Naisbitt Flashcards
How do developments in medchem impact drug discovery?
With greater knowledge, drugs can be developed to have higher affinities and hence be more selective - therefore a lower dose can be given with less adverse effects
What’s significant about sulphonamides?
1st synthetic antibacterial agents
Effective against a wide range of infections - bar Salmonella
Highly toxic in some patients
What is the MOA of sulphonamides?
They inhibit Dihydropteroate synthase - blocking para-aminobenzoic acid - which is responsible for synthesising folic acid.
Folic acid is critical for replication of bacteria - ONLY PATHWAY
Humans can get it through diet
What’s an issue with using sulphonamides clinically?
They can form toxic metabolites - resulting in allergic reactions and haematoxicity in some patients.
The hydroxylamine metabolites responsible bind to endogenous proteins - the protein is then attacked by immune system
What is the function of noradrenaline wrt asthma?
NA binds to the ß2 receptors and increases bronchodilation
However, NA is not selective, binding to ß1 adrenoreceptors - increasing heart rate.
NA also interacts with alpha receptors in blood vessels
What’s the difference in structure between noradrenaline and salbutamol?
Salbutamol has a t-But group stuck on the terminal amine
Also has extra carbon on upper OH group of catechol group
What does enteral and parenteral routes of administration describe?
Enteral = GI tract - sublingual, oral & rectal
Parenteral = non- GI tract - injections and inhalers
What factors must be considered when deciding the route of administration of drug?
Extent of transport across membranes - adsorption
Transit to site of action - distribution
Compliance - age, physical/mental ability
What is the definition of bioavailability?
The proportion of drug that passes into the systemic circulation following the first-pass metabolism
What is meant by first pass metabolism?
It is the metabolism of a drug after administration but before reaching the systemic circulation
What can be done if therapeutic failure is observed in a patient?
Increase dosage, increase doses per day, alter site of administration, change formulation
What factors affect the distribution of a drug?
Bulk flow in blood
Diffusion rate
Partitioning - into fat deposits
Binding to plasma proteins - no pharma effect, non-covalent forces
What’s the benefit of the small intestine with oral administration?
V. Large surface area ~ 200m^2
High blood flow ~ 1L/min
- maintains diffusion gradient
What does good absorption require a drug to be?
Drug must be water soluble
-so molecules in solution can be absorbed
And lipid soluble
-to pass through cell membranes
Rank the types of formulations in order of best—> worst
Solution
Emulsion
Suspension
Capsule
Tablet
What protein is bound to by acidic drugs?
Albumin
What protein is bound to by basic drugs?
Beta globin
Acid glycoprotein
What’s the issue with drugs binding to plasma proteins or partitioning into fat?
These drugs have no pharmacological effect
Toxic build up could also occur in fat deposits - low blood supply so drugs become trapped
Most drugs are weak acids and bases and so are often in ionised and unionised forms. Can ionised drugs cross cell membranes?
NO, only unionised molecules can cross cell membranes
The degree of ionisation - pH - determines the extent of transfer across cell membranes
What is the Henderson-Hasselbach equation?
pH = pKa + log [A-]/[HA]
What does a large [A-]/[HA] mean in the Henderson-Hasselbach equation?
A large value for [A-]/[HA] means that there are many ionised molecules for 1 unionised one.
A [A-]/[HA] of 0.01 means there are 100 unionised molecules for every ionised one
What’s the point of metabolising drugs?
Since most drugs are lipophilic they cannot be excreted efficiently
Such drugs must be metabolised to more polar products to aid excretion
Where is the main site of metabolism in the body? What’s the significance of pro-drugs?
In liver cells - usually abolishes a drugs pharmacological action
Pro-drugs are metabolised in the body to BECOME pharmacologically active.
What does cytochrome p450 require?
NADPH
Where does Phase 1 CYP450 metabolism occur?
On smooth endoplasmic reticulum of hepatocytes
What class of enzymes are responsible for Phase 2 metabolism?
Transferase enzymes - transferring a polar group from a conjugating agent to the Phase 1 metabolite
Mainly occurs in the liver
What compounds are excreted through the kidney?
Polar compounds - particularly phase 2 conjugates
How does the liver excrete drug metabolites?
Process is called biliary excretion - active secretion of drug molecules or their metabolites from hepatocytes into the bile.
Favours high MW polar compounds
What are the other routes of excretion other than the liver and kidneys?
Lungs - volatile compounds
Saliva
Sweat
Breast milk - think morphine overdose in baby
If the drug does not reach its target, what happens?
Nothing, no pharmacological effect is exerted/observed
