Principles of Pharmacology 1 Flashcards
In simple terms, what is meant by pharmacodynamics?
What a drug does to the body
In simple terms, what is meant by pharmacokinetics?
What the body does to a drug
What 3 questions do we ask when analysing the pharmacodynamics of a drug?
Where is the effect produced?
What is the target for the drug?
What is the response that is produced after interaction with this target?
Where is the euphoric effect of cocaine produced?
Dopaminergic neurons in the nucleus accumbens in the brain
What is the target site of cocaine?
The dopamine reuptake protein on the pre-synaptic terminal
What is the effect of cocaine after it interacts with its target site?
It blocks the reuptake protein so dopamine remains in the synapse for longer
What are the 4 target sites for drugs? Give an example drug for each
Receptors (eg nicotine)
Transport protein (prozac)
Enzyme (asprin)
Ion channel (anaesthesia)
What is selectivity?
How closely a drug binds to its target site
How is dose related to selectivity?
Drugs can bind to multiple targets but usually have higher selectivity for one target over others. Increasing dosage can cause it to bind to other unwanted targets and produce side effects
What are the 4 types of drug- receptor interactions?
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 an angonist?
Something that binds to a receptor and activates/opens the function
What is an antagonist?
Something that binds to a receptor and blocks the channel/function of it
What does affinity mean?
The strength of a drug receptor interaction
What does efficacy mean?
The ability of an individual drug molecule to produce an effect once bound to a receptor
Describe levels of affinity and efficacy in full agonists
They have high affinity and efficacy
What is potency?
The concentration or dose of a drug required to produce a defined effect
How is potency measured?
ED50- estimated half maximal dose
EC50- estimated half concentration
Out of potency and efficacy which is related to dose?
Potency
In pharmacokinetics, what does absorption mean?
The passage of a drug from administration to entering the blood plasma
What is bioavailability?
The fraction of the initial dose that gains access to the systemic circulation
What method of drug administration results in 100% bioavailability?
Intravenous injection
What are the 2 ways by which drugs travel around the body?
Bulk flow- in the bloodstream
Diffusional transfer- diffusion of individual molecules across a lipid membrane
What are the 4 mechanisms by which drugs can diffuse across plasma membranes?
Simple diffusion
Diffusion through an aqueous pore
Carrier mediated diffusion
Diffusion down an electrochemical gradient
Are drugs usually more water or lipid soluble?
Water
Describe how lipid solubility works with drugs? Are they more lipid soluble when ionised or unionised?
It is not an all or nothing concept
Drugs are either weak acids (donate H+) or weak bases (accept H+), they are more lipid soluble when they are unionised
What 2 factors determine if the drug is ionised or unionised?
The pKa
The pH in the part of the body
Describe ionisation/unionisation of a drug when the pKa and pH change
When the pKa of the drug and pH are equal the drug is 50% ionised and 50% unionised
If a drug is a weak acid, as the pH rises the ionised form will dominate
If a drug is a weak base, as the pH drops the ionised form will dominate
Where are most drugs absorbed and why not in the stomach?
Weak bases will be ionised in the stomach and so will be difficult to absorb, weak acids may be absorbed but will become ionised at the physiological pH
Most drugs are therefore absorbed by the transport proteins in the renal tubule, biliary tract, GI tract, blood brain barrier
What are the 4 factors that effect drug distribution?
Regional blood flow
Plasma protein binding
Tissue localisation
Capillary permeability
How will regional blood flow affect drug distribution?
Certain tissues eg the liver and the brain receive more blood than others so will receive a higher proportion of the total drugs in the bloodstream
How will capillary permeability affect drug distribution?
Some capillaries eg at the blood brain barrier are continuous and have no gap junctions, making it more difficult for drugs t o diffuse across as they transport proteins
How will plasma protein binding affect drug distribution?
Some drugs circulate bound to plasma proteins which will affect their distribution depending on:
Conc of plasma protein in blood
Affinity of drug to bind to plasma protein
Free drug conc
How will tissue localisation affect drug distribution?
If a certain drug has an equilibrium that favors a fat high environment (eg because its highly fat soluble) compared to an aqueous environment it will be localised to fat high tissues eg the brain
What is the main way drugs are manipulated so they can be metabolised?
The aim is to make them less lipid soluble so they remain in the blood and can be carried to the site of excretion
What is the first step in drug metabolisation?
Introduce a reactive (polar) group to the drug via oxidation, reduction or thiolysis
What enzyme is commonly used in step 1 of drug metabolisation?
Cytochrome P450 (for oxidation)
What is a pro drug?
A drug thats inactive until its metabolised
What is the second step in drug metabolisation?
Add a conjugate to the reactive group that makes the drug less lipid soluble
What is first pass (presystemic) metabolisation?
A lot of drugs are absorbed in the GI tract and and enter hepatic circulation so are metabolised before they even enter systemic circulation
How is first pass (presystemic) metabolisation solved? How does this lead to side effects?
Give higher doses of drug so some make it past the liver without being metabolised and enter systemic circulation. Different concs will make it into systemic circulation for different people when dose is increased, leading to different levels of side effects
What are the areas of drug excretion? Which 2 are the main ones?
Mainly in the kidney (in urine) and via liver (in bile)
Also can be via breast milk or via lungs
What are the routes for drug excretion in the kidney? Describe them
Glomerular filtration- 20% of plasma is filtered into the glomerulus
Secretion into the PCT- 80% of the remaining plasma, there are transporters for weakly acidic and basic drugs that can move them opposite to the gradient
Reabsorbtion in the DCT- lipid soluble drugs can be reabsorbed into the bloodstream here
How is reabsorption in the DCT affected?
Has the drug been past the second stage of metabolisation?- it will be a lot less lipid soluble if so so more likely to be excreted that reabsorbed
Urine pH- if urine pH is more basic then a weakly acidic drug will be less likely to be reabsorbed and will be excreted
How does biliary excretion work?
Drugs are removed from the plasma into the bile in the liver
What is enterohepatic recycling?
A glucuronide metabolite is transported into bile
Its excreted into the small intestine
The enzymes hydrolyse it and remove the glucuronide conjugate
The drug is a lot more lipid soluble
It returns to the liver and re-enters systemic circulation The drug ends up having a really prolonged effect
