Fundamental Principles of Pharmacology Flashcards
What is a drug?
A drug can be defined as; a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.
drugs that are used theraputically have how many names? what are they?
- chemical name –
e.g. (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid - common name – ibuprofen
- Proprietary (trade) names – e.g. “Nurofen”;
by what 2 things are drugs grouped
- Usually grouped according to therapeutic use e.g. analgesics, antihypertensives, antibiotics
- Or sometimes by mechanism of action e.g. cyclooxygenase inhibitor, beta- blocker
IE Ibuprofen is a cyclooxygenase inhibitor that acts as an analgesic
what kind of molecules are drugs?
Drugs are exogenous molecules that mimic or block the actions of endogenous molecules
what are 4 target proteins for drugs
- Receptors for neurotransmitters or hormones
- Enzymes
- Ion channels
- Carrier or transporter molecules
What are ligands?
The small drug molecules that bind to large target proteins are called “ligands”
What do modern computer modelling techniques allow for?
Modern computer modelling techniques allow drugs to be designed in silico.
how well a drug fits into its binding site is governed by 2 things, what are they?
the size and flexibility of the drug (steric factors)
how well a drug bind to its target protein is determined by what?
the nature of the chemical bonds that form between the molecule and binding site
what type of bonds do most drugs form with their target proteins?
(reversible)
hydrophobic & hydrogen bonds plus weaker van der Waals interaction
what type of bonds do most drugs form with their target proteins?
(irreversible)
covalent interactions
this leads to the formation of a ligand-protein complex which will alter the activity of the protein in some way
what are the two “S’s” essential in therapeutic drug use?
selectivity and specificity
what is one way we can achieve selectivity in drugs?
design drugs that bind with a high degree of specificity to their target protein.
Ideally they will bind ONLY to their target protein and no others
What is pharmacodynamics?
= what the drug does to the body
drugs actions at a molecular level on physiology of an organism
What is pharmacokinetics?
= what the body does to the drug
how its handles, how does it get to site of action, how. is it metabolised
What are PK/PD studies?
When drugs are being developed for therapeutic use, a true understanding of the drug’s effectiveness only comes when pharmacodynamics and pharmacokinetics are considered together, so-called PK/PD studies
What are the 4 critical elements of pharmacokinetics?
ADME;
- Absorption
- Distribution
- Metabolism
- Excretion
how long does the preclinical stage last?
5-10 years
only one or two drug candidates taken forward to human clinical trials
how long does a patent for a new drug last?
20 years
after which time anyone can copy the drug
what is Phase I of clinical trials known as?
Exploratory; first in human.
how is the chronic toxicity of the drug assessed in Phase I of clinical trials?
Chronic toxicity of the drug will have been assessed in at least 2 mammalian species (1 non rodent)
how long does phase I of the clinical trial last and what is its purpose?
6 months to a year
- SAFETY (check for side effects)
- TOLERABILITY (unpleasant symptoms e.g. headaches, nausea)
what do we look for in phase II of clinical trials?
Efficacy, proof of concept and safety
what is the primary purpose of Phase II of clinical trials?
to determine how clinically effective the drug is in patients
to confirm safety and tolerability
Describe Phase IIa of clinical trials.
-
Exploratory
- 50-200 patients; lasts approximately 1 year
- Dose and treatment regimen based on Phase 1 results
- Usually placebo-controlled, randomised, double-blind
describe phase 11b
Phase IIb
- Confirmatory
- 200-500 patients; lasts approximately 2 years
- Safety and efficacy compared to placebo or current treatment in randomised, double-blind design
what happens during phase III of clinical trials?
- Full scale evaluation of how EFFECTIVE and SAFE the treatment is compared to current standard treatment (or placebo)
how many patients is the drug tested in during phase III?
2000-10 000
how long does phase III last?
several years
what is the ultimate purpose of phase III of clinical trials?
Provides data to support registration;
once completed can apply for registration for use in specified condition
what is the point of phase IV of clinical trials?
post-market surveilance, monitors consequences of increasing exposure in tens of thousands of patients
Also yield information on the drug’s efficacy in sub-groups of the population (elderly, young)
ongoing
the relationship between drug concentration (or dose) and the response produced by the drug. is called what?
concentration-response curves.
what concentration-response curve do you get when looking at ‘drug concentration’
rectangular hyperbola
what concentration-response curve do you get when looking at ‘log drug concentration’
symmetrical sigmoid
What is the Emax of the log concentration-response curve?
Emax is the maximum effect (response) that a drug can produce e.g. an increase in heart rate of 70 beats per minute
Where is the EC50 on the log concentration-response curve?
The EC50 is the concentration of a drug that produces 50% of the maximum response
what does the EC50 indicate?
indicates the position of the curve on the concentration axis, used to quantify the potency of a drug
What is a receptor
Receptors are protein macromolecules usually inserted across the lipid bilayer of the cell
what are 2 main functions of a receptor
- Recognition or detection of extracellular molecules
- Transduction; having detected the presence of an extracellular molecule they then bring about changes in cell activity
Describe the binding of a drug to a receptor (and what it looks like graphically when receptors occupied (p) vs drug concentration [D]).
D+R ⇌ DR
Binding is reversible (in most cases
Describe the binding of a drug to a receptor (and what it looks like graphically when p vs log[D]).
D + R ⇌ DR
What is KD in terms of affinity?
The affinity of a drug for its receptor is quantified as “the MOLAR concentration of drug required to occupy 50% of the receptors at equilibrium”
what does the symbol KD stand for?
This concentration of drug is given the symbol KD
whats the relationship of KD and a drugs affinity?
Drugs with HIGH affinity have a LOW KD
What is KD in terms of equilibrium?
KD is the equilibrium dissociation constant
- k+1 and k-1 are rate constants that tell us something about the likelihood of the forward and backward reactions occurring
- Rate of FORWARD reaction = k+1[D][R]
- Rate of BACKWARD reaction = k-1[DR]
- At equilibrium, backward rate = forward rate, so k-1[DR] = k+1[D][R]
KD = k-1/ k+1 = [D][R]/ [DR]
What is KD a measure of?
The KD is a measure of how tightly the receptor holds on to the drug once they come together
What do agonists do which differs to other drugs?
- Many drugs bind to the receptor (i.e. have affinity), occupy it, and do little else
- AGONISTS however bind and then activate the receptor i.e. the agonist has efficacy
- After binding, agonists produce a change in the shape of the receptor - a conformational change - that will ultimately lead to a response in a cell or tissue
- Activation of receptor (R) by an agonist (A) produces a biological response
What are agonists?
- So agonists bind to the receptor (have affinity) and activate it (have efficacy)
- All naturally occurring neurotransmitters and hormones are agonists e.g. adrenaline, acetylcholine, insulin, dopamine + many more
- Agonists can be either partial agonists or full agonists
whats the efficacy of full agonists and how effective it is at producing a biological response
Full agonists have high efficacy and as a result are very effective at activating receptors and producing a biological response
whats the efficacy of partial agonists and how effective it is at producing a biological response
Partial agonists have low efficacy and are therefore less effective at activating receptors and less able to produce a biological response
what kind of response do full agonists make
Full agonists often produce maximal response whilst activating only a fraction of the available receptors (p) i.e. there are lots of spare receptors
what kind of response do partial agonists make
Partial agonists often fail to produce a full response despite occupying all the available receptors
Why as an agonist is EC50 = KD not possible?
the overall response to an agonist is determined by both its affinity and its efficacy; receptor occupancy is determined only on affinity
What are antagonists?
They act to inhibit the effects of a neurotransmitter or another drug
What is the most common type of drugs used?
- Reversible competitive antagonists
e.g. pancuronium, cetirizine, propranolol
What effect do reversible competitive antagonists produce on a log concentration vs response curve?
Reversible competitive antagonists produce a parallel shift to the right of the AGONIST log concentration vs response curve.
The extent of the shift in the position of the agonist curve produced by the antagonist can be measured using what
the “dose-ratio” i.e. the ratio of the concentration of agonist producing the same response in the presence and absence of the antagonist
What is the ‘extent of the shift’ a measure of?
The ‘extent of the shift’ is a measure of the affinity of the ANTAGONIST for the receptor
what is the affinity of an antagonist quantified by
pA2
what does a bigger pA2 mean?
bigger the pA2, higher the affinity of the antagonist for the receptor
how can you overcome the inhibitory effects of an antagonist?
increasing the concentration of the AGONIST
