Clin Pharm Flashcards
What is the difference between pharmacodynamics and pharmacokinetics
PD - the biological and physiological effects of the drugs, their modes of action and relationship with concentration
PK - study of characteristics of the time course and extent of drug exposure
What are the 5 main cellular receptors that drugs interact with?
- Ion channels
- Nuclear receptors
- Enzymes
- GPCRs
- Receptor kinases
What are the 3 main cellular consequences of receptor activation?
- Ion channel opening or closing
- Biochemical messengers activated and initiate signalling pathways
- A normal cellular function is physically inhibited
Define a drug antagonist
It binds to the receptor, produces no cellular effect but inhibits access of agonists and prevents their effects
Define a partial agonist
A drug which fails to produce a maximal response even when all the receptors are occupied
(this is compared to a full agonist, in some cases you don’t need all the receptors to be filled to have the maximal effect)
What are the 5 types of antagonism?
- Competitive antagonism
- Non-competetive antagonism (binds to a site other than the receptor domain to cause a conformational change)
- Irreversible antagonism
- Physiological anatagonims (the action of the two agonists cancels each other out)
- Antagonism by neutralisation (the drugs bind to eachother and become inactive)
Important because drugs are safer if they can be removed from the receptor (hence are reversible)
What is drug tolerance?
This is where you require more drug to have the same effect
This can occur due to desensitiation (which can link to receptor down/up regulation)
Define drug potency
The amount of drug required to produce 50% of its maximal effects
(in practice it is generally the amount of drug needed to have an effect)
Define:
- EC50
- LD50
- Therapeutic index
- Margin of safety
- Effective concentration - concentration of drug that induces a clinical effect in 50% of patients
- Lethal dose - concentration of drug that induces death in 50% of patients
- Therapeutic index - a measure of drug safety (LD/EC)
- Margin of safety is the margin between the therapeutic and lethal doses of a drug - the larger it is generally the safer the drug
What are the 3 main methods of metabolism/excretion of drugs by the body?
- Liver metabolism and then extretion in the biliary system
- Excretion (+/- metabolism) by the kidney
- Excretion by the lungs (exhalation is volatile)
But remember drugs can also accumulate in other compartments such as the ECF, ICF, CSF, bone and skin
(and in milk in lactating animals for some drugs)
What are the 5 mechanisms by which drugs can cross membranes
- Passive diffusion (rapid for lipophilic, non ionic and small molecules)
- Facilitated diffusion
- Aqueous channels for small hydrophilic drugs down a gradient (don’t exist in BBB)
- Active transport
- Pinocytosis for very large molecules
Why is the ionisation state of a drug important?
Because the body pH will influence it - basic drugs are ionised and retained in acidic fluids and ionised drugs cannot diffuse across membranes
What are ATP binding cassette transporters and where are they found
The are responsible for outwards transport of endogenous and exogenous compounds - found in the GI tract and CNS
They prevent the absorption of toxins, xenobiotics or other drugs
Define bioavailability and how can you calculate it
The proportion of the administered dose that reaches the central compartment (i.e. the circulation)
Plot of plasma concentration vs time and calculate area under curve - compared for normal administration (oral etc.) vs i.v
Generally the more complex the drug formulation the lower the bioavailability
Even of the same drug, liquid preparations tend to have more consistent bioavailability than solid
What are the main pros and cons of oral drug formulations
- Unionised drugs can cross the gut wall - depending on drug pH it will be absorbed at different GI sites (also influenced by GI surface area)
- Convenient, cheap and non need for sterility - and can even get the dose back if you act fast enough
- But can have massive variability due to physiology, feeding, disease etc.
- Have to consider feeding or starvation
- V/D can affect treatment
What are the main pros and cons of IM drugs
Pro - More consistent absorption that oral or s/c (although rate is dependent on local blood flow) - More rapid onset also - Sustained effects possible - Can be administered in unconscious, vomiting or fractious patients - Certainty of administration Cons - Pain - Muscle damage - Dose cannot be removed once given
Describe water and lipid soluble boluses and their pros and cons
Bolus injection
When water soluble the drug is already dissolved in water and so mixes with tissue fluid rapidly for absorption - rate will be dependent on local blood flow
Lipid soluble ones have to wait for the drug to dissolve in the tissue fluid first
Cons - risk of pain, muscle damage haematoma, abscessation, inadvertent iv
Why is inhalation used so commonly for anaesthetic drugs?
Because the lung has such a huge surface area for absorption directly into the bloodstream
Also avoids the first pass effect
However it does require very small drug particle size
What are the main influences on drug distribution
- Membrane permeability of a drug
- Plasma/tissue protein binding (inactivates the protein and they get caught in equilibrium)
- Blood flow
- Depot (fat) storage
Discuss drug binding to plasma proteins
- Acidic drugs bind to albumin whereas basic drugs bind to alpha glycoprotein
- ALso some binding to lipoprotein and potentially erythrocytes
- Once bound the drug is inactive but also cannot be metabolised or excreted
- Forms an equilibrium
- So not a good thing if the drug has high toxicity
- Degree of binding varies between drugs
- Remember if you use two drugs that bind to the same protein site, then competition will lead to higher free concentrations for both drugs
Discuss fat storage of drugs
Lipophylic drugs can accumulate in fat which leads to slow and gradual release and can increase half life of the drug
(e.g. thiopentone sedation)
How does inflammation affect drugs in the body
Inflammation increases membrane permeability and increases blood flow to tissues
Tissues also become acidic so alkaline drugs may not be taken up as easily (so become less effective)
How does the BBB prevent drug entry and what drugs can cross it?
Polar molecules do not pass through and there are ABC cassette pumps to remove drugs
Small, moderately lipophilic drugs that aren’t a strong ligand of efflux pumps can generally get through
Why are drugs metabolised?
To make them more polar and water soluble for excretion
In some cases the metabolites are the active form
Describe the two phases of drug metabolism
Phase 1 - drugs are oxidised/reduced to a more polar form (involves P450 enzymes)
Phase 2 - a polar group such as glutathione is conjugated t the drug to make it more water soluble - this stage is reduced in carnivores (e.g. cats and paracetamol)
What is the enterohepatic circulation
This begins with the biliary excretion of drugs, which is complicated by reabsorption of bile salts, fats, toxins and hence drugs, in the SI and LI - leads to drug recirculation without significant excretionn
(for example cardiac glycosides in dogs)
Give some specific examples of drugs metabolised differently/to note in different species
- Paracetamol in cats
- Propofol anaesthetic is not metabolised as effectively in cats
- Dogs have deficits in N-acetylated derivated such as sulphonamides - so are more susceptible to methaemaglobinaemia
Give 3 examples of conditions that can impact the first pass effect
- Diarrhoea
- Severe fasciola hepatica infection in sheep
- Severe brain damage - may affect control of circulation in the gut and liver
- Feline LUT disease - production of some renal metabolites like urea that can change the way that drugs are metabolised
What are the 4 main factors that affect renal excretion of drugs
- GFR - because drugs only pass through by diffusion (unless protein bound)
- Tubular secretion - as some drugs are actively secreted
- Tubular reabsorption (less likely as metabolites are ionic
- Altered urinary pH
What is total body clearance?
This is the plasma volume that is cleared per minute - linked to organ flow and function as well as intrinsic clearance
It is closely tied liver and kidney functions - and you need to decrease the dose if these organs are diseases:
- Kidney failure - 75% of normal dose
- Hepatic failure - 50% of normal dose
Describe the single compartment model
The drug is confined to a single compartment - e.g. delivered into a restricted to the plasma and then removed solely by glomerular filtration
This means removal of the drug from the body occurs as a proportional rate to the amount remaining at any one time (decline is exponential
What assumptions does the single compartment model rely on
- Drug in the blood is in rapid equilibrium with drug in the extravascular tissues
- Drug concentration is proprtional to the concentration of drug in the blood at all times
- Drug is mixed instantaneously in blood or plasma
- Drug elimination follows first order kinetics
What is first order kinetics in terms of drug excretion
This is here the drug is removed unchanged by renal filtration by a non-saturated process
(fits with the one compartment model or the second, linear phase of the two compartment model
Essentially as the plasma concentration falls the rate of excretion will also fall
What are zero order kinetics in terms of drug excretion
Here drug excretion rate is constant irrespective of concentration - these drugs are more difficult to use reliably or safely
(also become a problem if you reach saturation point - for example using several drugs at once)
What is the equation for clearance rate?
How is the graph of it important?
CL = rate of elimination/arterial plasma concentration
It is useful for calculating dose rates when continuous or repeat dosing is used
The area under the graph relates to dose and clearance - important for evaluating the availability of drugs when administered by routes other than iv
What is apparent volume of distribution?
It allows you to work out where in the body the drug is going (the volume can correspond to compartments)
What are the volume of distribution/volumes for:
- Total body water
- ECF
- ICF
- Circulating blood volume
- Plasma volume
- Total body water = 600-650ml/kg
- ECF = 200-250ml/kg
- ICF = 300-350ml/kg
- Circulating blood volume - 85-90ml/kg
- Plasma volume - 45-50ml/kg
WHat is a loading dose and how do you calculate it
It is used to get the drug to steady state (therapeutic) more rapidly, and is then followed by maintenance doses
Calculated:
D = V’d x BW x (required plasma conc)
What are the multicompartment models?
These allow for uptake of drug differently by different tissues and takes into account the different blood flows to these tissues
Tissues that share the same pharmacokinetic propertie become one compartment
Describe the two compartment model
The decline in drug conc has 2 components, with the distribution phase representing mixing between these compartments - once the different compartments are in equilibrium the elimination becomes a single, first order process
What factors affect neonatal pharmakokinetics particularly
(Wide species differences in terms of time - generally 10-12wks for dogs)
- See increased GI drug absorption
-Lower binding to plasma proteins
- A lower ratio of body fat:fluid
- Large ECF volume
- Increased permeability of BBB
- Slower biotransformation and elimination (longer half life)
Also need to consider liver and kidney function (take 7 weeks and 2-3 days respectively to reach adult function)
What are the 6 main types of drug interaction?
- Altered absorption
- Altered metabolism
- Plasma protein binding
- Altered excretion
- Receptor interactions
- Physiochemical
