Lecture 3 - The challenges of drug discovery and development Flashcards
what is a drug target?
Drugs are administered to achieve a biological response that alleviates the symptoms or cause of an illness
A biological process is responsible for producing the symptoms or causing the illness
At the molecular level, a drug target is usually a biomacromolecule (receptor, enzyme, ion channel) involved in the biological process
The drug molecule interacts with the molecular target and produces a response that is clinically beneficial
The drug target is not in a test-tube – it is buried somewhere in a physiological system i.e. in a patient
The response is not necessarily immediate (clinically), and may require a prolonged exposure of the target with the drug, by repeated dosing
What properties do we need out drugs to have?
Selective for the target to avoid adverse effects
High affinity for the target (potency)
Good bioavailability :
- Water solubility to allow for oral formulation
Water solubility for intravenous injection
- Lipophilicity to allow absorption from the gastro-intestinal tract
- Lipophilicity for depot injections
- Stability within the gastro-intestinal environment and low first pass
Slow metabolism to allow for sustained activity and reduced dosing frequency
No toxic metabolites
Bodily distribution to facilitate access to the target and reduce elimination rate
describe the parhmacodyanmci and pharmacokinetic properties of drugs
Drug molecules must have functional groups that permit engagement with and fit into the target protein (‘key in lock’ analogy) at the molecular level in order to generate a pharmacodynamic output
[enzyme inhibition; receptor antagonism/agonism]
Drug molecules must have functional groups that produce the right pharmacokinetic profile to enable access to the target for sustained period of time
[ADME]
what do we need our drug to be like after administration?
After oral administration, for drug molecules to be absorbed through the membranes of the epithelial cells that line the small intestine, they must:
Diffuse through lipid membranes – i.e they must be lipophilic
Be single molecular entities – i.e they must be individual molecules and not aggregates
why do we administer drugs as a water-soluble form?
When the tablet disintegrates to release the drug aggregates, the salt will dissolve more rapidly in a smaller volume
More soluble forms will dissolve more rapidly and get the drug to the absorbing surface faster and in higher concentrations
how do drug meolules diffuse through the lipid membranes?
water soluble form - charged and hydrophilic is in equilibrium with the lipid soluble form which is uncharged and lipophilic.
the pKa of the drug and the pH of the solution it is dissolved in determines whether the drug can be converted in its lipophilic form.
how can Log D predict oral absorption ?
if Log d is positive then the drug is lipophilic. the drug will favour distribution into the ‘oil’ layer, and will therefore be absorbed
if log D is negative then the drug is hydrophilic. the drug will favour distribution into the ‘water’ layer, and will not be absorbed
what are physiological factors affecting oral administration and absorption?
Secretion of bile salts
hepatic portal vein
1st pass metabolism
induced metabolism
reduced efficiency
secretion of enxymes
secretion of bicarbonates
low blood supply
low surface area
pH 1-3
enzyme degradation
acid degradation
mucous complexation
variable volume
variable residence tiem
high blood supply
high surface area
pH 7-8
enzyme degradation
mucosa complexation
what are factors to consider when selecting an appropriate formulation ?
Drug physicochemical attributes
Route
Dose
Rate of delivery
what is the onset of action of different routes of foruamltiosn ?
IV 30 – 60 seconds
Sublingual 3 – 5 min
IM 10 to 20 min
Rectal 5 to 30 min
Oral 0.5-3 h (and extended)
what are dosage form options dictated by route ?
Topical/skin - Cream, ointment, lotion, spay, aerosol
Eyes, ears and nose - Drops, sprays
Pulmonary - Metered dose inhalers, dry-powder inhalers
Parenteral - Solutions, sometimes emulsions, suspensions, liposomes.
Oral route - Solid dosage forms (tablets, capsules, range of release rates) liquids
Distribution – what are the effects on metabolism and excretion?
If the drug is retained in the plasma because it is water soluble, it can reach the organs of elimination (kidney, liver) more quickly – shortens the duration of action
However, if the drug in the plasma is highly bound to plasma proteins, it cannot be filtered and removed by the kidney as effectively – can extend the duration of action
If the drug is widely distributed throughout the tissues, it takes longer to reach the organs of elimination because it has been sequestered from the circulation, which can extend its half-life
However, if the drug is retained in the tissues, less of it can reach its target, which can reduce the clinical response
But remember, the process is dynamic and by maintaining an equilibrium, the drug will eventually be cleared
how is drug eliminated ?
Drug Metabolism
Biotransformation of a drug into a form that is readily excreted by modification of its molecular properties
(to a more water-soluble species)
Drug Excretion
Removal of modified species from the body, primarily via the kidney for water soluble species
summarise Phase I and pHase II
Products are generally more water soluble
These reactions products are ready for excretion
There are many complementary, sequential and competing pathways
Phase I and Phase II metabolism are a coupled interactive system interfacing with endogenous metabolic pathways
