and therefore bulk flow transfer will then deliver the drug to its intended site of action.
- With all other routes of administration, in order for the drug to reach the bloodstream, it is first going to need to be transferred across at least one lipid membrane.
What are the four main mechanisms by which drugs can cross lipid membranes?
Describe them
- pinocytosis
- pinocytosis involves a small part of the cell membrane enveloping the drug molecule and forming a vesicle containing the drug
- the vesicle can then release the drug on the other side of the membrane
- whilst this is relevant for some molecules, it is not used in many instances
- e.g. insulin access to the brain
- diffusion through lipid
- diffusion through aqueous pores
- carrier proteins
What are the major mechanisms for drug transfer across lipid membranes?
- most drugs move across membranes either by:
- diffusion across lipid membranes or
- by carrier-mediated transport, which involves a transmembrane protein that binds drug molecules on one side of the membrane and then transfers them across to the other side of the membrane.
- Diffusion across aqueous pores; i.e., the gaps between epithelial/endothelial cells that make up the membrane, is not a major route for movement of drugs across membranes.
- Most pores are less than 0.5 nm in diameter, and since there are very few drugs this small, there is little movement of drugs across this aqueous route.
What is a huge determinant of drug action when drugs diffuse through lipid?
- lipid solubility
- For example, it can determine drug absorption from the gut or drug penetration into tissues or drug elimination in the kidneys
Describe some lipid membranes that need to be crossed before a drug can exert its action through these routes of administration:
- oral
- inhalational
- intra-nasal
- Oral:
a) small intestine microvilli
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect. - Inhalational:
a) alveoli/bronchi
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect. - Intra-nasal:
a) mucous membranes of nasal sinus
b) blood vessel wall to enter blood
c) blood vessel wall to access relevant tissue for effect.
Describe the lipid membranes passed during the oral route of drug adminstration
What is a very important factor to consider when thinking about the lipid solubility of drugs?
- most drugs are either weak acids or weak bases
- these drugs will exist as a combination of both ionised and unionised forms.
What are the pKa and acid/base properties of aspirin and morphine?
Observe their structures
- aspirin:
- a weak acid
- pKa 3.5)
- morphine:
- a weak base
- pKa 8.0
What would happen if aspirin and morphine were at physiological pH (7.4)?
- Aspirin would act as a weak acid and dissociated / donate protons (H+) into solution
- morphine would act as a weak base and accept protons (H+) from solution
What are some important points in terms of absorption when it comes to pKa of aspirin and morphine?
- The unionised (uncharged) forms of aspirin and morphine are going to be more lipid soluble than the ionised (charged) forms of the drugs;
- charged molecules are more polar and thus less lipid-soluble, and will find it difficult to cross membranes. - The pH of the cellular/tissue/fluid environment will be a huge determinant of absorption of drugs across lipid membranes.
- Weak acids will be mainly unionised in acidic environments (pH lower than their pKa) and weak bases will be more unionised in alkaline environments (pH higher that their pKa).
How would you represent weak bases in an equation?
How would you represent weak acids in an equation?
What does dissociation of the protonated form of the weak acid/base drug involve?
- dissociation of the protonated form of the drug involves the loss of the proton (H+).
What equation describes the relationship between the pKa, the pH, and the relative concentrations of the acidic and basic forms of the drug?
- the Henderson-Hasselbalch equation
Observe the maths recap on logs
Does the pKa of a drug change?
How does the body affect the drug?
- The pKa of a drug WILL NOT change.
- However, as the drug passes through the body, the pH of the different body compartments WILL change.
- Therefore the pH of the body compartment will have a significant impact on the realtive proporations of the ionised and unionised forms of a weakly acidic or weakly basic drug in that particular compartment.
- If the pH and pKa are the same, then the ionised:unionised ratio will equal 1.
- or 50% of the drug is ionised and 50% of the drug is unionised when the pH = pKa.
The table below shows three separate aqueous body compartments separated by lipid membranes.
Using the Henderson-Hasselbalch equation, calculate the ratio of the ionised and unionised forms of aspirin and morphine across the different body compartments
- 0.0001 means: for every 10,000 molecules of ionised drug (A-), there is 1 molecule of unionised drug (AH)
- 0.0003 means: for every 100,000 molecules of ionised drug (A-), there are 3 molecules of unionised drug (AH)
- 100,000 means: for every 100,000 molecules of ionised drug (NH+) there is 1 molecule of unionised drug (B)
Looking at this data, what can we observe about the ionisation of aspirin?
- Aspirin is largely unionised in the stomach:
- As a result, a significant proportion of the drug (the unionised form) should easily cross the lipid membranes of the stomach and thus gain access to other body compartments.
- Aspirin is largely ionised in the blood and urine:
- As a result, a very significant proportion of aspirin will struggle to diffuse across the lipid membranes of the blood vessels and kidney tubules and this will remain ‘trapped’ in these compartments.
What is the pH partition hypothesis?
- the proportion of drug in any body compartment is dependent on pH and results in the phenomenon of ‘ion trapping’.
- Acidic drugs tend to become ‘trapped’ in compartments with high pH and basic drugs tend to become ‘trapped’ in body compartments with low pH.
What are carrier transport systems?
What do carrier proteins bind to?
- Carrier transport systems are present to regulate the entrance and exit of physiologically important molecules across lipid membranes.
- The carrier protein binds to one of more molecule(s) and transports the molecule to the other side of the membrane.
- Drugs that resemble endogenous molecules may also interact with these carrier systems.
- As a result, it is possible for less lipid-soluble drugs to gain access to tissues via this route.
In terms of pharmacokinetics, the most important carrier systems relating to drug action are found in the?
What are they responsible 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 gastrointestinal 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 rather than systemic?
- You can deliver the drug directly to the intended site of action
- You can administer a high local concentration without worrying about systemic effects
Which drugs are administered systemically or locally?
Describe how regional blood flow means for drug distribution?
- With regard to regional blood flow, different tissues receive differing amounts of the cardiac output.
- At rest the following tissues would receive the following percentage of the cardiac output as seen in image
- As a result, more drug will be distributed to those tissues that receive most blood flow.
- It is important to remember that the distribution of blood to tissues can increase or decrease depending on the circumstances;
- e.g., during exercise more blood will be diverted to the muscles, whereas after a large meal more blood will be diverted to the stomach and intestines.
Describe the binding reaction of drugs with plasma protein binding sites
What are the different types of capillary structures found in the cardiovascular system?
Describe continuous capillary structures
- what drugs cross through?
- In the section on absorption, we mentioned that the major routes for drug absorption were diffusion across lipids or via carrier proteins.
- Most of the capillaries in the body have the ‘continuous’ structure illustrated here – 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 the capillary structure in the brain
Is it easy for drugs to access?
- 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 (BBB) 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 discontinuous capillary structures
- example tissue
- drug access
- 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 (bio)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.
Describe fenestrated capillary structures
- example tissue
- drug access
- 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 the 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 the excretion of these drugs.
What happens when some drugs have high oil/water partition coefficients?
- For example, some general anaesthetics can have an oil/water partition coefficient of 5000.
- As a result, the 2% that reaches the body fat will accumulate in this tissue very effectively.
- The drug that resides in the body fat will then 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)
Looking at this diagram, describe how morphine will accumulate in the adipose tissue at equilibrium?
- At equilibrium, morphine will partition equally between the blood and adipose tissue.
- At equilibrium, the anaesthetic will partition to a greater extent in the adipose tissue.
- As a result, more anaesthetic will accumulate in the adipose tissue
What are functionalisation reactions?
- Functionalisation reactions can be oxidations, reductions, or hydrolyses
- that lead to the introduction, interconversion, or unmasking, of functional groups.
Look at these examples and identified which is oxidised, reduced and hydrolysed?
Describe some of the main functionalisation reactions and their target functional groups
Note that in most cases, the metabolites of functionalisation reactions will have a very similar structure to the parent drug, and often produce pharmacologically active drug metabolites.
Describe conjugation reactions
- Functionalisation reactions usually produce metabolites with (additional) functional groups that can undergo subsequent conjugation.
- Note that a drug may already contain a functional group suitable for conjugation without any functionalisation occurring.
- The result of conjugative metabolism is the covalent attachment of an endogenous molecule, with the resulting metabolite typically less pharmacologically active (or completely inactive) and less lipid-soluble.
- This facilitates excretion in the urine or bile.
Describe the main types of conjugation reaction and their target functional groups
As you will see, most of these are named in a fairly memorable/sensible way. You will also note that most target nucleophilic functional groups (-OH, -NH2, etc.) but glutathione conjugation targets electrophiles.
Observe the main route of aspirin metabolism
What are the three major mechanisms for drug excretion via the kidney?
What affects the extent of which mechanism is chosen?
- glomerular filtration
- active tubular secretion or reabsorption
- passive diffusion across tubular epithelium
The extent that drugs are excreted by these three mechanisms differs enormously, and explains why excretion of different drugs can vary so much.
- This is also influenced by the rate and route(s) of metabolism
Describe the steps of enterohepatic recycling
- A glucuronide metabolite is transported into the bile.
- The metabolite is excreted into the small intestine, where it is hydrolysed by gut bacteria releasing the glucuronide conjugate.
- Loss of the glucuronide conjugate increases the lipid solubility of the molecule.
- Increased lipid solubility allows for greater reabsorption from small intestine back into the hepatic portal blood system for return to the liver.
- 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.
