Principle of Pharmacology Flashcards
What is pharmacology?
Pharmacology is the study of drug action
What is therapeutics?
Therapeutics is concerned with drug prescribing and the treatment of disease. As such, therapeutics is more focused on the ‘patient’.
What is pharmacodynamics?
harmacodynamics deals with ‘what the drug does to the body’
What is pharmacokinetics?
Pharmacokinetics deals with ‘what the body does to the drug’
What 3 questions must you ask to consider how a drug exerts its effects on the body?
Where is this effect produced?
What is the target for the drug?
What is the response that is produced after interaction with this target?
Where is the effect of Cocaine produced?
Dominergic neurons in Nucleus accumbens
What is the target for Cocaine?
Dopamine reuptake protein on the pre-synaptic terminal
What is the response produced after Cocaine binds to the target?
Cocaine will BLOCK the dopamine reuptake protein.
This means that dopamine is not removed from the synapse as quickly, and is thus more available to bind to the dopamine (D1) receptor.
Activation of this receptor is what causes euphoria.
What are the 4 classes of drug target?
Receptors
Enzymes
Ion channels
Transport proteins
What target does aspirin work on?
Enzyme
What target does local anaesthetic work on?
Ion channel
What target does prozac (anti-depressant) work on?
Transport protein
What target does nicotine work on?
Receptor
Why can incomplete specificity be an issue?
E.g dopamine, noradrenaline and serration have similar structures
So a drug that provides a therapeutic effect via a dopamine receptor might also interact wit serotonin and adrenergic receptors producing side effects
Why is dose important?
You want a dose high enough to produce the therapeutic effects
But not too high as to cause side effects
Give an example of a drug that causes side effects at a high dose?
Pergolide (specific at low doses)
Anti-parkinsonian via dopamine receptor
Hallucinations via serotonin receptor
Hypotension via adrenergic receptor
Why does the complex manner in which the body handles the drug cause issues?
difficult to accurately predict how much drug might arrive at your specific drug target
Give four examples of chemical reactions that drugs can interact with receptors via?
Electrostatic interactions
Hydrophobic interactions
Covalent bonds
Stereospecific interactions
What is the most common chemical reaction that drugs interact with receptors via?
Electrostatic interactions
Includes hydrogen bonds and Van Der Waals forces
Why are hydrophobic reactions important?
Lipid soluble drugs
What is the least common chemical reaction that drugs interact with receptors via?
Covalent bonds
The interactions tend to be irreversible
What are stereospecific interactions?
Great many drugs exist as stereoisomers and interact stereospecifically with receptors
What do agonists do?
Bind and activate receptors
What do antagonists do?
Bind and inactivate receptors
What are two key properties of agonists?
Affinity and Efficacy
What does the affinity of a drug determine?
Strength of binding to the drug receptor
Affinity is strongly linked to receptor occupancy
What is important to note about each individual drug receptor interaction? (affinity)
They are transient lasting only milliseconds
At any given moment a drug molecule might be bound to a receptor, or it may have unbound and may currently be free with the potential to bind another receptor
If two drugs are in a tissue the one with the higher affinity will be bound to more receptors
What does efficacy refer to?
Ability of an individual drug molecule to produce an effect once bound to a receptor
What is important to note about each individual drug receptor interaction? (efficacy)
It may produce a complete response, or no response, or some partial response
What are the three classes of drug interaction at the receptor level?
Based on differences in efficacy:
antagonists
partial agonists
full agonists
What does potency refer to?
Concentration or dose of a drug required to produce a defined effect
What is the standard measure of potency?
to determine the concentration or dose of a drug required to produce a 50% tissue response
What is the standard nomenclature for potency?
EC50 (Half maximal effective concentration or the ED50 (Half maximal effective dose)
What is the difference between EC50 and ED50?
The concentration of a drug that produced a 50% response would be the EC50
In trial when it is hard to determine a 50% response e.g. breathlessness
ED50 is the dose of drug that produced the desired effect in 50% or the individuals tested
How is potency related to dose?
The less drug you require to produce a particular effect, the more potent the drug is
How is efficacy related to dose?
It is not
What are the major pharmacokinetic factors?
Absorption
Distribution
Metabolism
Excretion
What is bioavailability?
the fraction of the initial dose that gains access to the systemic circulation
deals with the outcome of drug transfer into the systemic circulation (i.e. how much)
What does absorption deal with?
process for drug transfer into the systemic circulation
What is a huge determinant of absorption and bioavailability?
Site of administration
e.g IV administration the bioavailability is 100% as it is injected straight into the circulation
Name some common forms of drug administration
Oral
Inhalational
Dermal (Percutaneous)
Intra-nasal
What are the two ways drugs can move around the body?
Bulk flow transfer (i.e. in the bloodstream)
Diffusional transfer (i.e. molecule by molecule across short distances)
What are the 4 ways chemicals can diffuse across plasma membranes?
Simple diffusion
Diffusion across aqueous pores
Carrier mediated transport
Pinocytosis
What is pinocytosis?
small part of the cell membrane enveloping the chemical molecule and forming a vesicle containing the drug
Rarely used to transport drugs
Why is diffusion across aqueous pores not commonly used for drug movement across membranes?
ost pores are less than 0.5nm in diameter, and since there are very few drugs this small, there is little movement of drugs across this aqueous route
What are the 2 ways drugs commonly move across membranes?
diffusing across lipid membranes – drugs need to be suitably lipid soluble to do this
carrier mediated transport, which involves a transmembrane protein
Why is lipid solubility not an ‘all or nothing deal’?
Most drugs are either weak acids or weak bases. This means that these drugs will exist in two forms - ionised or unionised
Asprin is a a weak acid, what does this mean?
In it’s ionised state it will donate protons i.e. H+.
Morphine is a weak base , what does this mean?
In it’s ionised state it will accept protons i.e. B(Morphine)H+
Is the ionised or unionised form of the drug more lipid soluble?
unionised form of the drug retains more lipid solubility and is more likely to diffuse across plasma membranes
What two things influence whether the drug is ionised or not?
- the dissociation constant (pKa) for that drug
2. the pH in that particular part of the body
When will the drug be equally dissociated between the ionised and unionised?
If the pKa of the drug and the pH of the tissue are equal, then the drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised
Asprin has a pKa of 3.5, what does that mean?
For aspirin, when the pH is 3.5, it will be equally dissociated between the two forms.
For weak acids, as the pH decreases, the unionised form starts to dominate. As the pH increases, the ionised form starts to dominate.
Morphine has a pKa of 8, what does that mean?
when the pH is 8.0, it will be equally dissociated between the two forms.
For weak bases, as the pH decreases, the ionised form starts to dominate. As the pH increases, the unionised form starts to dominate.
Why can weak base drugs still be absorbed despite the pH of the stomach?
Once the drug eventually reaches the small intestine, it will be able to access a huge number of transport proteins that will enable absorption from the gastrointestinal tract
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
What are the carrier systems 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)
excretion of drugs from the body (excretion from the kidney of the gastro-intestinal tract)
What are the factors that affect drug distribution?
Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation
What percentage of the cardiac output do the major organs receive?
Liver – 27% Heart– 4% Brain – 14% Kidneys – 22% Muscles – 20%
What is important to note regarding regional blood flow and drug distribution?
Distribution of blood to tissues can increase or decrease 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 often happens to drugs when they enter systemic circulation?
Bind to plasma proteins
Up to 99% bound
Which plasma protein is particularly good at binding acidic drugs?
Albumin
What are the three factors the amount of drug bound to plasma proteins depends on?
The free drug concentration
The affinity for the protein binding sites
The plasma protein concentration
What is the protein binding reaction?
D (Free Drug) + P (Protein binding site) ↔ DP (Drug-protein binding site
Can bound drugs diffuse into tissues?
Only free drug is available to diffuse out of the blood and access tissues.
Any drug that is bound to plasma proteins CANNOT leave the blood until it dissociates from the protein.
What are the three types of capillary structure?
Continuous
Fenestrated
Discontinuous
What are the two types of junctions of capillary cells?
H2O filled gap junction
Tight junction
What capillary structure is there in the blood brain barrier?
Continuous
With the addition of tight junctions between endothelial cells
Makes the brain the most difficult tissue in the body for drugs to gain access to
What is discontinuous capillary structure?
Big gaps between capillary endothelial cells
What does discontinuous capillary structure allow for?
Allows for drugs to easily diffuse out of the bloodstream and access the liver tissue
Give an example of a tissues with 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 are circular windows within endothelial cells that allow for passage of small molecular weight substances including some drugs
Give an example of a tissues with fenestrated capillary structure?
glomerulus of the kidney
What does fenestrated capillary structure allow for in the kidneys?
This allows for some small drugs to pass from blood to kidney tubules which will enhance excretion of these drugs
What is the difference between fat and water soluble drugs entering the brain?
Relative position of that equilibrium.
The brain has the higher fat content whereas the blood has the higher water content
What will the equilibrium be like for a fat-soluble drug?
more heavily weighted towards retention in the brain
What will the equilibrium be like for a water-soluble drug?
more heavily weighted towards retention in the plasma
What does drug metabolism involve?
Conversion of drugs to metabolites that are as water soluble as possible and easier to excrete
What enzymes are mainly responsible for drug excretion and where are they found?
Cytochrome P450 enzymes
Liver
What are the two kinds of biochemical reaction involved in drug metabolism?
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.
What is the aim of phase one of drug metabolism?
introduce reactive polar groups into their substrates
What are the three reaction that can facilitate phase 1?
Oxidation
Reduction
Hydrolysis
What is the most common form of phase 1 metabolism?
Oxidation
What do all phase 1 oxidation reactions start with?
Hydroxylation step utilising the cytochrome P450 system
What does phase one often produce?
introduce reactive polar groups into their substrates
What are pro-drugs?
Drugs that will only produce an effect once it has been metabolized to the respective metabolite
Parent drug has no activity of its own
What happens in phase two?
attachment of a substituent group
almost always resulting in a metabolite that is inactive and far less lipid soluble
What does phase two facilitate?
Excretion in the urine or bile
What class of enzymes are phase 2 ones generally?
Transferases
What is first pass hepatic metabolism?
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
What is the issue with first pass hepatic metabolism?
he drug can be heavily metabolized and as a result, little active drug will reach the systemic circulation
What is the solution for first pass metabolism?
administer a larger dose of drug to ensure enough drug reaches the systemic circulation
What is the problem with increasing the dose to combat first pass hepatic metabolism?
the extent of first pass metabolism varies amongst individuals
the amount of drug reaching the systemic circulation also varies
drug effects and side effects are difficult to predict
What are the two most important ways drugs are excreted?
via the kidney (in urine)
via the liver (in bile).
What are the three major routes for drug excretion via the kidney?
- Glomerular filtration
- Active tubular secretion (or reabsorption)
- Passive diffusion across tubular epithelium
What are the main features of glomerular filtration?
allows drug molecules of molecular weight less than 20,000 to diffuse into the glomerular filtrate
smaller drugs have an additional route for excretion so it occurs quicker
What are the main features of active tubular secretion?
more drug is delivered to the proximal tubule than the glomerulus.
two active transport carrier systems
What are the two active transport carrier systems I he PCT?
One is very effective at transporting acidic drugs
One is very effective at transporting basic drugs
What are the main features of passive diffusion?
If drugs are particularly lipid soluble, then they will be reabsorbed, passively diffusing across the tubule back into the blood
What are the two factors that influence the extent of reabsorption?
Drug metabolism
Urine pH
Why does urine pH affects the extent of reabsorption in the kidney?
an vary from 4.5-8. Based on the pH partition hypothesis mentioned previously, acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH
What are the main features of Biliary excretion?
Liver cells transport some drugs from plasma to bile
Effective at removing phase 2 glucuronide metabolites
What is the path of excretion via biliary excretion?
Drugs transported to the bile are then excreted into the intestines and will be eliminated in the faeces.
Give an example 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.
