Fundamentals: Pharmacology - Introduction to pharmacology Flashcards
Define drug
Any substance that brings about a change in biological function through its chemical actions
Define agonist
A molecule that binds to a receptor and activates it in some way to bring about an action either directly or indirectly
Define antagonist
Molecule that binds to a receptor and inhibits it in some way
Define receptor
Site where ligand binds to effect a change or inhibit the usual action
What are chemical antagonists? Give an example
Drugs which interact directly with other drugs, e.g. protamine binding to heparin to inhibit its activity
Define xenobiotic
Chemical substance found within an organism that is not naturally produced or expected to be present within the organism
Define poison
Drug that has almost exclusively harmful effects
Define toxin
Poison of biologic origin (i.e. synthesised by plants or animals, in contrast to inorganic poisons like arsenic and lead)
What is the range for the molecular weights of most drugs and why?
100-1000 MW
Must be at least 100 MW to be sufficiently unique enough in size, charge etc to bind selectively to target receptors
If larger than 1000 MW it is difficult for the drugs to reach their target site unless directly administered into the compartment (e.g. alteplase)
What are the three major types of drug-receptor bonds, from strongest to weakest?
Covalent
Electrostatic
Hydrophobic
What drugs are generally more selective: those that bind through strong bonds, or weak bonds? Why?
Weak
Require a very precise fit of the drug to its receptor if an interaction is to occur
What kind of bond forms between aspirin and its target? What is the clinical relevance of this?
Acetyl group of acetylsalicylic acid (aspirin) forms a covalent bond with cyclooxygenase (enzyme target in platelets)
This bond is not readily broken, meaning the platelet aggregating-blocking effect of aspirin lasts long after free acetylsalicylic acid has left the bloodstream (about 15 mins) and is reversed only by synthesis of new enzyme in new platelets, a process taking several days
How many diastereomers does a drug have if it has two asymmetric centres? Give an example of one such drug
4
E.g. ephedrine
Why is it that one enantiomer is often more potent than the other?
Because it fits the receptor better (a “left-oriented” molecule is more effective at binding a left-hand receptor than its “right-oriented” enantiomer)
Describe the difference in action between the isomers of carvedilol, and how this relates to carvedilol’s chemical structure
Carvedilol has a single chiral centre and so has two enantiomers
Of these, the S(-) isomer is a potent β-receptor blocker, and the R(+) isomer is 100-fold weaker at the β-receptor
Both isomers are equipotent α-receptor blockers
Describe the difference in action between ketamine’s enantiomers
Ketamine’s (+) enantiomer is a more potent anaesthetic and less toxic than the (-) enantiomer - unfortunately the drug is still used as a racemic mixture
Why do different enantiomer’s often have a different duration of action?
Because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolising enzymes
Define partial agonist
An agent that activates but to a sub-maximal level: may act as an agonist or antagonist depending on the presence of a full agonist
Define allosteric modulator
Drugs that bind to the same receptor molecule but do not prevent binding of the agonist; may enhance (allosteric activators) or inhibit (allosteric inhibitors) the action of the agonist
Define inverse agonist
Drug that binds to the inactive state of receptor molecules and decreases constitutive activity
Define constitutive activity
Ligand-independent activity (i.e. basal activity in absence of agonist)
What is the difference between competitive and noncompetitive antagonists?
The action of competitive antagonists can be overcome by sufficient concentrations of agonist (reversible); noncompetitive antagonists bind to receptors in an irreversible or near-irreversible fashion, and their action cannot be overcome by increasing agonist concentration
What is a physiologic antagonist? Give an example
Drug that counters the effect of another drug by acting on different receptor within an endogenous regulatory pathway to cause opposing effects, e.g. glucocorticoids vs insulin on blood glucose levels
Define potency
Amount of effect for a given concentration or dose
What is EC50/ED50?
The concentration or dose of drug required to produce 50% of its maximal effectD
Define efficacy
Maximal effect that can be achieved by a drug
What is TD50?
The dose of drug required to produce a specified toxic effect in 50% of animals (i.e. median toxic dose)
What is LD50?
The dose of drug required to produce a lethal effect in 50% of animals (i.e. median lethal dose)
What is the difference between graded and quantal dose-effect curves?
Graded dose-response curves show degree of response in relation to drug dose; quantal dose-effect curves show the proportion of a population that receives the “either-or” effect of a drug in relation to its dose
What is ED50 in the context of a quantal dose-effect curve?
Median effective dose required to produce the effect in 50% of the population studied
Define therapeutic index
Dose of drug required for desired effect vs dose required for undesired effect (e.g. TD50:ED50)
Define therapeutic window
The range between the minimum toxic dose and minimum therapeutic dose
Define tachyphylaxis
“Rapid protection”: when responsiveness to a drug diminishes rapidly after its administration
Define drug tolerance
When responsiveness to a drug diminishes with its continual administration
Draw a dose-response curve
Show the effect of competitive and noncompetitive antagonists on a dose-response curve for a given agonist. What is the effect of a partial agonist?
Partial agonist has a similar effect to a noncompetitive antagonist
Explain the difference between efficacy and potency using dose-response curves
Outline the five different mechanisms of drug signaling, and give an example of a drug for each
- Intracellular receptor for lipid-soluble agents (e.g. steroids, thyroid hormone)
- Ligand-regulated transmembrane enzymes: including receptor tyrosine kinases (e.g. insulin)
- Cytokine receptors: bind a separate protein tyrosine kinase (e.g. GH, EPO, interferon)
- Ion channels (e.g. ACh, GABA, verapamil with voltage-gated Ca2+ channels)
- G proteins and second messengers (e.g. adrenoceptors, glucagon, thyrotropin)
Outline the function of G-protein coupled receptor
- Ligand binds receptor
- G protein is activated
- G protein activates effector (enzyme or ion channel)
- Effector changes concentration of intracellular second messenger (e.g. cAMP, Ca2+)
What role does ionisation and pH partitioning play in the ability of a drug to cross membranes?
The ionised form of a drug is less lipid permeable
The protonated form of an acidic drug is neutral and therefore more lipid permeable (crosses membrane easily): acids tend to be unprotonated in alkaline environments and so accumulate
The UNprotonated form of a basic drug is neutral and therefore more lipid permeable: bases tend to be protonated in acidic environments and so accumulate
Define pharmacokinetics
Action of the body on the drug
Absorption, Distribution, Metabolism, Elimination
Define volume of distribution
Apparent space in the body required to contain the drug if the drug is to be spread homogenously at the concentration found in blood (Cb), plasma (Cp), or water (unbound, Cu)
What is the formula for volume of distribution?
Vd = (amount of drug in the body / concentration)
What does it mean if a drug has a high Vd?
The drug is not homogenously distributed and has a higher extravascular concentration
Define clearance. How is total clearance calculated?
The body’s ability to eliminate a drug
Total clearance is the sum of the clearance in different organs, e.g. CL(total) = CL(kidney) + CL(liver) + CL(other)
What is the formula for clearance?
CL = (rate of elimination / concentration)
What is first order elimination?
Occurs when elimination is not saturable
Rate of elimination is proportional to concentration, and can be calculated by dividing concentration by AUC of the time-concentration profile
What is the difference between clearance and elimination rate?
Clearance: volume of blood cleared of drug per unit time (not proportional to dose in first order elimination)
Elimination rate: amount of drug cleared from the blood per unit time (proportional to dose in first order elimination)
Describe capacity-limited elimination
Clearance varies depending on drug concentration due to saturation of elimination pathways at higher does
Give three examples of drugs which undergo capacity-limited elimination
- EtOH
- Phenytoin
- Aspirin
How is rate of elimination calculated in capacity-limited elimination?
Rate of elimination = (Vmax x C) / (Km + C)
Where Vmax = maximum elimination capacity
Km = drug concentration at 50% of Vmax
Describe flow-limited elimination
Drugs which are cleared very rapidly by the organ of elimination, such that rate of elimination is mainly dependent on blood flow to that organ (+/- plasma protein binding and blood cell partitioning)
Give four examples of drugs which undergo flow-dependent elimination
- Morphine
- Propranolol
- Lidocaine
- Verapamil
What is zero-order elimination?
Rate of elimination is independent of drug concentration
Define half-life
Time required to halve the amount of drug in the body
What is the formula for half-life?
t1/2 = (0.7 x Vd) / CL
Where Vd = volume of distribution
CL = clearance
Define bioavailability. What factors affect oral bioavailability?
Fraction of unchanged drug reaching the systemic circulation following administration by any route
Affected by absorption and first pass metabolism for orally administered drugs
Define first pass elimination
Metabolism occurring before drug enters systemic circulation
Give two examples of sites of first pass elimination
- In gut wall via CYP3A4
- Hepatic (most common)
What effect can grapefruit have on gut absorption of some drugs?
May increase gut absorption by inhibiting P-glycoprotein (which ordinarily is associated with reverse transporter that pumps drug out of gut wall cells and back into gut lumen)
How is the effect of first pass elimination expressed? How is this calculated?
Extraction ratio
ER = CLliver / Q
Where Q = hepatic blood flow (~90L/hr)
What is the formula for systemic bioavailability of drug past first pass elimination?
F = f (1 - ER)
Where F = systemic bioavailability
f = extent of absorption
What is steady state?
Where dosing rate is equal to rate of elimination, so drug concentration is consistent
What is a maintenance dose? What is a loading dose?
Maintenance dose: dose given to maintain steady state
Loading dose: dose given to promptly raise plasma drug concentration to target concentration (e.g. in drugs with long t1/2)
What is the formula for dosing rate of a maintenance dose?
Dosing rate (steady state) = rate of elimination (steady state) = CL x TC
Where CL = clearance
TC = target concentration
What is the formula for dosing rate for oral drugs with <100% bioavailability?
Dosing rate (oral) = dosing rate (steady state) / F(oral)
What is the formula for maintenance vs loading doses?
Maintenance dose = dosing rate x dosing interval
Loading dose = Vd = TC
Loading dose (intermittent dosing) = maintenance dose x accumulation factor
Compare and contrast phase I and II reactions
Phase I (“synthetic”): usually converts parent drug to more polar metabolite by introducing or unmasking a functional group (via oxidation, reduction, hydrolysis or cyclisation)
Phase II (“synthetic”, conjugation): drug is combined with charged molecules (e.g. glucuronic/sulfuric/acetic/amino acids) to form highly polar conjugate, making the drug more water soluble and easier to excrete
Give an example of a drug in which phase II reaction precedes phase I
Isoniazid
P450 inducers
SCRAP GPS:
St John’s wort
Carbamazepine
Rifampicin
Alcohol (chronic)
Phenobarbitone (barbiturates)
Griseofulvin/glucocorticoids
Phenytoin/poiglitazone
Sulfonylureas
P450 inhibitors
SICKFACES.COM
Sulphonamides
Isoniazid (also induces one enzyme)
Ciprofloxacin
Ketoconazole
Fluconazole
Alcohol (binge)
Cimetidine
Erythromycin
Sodium valproate
Chloramphenicol
Omeprazole
Metronidazole
Grapefruit
What is the purpose of phase I drug trials? How are they conducted and what is the typical blinding?
Aims to determine the probable limits of safe clinical dosage range
Effects of drug as a function of dosage is established in a small number (20-100) of healthy volunteers
Normally non-blinded
What is the purpose of phase II drug trials? How are they conducted and what is the typical blinding?
“Proof of concept”
Drug is studied in patients with target disease to determine its efficacy and doses to be used in subsequent trials
Modest number of patients (100-200) studied in detail
Often single-blind
Which drug trial phase has the highest rate of failure?
Phase II (only 25% of drugs move on to phase III)
What is the purpose of phase III drug trials? How are they conducted and what is the typical blinding?
To further establish and confirm safety and efficacy
Drug evaluated in larger numbers (usually 1000s) of patients with target disease
Usually double-blind
What is the purpose of phase IV drug trials? How are they conducted?
To detect rare adverse events
After-market monitoring for safety under actual conditions of use in large numbers of patients
How is dose in solution calculated (i.e. as %)?
100% = 1g in 1mL
1% = 10mg in 1mL
0.5% = 5mg in 1mL
