Principles Of Pharmacology Flashcards
What is the definition of pharmacology?
The study of how a drug interacts with living organisms and how this influences physiological function.
What is the difference between Pharmacology and Therapeutics?
Therapeutics is concerned with drug prescribing and the treatment of disease. Therefore, therapeutics is more focused on the ‘patient’. Pharmacology is more focused on the ‘drugs’.
What is the basic difference between pharmacodynamics and pharmacokinetics?
Pharmacodynamics deals with ‘what the drug does to the body’ and pharmacokinetics deals with ‘what the body does to the drug’.
What questions should you ask yourself when trying to consider how a drug exerts it’s 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?
For a drug to produce a measurable effect, what must it do?
It must ‘bind’ to a specific target in the body (Receptors, Enzymes, Ion channels, Transport proteins).
What makes a drug an effective therapeutic agent?
It shows a high degree of selectivity for a particular drug target.
Why is the dose of drug administered important?
Drugs are selective for a specific target but may also have some selectivity for other targets. The higher the dose, the more likely it is for unwanted side-effects as the drug may work on other targets.
What are four different ways drugs can interact with their target?
Electrostatic interactions - this is the most common mechanism and includes hydrogen bonds and Van der Waals forces.
Hydrophobic interactions - this is important for lipid soluble drugs.
Covalent bonds - these are the least common as the interactions tend to be irreversible.
Stereospecific interactions - a great many drugs exist as stereoisomers and interact stereospecifically with receptors.
What is the basic reaction between a drug and receptor?
Drug (e.g. Adrenaline) + Receptor ⇌ Drug-Receptor Complex
What happens to the equilibrium when you increase the concentration of the drug?
If you were to increase the concentration of the drug, then the
equilibrium is strongly shifted to the right - this is because there is
more drug available to bind to free receptors (vice versa for reduced concentration).
What is the strength of each drug-receptor complex determined by?
The strength of each drug-receptor complex is determined by the affinity of the drug. As a result, affinity is strongly linked to receptor occupancy.
What is efficacy?
Efficacy refers to the ability of an individual drug molecule to produce an effect once bound to a receptor.
Define an antagonist, partial agonist and full agonist in terms of efficacy.
Antagonist - has affinity for the receptor but no efficacy. When bound to the receptor, it is effectively ‘blocking’ that receptor and preventing an agonist from binding to the receptor and inducing activation.
Partial agonist - has affinity for the receptor and sub-maximal efficacy. When bound to the receptor, it can produce a partial response, but cannot induce the maximal response from that receptor.
Full agonist - has affinity for the receptor and maximal efficacy. When bound to the receptor, it can produce the maximal response expected from that receptor.
What is potency and how is the potency of a drug measured?
- Potency refers to the concentration or dose of a drug required to produce a defined effect.
- The standard measure of potency is used to determine the concentration or dose of a drug required to produce a 50% tissue response.
What is the standard nomenclature for the standard measure of potency?
The standard nomenclature for this measure is the EC50 (Half maximal effective concentration) or the ED50 (Half maximal effective dose).
What is the difference between EC50 and ED50?
EC50 - The concentration that produced a 50% response
ED50 - The dose of drug that produced the desired effect in 50% of the individuals tested
What is the difference between a highly potent drug and a highly efficacious drug?
- A highly potent drug produces a large response at relatively low concentrations.
- A highly efficacious drug can produce a maximal response and this effect is not particularly related to drug concentration.
Is efficacy related to dose?
No, but potency is
What is the clinical relevance of the difference between potency and efficacy?
Efficacy is more important as you want to know if the drug you are giving can induce a maximal response. If you had two drugs with equal efficacy, it’s doesn’t matter if one is more potent (you can give the less potent one at a higher conc.)
Name 4 pharmacokinetic factors that determine the amount of drug that reaches a tissue.
Absorption
Distribution
Metabolism
Excretion
Define absorption and bioavailability
Absorption can be defined as the passage of a drug from the site of administration into the plasma.
Bioavailability is the fraction of the initial dose that gains access to the systemic circulation.
What is an important determinant of absorption and bioavailability?
Site of administration
Name five examples of forms of drug administration
Oral
Inhalational
Dermal (Percutaneous)
Intra-nasal
Intra-venous (100% bioavailability as directly into bloodstream)
With most forms of drug administration, the bioavailability is likely to be less than 100%. Why?
Drugs can move around the body in two ways;
Bulk flow transfer (i.e. in the bloodstream) or diffusional transfer (i.e. molecule by molecule across short distances)
IV - drug is injected straight into the bloodstream - bulk flow transfer will deliver drug to its intended site of action.
Other routes of administration - before drug reaches the bloodstream, it is first going to need to diffuse across at least one lipid membrane.
How do most drugs move across membranes?
By diffusing across lipid membranes (need to be lipid soluble)
By carrier-mediated transport
Why are the majority of drugs water soluble, rather than lipid soluble?
A large proportion of drug molecules are given orally - need to be water soluble to dissolve in the aqueous environment of the GI tract to allow absorption
What two forms do most drugs exist in and why?
Most drugs are either weak acids (e.g. aspirin) or weak bases (e.g. morphine)
Exist in two forms - ionised or unionised
In which form does the drug retain more lipid solubility?
Unionised form
What does the form (ionised or unionised) of the drug depend on?
- The dissociation constant (pKa) for that drug
- The pH in that particular part of the body
What happens when the pKa of the drug and pH of the tissue are equal?r
The drug will be equally dissociated between the two forms i.e. 50% ionised and 50% unionised.
For weak acids what happens when the pH decreases?
Unionised form starts to dominate
For weak bases what happens when the pH decreases?
Ionised form starts to dominate
What mechanisms help combat ‘ion trapping’ (e.g. weak base trapped in the stomach in ionised form because of the low pH)?
Transport proteins (e.g. along the GI tract, tissues) allow movement of the drug into blood/tissue
Where are the most important carrier systems relating to drug action found?
Renal tubule
Biliary tract
Blood brain barrier
Gastrointestinal tract
What factors affect tissue distribution of a drug?
Regional blood flow
Plasma protein binding
Capillary permeability
Tissue localisation
How does regional blood flow affect drug tissue distribution?
Different tissues receive different amounts of cardiac output. More drug will be distributed to tissues that receive the most blood flow.
However, blood flow to tissues may increase/decrease depending on circumstance (e.g. more blood flow to muscles during exercise; more blood flow to stomach and intestines after a large meal).
What is the most important plasma protein for plasma protein binding?
Albumin
Is albumin particularly good at binding acidic or basic drugs?
Acidic
What does the amount of drug bound to plasma proteins depend on?
The free drug concentration
The affinity for the protein binding sites
The plasma protein concentration
What is the binding capacity of albumin?
1.2mmol/l
(concentration of albumin in the blood is approximately 0.6mmol/l; 2 binding sites)
What is the relevance of the binding capacity of albumin?
- Plasma concentration required for a clinical effect for nearly all drugs is considerably less than 1.2mmol/l
- Plasma proteins are NEVER saturated with drugs
- Differences in the extent of plasma protein binding for individual drugs is largely due to the particular affinity for the protein binding sites
Can drugs bound to plasma proteins leave the blood?
No, it must dissociate first. Only free drug is available to diffuse out of the blood.
What is an example of a tissue with a discontinuous capillary structure and how does this contribute to its function?
Liver - key metabolic tissue in the body - deals with metabolism of a huge variety of chemicals including the majority of drugs.
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 a tissue with a fenestrated capillary structure and how does this contribute to its function?
Glomerulus of the kidney - kidney is a key tissue involved in excretion of chemicals including a large number of drugs
Fenestrations allow for passage of small molecular weight substances including some drugs - small drugs can pass from blood to kidney tubules - enhances excretion of these drugs
Explain how tissue localisation can affect drug distribution with an example
- Consider two drugs - one water-soluble, one lipid-soluble
- Both diffuse into the brain down their concentration gradient until an equilibrium is reached between the brain and blood
- Difference between those two drugs is the relative position of that equilibrium
- Brain has the higher fat content whereas the blood has the higher water content
- Lipid-soluble - equilibrium heavily weighted towards retention in the brain
- Water soluble - equilibrium is going to be more heavily weighted towards retention in the plasma.
- Larger proportion of lipid-soluble drug is going to be ‘localised’ in the brain compared with the water soluble drug
What does the process of metabolism involve?
The conversion of drugs to metabolites that are as water soluble as possible and easier to excrete
What enzymes are mainly responsible for drug metabolism in the liver?
Cytochrome P450 enzymes
What two kinds of biochemical reaction does drug metabolism involve?
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.
Outline Phase 1 metabolism
Aim is to introduce reactive polar groups into their substrates
Reactions can occur by oxidation, reduction and hydrolysis
Most common reaction is oxidation
All oxidation reactions start with a hydroxylation step utilizing the cytochrome P450 system - aim is to incorporate oxygen into non-activated hydrocarbons
What is the end result of Phase 1 metabolism?
To produce metabolites with functional groups that serve as a point of attack for the conjugating systems of phase 2
Phase 1 metabolism often produces pharmacologically active drug metabolites. What is the relevance of this?
Sometimes the parent drug has no activity of its own, and will only produce an effect once it has been metabolized to the respective metabolite – these drugs are known as pro-drugs.
Metabolism is required for the pharmacological effect.
Do active metabolites always have positive effects?
No, active metabolites can have negative unintended effects. Liver damage as a result of paracetamol overdose, is due to a certain metabolite and NOT paracetamol itself.
Outline Phase 2 metabolism
Phase 1 adds the functional groups that are susceptible to conjugation in phase 2
Result of phase 2 metabolism is the attachment of a substituent group - the resulting metabolite is nearly always inactive and far less lipid soluble than the phase 1 metabolite - facilitates excretion in the urine or bile
What’s the difference between phase 1 and phase 2 enzymes?
Phase 1 enzymes are predominantly part of the cytochrome p450 family
Phase 2 enzymes are predominantly transferases - transfer the substituent group onto the phase 1 metabolite
What is first pass (pre-systemic) metabolism and why does it present an issue for orally administered drugs?
Orally administered drugs - predominantly absorbed from the small intestine - enter the hepatic portal blood supply where they will first pass through the liver before they reach the systemic circulation
Drug can be heavily metabolized in liver - little active drug will reach the systemic circulation (although first pass metabolism is a prerequisite for activity of prodrugs)
What is a solution to first pass metabolism?
Administer a larger dose of drug to ensure enough drug reaches the systemic circulation
What is the problem with administering a larger dose of drug to combat first pass metabolism?
The extent of first pass metabolism varies amongst individuals, and therefore the amount of drug reaching the systemic circulation also varies
Drug effects and side effects are difficult to predict
Name 4 drug routes for excretion and elimination
- Via the lungs (alcohol breath test)
- Breast milk (care needs to be taken - can affect the baby)
Most important routes of excretion: - via the kidney (in urine)
- via the liver (in bile)
What are the 3 major routes for drug excretion via the kidney?
- Glomerular filtration
- Active tubular secretion (or reabsorption)
- Passive diffusion across tubular epithelium
Extent to which drugs use processes is different - also impacted by the rate of metabolism
Outline glomerular filtration
Allows drug molecules of molecular weight less than 20,000 to diffuse into the glomerular filtrate
These drugs have an additional route for excretion (glomerular filtration) compared with larger drugs – this should result in a quicker rate of excretion
Outline active tubular secretion
- Most important method
- 20% of renal plasma filtered at the glomerulus, remaining 80% of the renal plasma passes through the blood supply to the proximal tubule
- More drug is delivered to the proximal tubule than the glomerulus
- Proximal tubule capillary endothelial cells contain two active transport carrier systems - one for acidic and one for basic drugs
Outline passive diffusion
Leads to reabsorption from the kidney tubule
If drugs are particularly lipid soluble, then they will be reabsorbed (along with water - 99% reabsorbed) passively diffusing across the tubule back into the blood
What factors affect passive diffusion?
- Drug metabolism – phase 2 metabolites tend to be considerably more water soluble than the parent drug and are therefore less well reabsorbed
- Urine pH – this can vary from 4.5-8. Acidic drugs will be better reabsorbed at lower pH and basic drugs will be better reabsorbed at higher pH - unionised forms - better lipid solubility
Outline biliary excretion
Liver cells transport some drugs from plasma to bile – primarily via transporters similar to those in the kidney
Particularly effective at removing phase 2 glucuronide metabolites
Drugs transported to the bile are then excreted into the intestines and will be eliminated in the faeces
Outline enterohepatic recycling
- Glucuronide metabolite is transported into the bile
- Metabolite is excreted into the small intestine - 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
- Molecule returns to the liver where a proportion will be re-metabolised - a proportion may escape into the systemic circulation to continue to have effects on the body
