Theme I: General principles of drug action Flashcards
What does pharmacodynamics mean. What does it help determine
- The effect of the drug on the body
- How it interacts with the target and where in the body.
- How it produces an action in the cell
- Helps determine the appropriate doses for patients
What does pharmacokinetics mean. What does it help determine
- What the body does to the drug
- How it is absorbed, distributed, metabolised and excreted.
- Helps determine the frequency / duration/ route of administration of drugs. To ensure the correct drug concentration in plasma
5 factors that affect the ability of drugs to bind to their targets (BP01)
- Shape
- Charge distribution: determines the type/ strength of bond that will be created
- Stereochemistry: how the 3D structures are orientated
- Hydrophobicity (how easily it gets through lipid bilayer)
- ionisation (pKa)
What are the 4 main chemical bonds and a brief description, in increasing strength
- Van der Waals forces: Shifting electron density resulting in fleeting + & - charges. These transient areas attract to molecules of opposite charge.
- Hydrogen bonds: Hydrogen bound to oxygen or nitrogen makes it more positively polarised, so are attracted to negatively polarised atoms like oxygen.
- Ionic bonds: Atoms with excess electrons (- ions) and atoms with deficient electrons (+) are attracted.
- Covalent bonds: Two bonding atoms sharing electrons.
What is an agonist
- A ligand that binds to a receptor to elicit a cellular response.
- Enhances the action of endogenous chemicals.
- 2 step process: creates an agonist-receptor complex then the receptor causes action within the cell.
What is an antagonist
- Blocks the action of endogenous chemical messengers or agonists.
- Similar structure to endogenous chemical but does not cause any biological response
What are the 3 different binding sites on a receptor
- Orthosteric/ active sites: the normal site where endogenous products bind
- Allosteric site: different site to where endogenous products bind (modulates enzymatic activity)
- Effector region: other regions of the receptor
What does efficacy & potency mean. What factors affect potency
- Efficacy is how how effective a drug is at activating a receptor. It refers to the maximum effect it can produce.(Full agonists have high efficacy)
- Potency is how much drug is needed to produce an effect. High potency means low concentration needed to elicit a response.
- Potency relies on affinity, efficacy, receptor density & efficiency of stimulus-response mechanisms.
What is equilibrium dissociation constant (Kd) of a drug. What does low Kd mean
- It shows the affinity between a given receptor & drug.
- used to compare affinity of different drugs on the same receptor.
- Dissociation is low when affinity & potency is high: tighter ligand-receptor interaction.
What is a full, partial & inverse agonist. Relate them to efficacy
- Full agonists can produce the maximum response in a system, while only occupying a small percentage of receptors. High efficacy.
- Partial agonists are unable to produce a maximum response even when occupying all receptors. Low efficacy.
- Inverse agonists have higher affinity for the inactive receptor-effector complex than the active. Form a complex and inhibit the effects, exerting opposing effects. (Similar effect to competitive antagonist)
What’s the meaning of spare receptors
- Not likely there will be linear relationship between receptor occupancy and effect, where Kd (dissociation) and EC50 are equal (ie. 50% occupation causing 50% effect)
- Many receptors amplify the signal duration & intensity. So a maximum response can occur even with a small fraction of receptors occupied. Receptors left over that are not bound to
What causes desensitisation of receptors (with regards to drugs)
- Continued and repeated administration of drugs can reduce its effects (tachyphylaxis)
- Due to conformational changes of receptors, depletion of mediators, altered drug mechanisms etc.
Explain the 3 classes of antagonist (chemical, physiological and pharmacological) Give examples
1- Chemical: deactivates an agonist by binding to it and the agonist can no longer act on a receptor. (protamine binds heparin)
2- Physiological: 2 agents with opposite effects cancel each other out. Have opposing effects (glucocorticoids and insulin)
-^These 2 are not receptor antagonists
3- Pharmacological: binds to a receptor and blocks the action of an agonist
How do competitive antagonists work, is it reversible and what the agonist-response curve looks like. Give an example of a drug
- Bind to the normal active site on a receptor, preventing agonist binding so blocking the response.
- It is reversible, by increasing concentration of agonist because it will be able to outcompete it.
- Causes parallel shift to the right, with same form
- Cimetidine on the H2 receptor. Atropine on muscarine receptor.
What the dose ratio tells us and the Schild plot.
- Dose ratio compares the ability of antagonists to inhibit agonists. It is the factor of how much we need to increase the agonist concentration when put in the presence of an antagonist
- EC50 of agonist + antagonist / EC50 of agonist
-Schild plot can be drawn to work out the concentration of competitive antagonist used to inhibit the agonist. It is when the linear line intersects the x axis. = the log Kb value
What are non-competitive active site antagonists, are they reversible and what does the curve looks like (EC50 and Emax)
- Bind to active sites of receptors with strong covalent bonds so difficult to dissociate even when increasing agonist concentration.
- irreversible
- Increased EC50 so more agonist is required, and Emax is reduced so will never get a maximum response.
- Need to wait for the receptor to regenerate for it to be reversible.
What is a allosteric site antagonist, and is it reversible or irreversible
- Non-competitive
- Bind to allosteric site which changes the shape of receptor, inhibiting the binding & action of agonists
- Can be irreversible or reversible
What is a therapeutic window/ index of a drug. Why is a large window ideal
- The range of which a drug causes therapeutic effect, before having a toxic effect.
- Larger window is safer in general
- Large window useful for treating diseases with varying severity and symptoms (eg. penicillin for pain) because different doses will be required, and you still want it causing an effect without being toxic.
What is a graded and quantal dose-response relationship
- Graded: Response of a particular individual and tissue to different drug concentrations.
- Quantal: Percentage response in a population, against dose of agonist or antagonist. Dose required to produce an absolute effect. Determined in each member of the population.
Mechanisms of a G protein coupled receptor
- Neurotransmitter or hormone binds to the membrane-bound receptor.
- This receptor changes shape and interacts with Gs protein (a single polypeptide chain consisting of alpha, beta and gamma subunits), which releases GDP and binds GTP.
- Then there is a secondary messenger system
- Alpha subunit of G protein dissociates and activates Adenyl cyclase, then forms cAMP, protein kinase A, activating calcium channels and then causes contraction.
- Depending on the G protein this pathway can also be inhibited.
eg. opioid, adrenoreceptors, muscarinic ACh
Mechanisms of ligand gated ion channels (give an example), and how this compares to voltage gated channels.
- Ligand-gated channels are linked to receptors, unlike voltage-gated
- Ligand-gated channel opens when ligand binds, changing the excitability of a cell, causes hyperpolarization/ depolarisation, and changes the likelihood of an action potential occurring.(eg. nicotinic acetylcholine receptor)
- Eg. hyperpolarisation used for anaesthetics
-Voltage-gates requires a change in electrical potential across a membrane to cause channels to open/ close.
Mechanism of enzyme (kinase) linked receptors
- Extracellular signal proteins (eg insulin) binds to extracellular domain.
- This domain is connected to an intracellular domain (eg. tyrosine kinase) and is activated.
- Tyrosine is autophosphorylated and then phosphorylates other proteins. Phosphate group is transferred between amino acids in different proteins.
- Activation of multiple signalling pathways. Causing the biological effect of insulin
Nuclear receptors mechanism. Give an example of a hormone that acts on this receptor
- Receptor present in cytosol or nucleus.
- Lipid soluble hormone must diffuse across the membrane to bind to it.
- Activated receptor moves to nucleus if not already.
- The drug-receptor complex binds to chromatin and unwinds it, initiating gene transcription. Switch genes on or off
- mRNA is then translated into specific proteins that result in a specific biological response.
- Takes a while for response to occur because drug needs to get through membrane
- Eg. steroid hormone (glucocorticoids)
Stages of pharmacokineteics (absorption etc.)
- Absorption: drug transferred from site of administration, crosses membranes and into plasma/ systemic circulation
- Distribution: once absorbed into blood it is distributed into tissues (usually passive diffusion of the uni-ionised form)
- Metabolism & excretion: once the drug has been established and reached equilibrium between tissue & plasma it is broken down (inactivated and made water soluble) and eliminated in urine or faeces
3 ways drug can cross lipid membrane and be absorbed
1-Passive diffusion: down concentration gradient through the lipid bilayer
2-Diffusion through aqueous channel: for aqueous drugs
3-Carrier-mediated active transport
Advantages and disadvantages of oral administration and the different absorption sites when administered this way
-Oral is easy, non-invasive, done at home. BUT can be unreliable if GI absorption isn’t effective due to vomitting or diarrhoea.
- Stomach absorption: not common site due to low pH changing ionising state of drug. Only some weak acids can work here.
- small intestines: weak acid & bases well absorbed. Large surface area, highly vascular and very permeable. Enterocytes of epithelium contain enzymes & transporters that metabolise drugs. However unreliable if patient is vomitting or has diarrhoea. The drug could bind to food so cannot be absorbed. The drug must cross several barriers. Potential first pass metabolism
- Sublingual: Rapid response as it utilises venous drainage from the mouth straight to the superior vena cava so avoids gut & hepatoportal circulation.
Factors that affect GI absorption
- very high or very low gastric motility and emptying causes low absorption (vomitting, diarrhoea)
- low gut pH makes strong acids and bases ineffective. Low pH means alkaline drugs are in ionised state so not lipid soluble so poorly absorbed.
- Drug can bind to food or bile which decreases absorption
- Particle size and formulation of drug affects absorption.
- Some drugs can either be slow releasing or fast acting.
What is drug bioavailability (F) What causes low F. What are the limitations involved in the data that F shows
- proportion of administered drug dose which enters the systemic circulation
- First-pass metabolism (eg. being metabolised in the intestine or liver before reaching the systemic circulation) causes drug to be lost, so F is lower.
- IV has F=1 because it enters straight into the blood plasma
- Doesn’t take into consideration rate of absorption, or variations in individuals’ enzyme activity, gut pH and intestine motility.
Meanings of unionised and ionised drug and how this affects drugs crossing membrane
- Drugs can be in an un-ionised/non-polar/neutral, or ionised state depending on the environmental pH
- Acid in acidic environment is neutral, acid in alkaline is ionised.
- Neutral substances are lipid soluble so can easily move across cell membranes and therefore have high absorption.
- Ionized substances have lipid solubility and low absorption
How pKa and pH can be used to work out ionisation and absorption of drugs. What if pKa is 2 and pH is 2
- pKa is a measure of strength of an an acid or base drug. It is the disassociation constant (ACID = ACID + H)
- pH minus the pKa gives level of ionisation. It tells you the amount of drug that is unionised and neutral.
- if a drug of pKa 2 is put in a solution with pH 2 then 50/50 ionised and neutral.
How the concentration of a drug in plasma against time differs between drugs taken orally or by IV. What Cmax and Tmax is on the curve
Cmax: maximum concentration of the drug in plasma after administration
Tmax: time at which Cmax is reached
- IV drugs enter straight into blood plasma so the concentration curve starts at Cmax and then slowly decreases over time. Tmax very low.
- Drug taken orally takes a while to reach Cmax while it is being absorbed, so longer Tmax
- Cmax will be smaller than for IV.
- Once the drug is established and achieves equilibrium between tissue and plasma (Cmax), the curve decreases as the body starts metabolising and excreting it.
