Medicinal Chemistry Dr Bansal Flashcards
(50 cards)
What deposits in the arteries making them narrow
Lipids, cholesterol, calcium
What 5 drugs classes can we give for hypertension
1) ACE inhibitors
2) ARBs
3) calcium channel blockers
4) diuretics
5) beta blockers
What are the 3 reasons bp can increase
1) increase in frequency of heart contractions
2) constricted blood vessels
3) retaining more water and salt = increased blood volume
How do calcium channel blockers work + examples
CCBs prevent/reduce the entry of Ca ions into the cell reducing contractility and energy demand
Examples =
non-dihydropyridines (verapamil, diltiazem)
Dihydropyridines (nifedipine, amlodipine)
diuretics mechanism
Diuretics inhibit the Na+/K+/cl- transporter causing a decrease in Na+ reabsorption, causing more water to be removed from the blood = reduced blood volume
What is the difference between loop diuretics and thiazide-like diuretics + examples
Loop = loop of henle (Na/K/Cl transporter inhibition) these are stronger = furosemide, bumetanide
Thiazide-like = distal convoluted tubule = indapamine, metolazone
Where angiotensinogen released from
LIVER
Where is renin released from
KIDNEYS
How is angiotensin I formed
When angiotensinogen combines with renin
Where is ACE released from
LUNGS
How is angiotensin I converted into angiotensin II
ACE enzymes
What does angiotensin II do
It causes the adrenal gland to release aldosterone which causes Na/water retention leading to oedema
It also causes vasoconstriction
What structural change does Angiotensin I go through when being converted to Angiotensin II
Angiotensin I has 10 AAs and ACE causes the decapeptide (10) to breakdown into a octapeptide (8) - it does this by hydrolysing the C-TERMINAL dipeptide
Angiotensin II has 8 AAs
Why are some ACE inhibitors prodrugs + example of 2
They are too hydrophobic so the -SH group in enalapril was replaced with a CARBOXYLATE group = enalaprilat
E.g. enalapril converted to Enalaprilat = active form
Ramipril gets converted to Ramiprilat inside the body = active form
What are the key structural groups in enalaprilat
Has double bond oxygen to bind to the Zn2+
Has a hydrophobic pocket
Has another double bond oxygen to form H bonds
How do ARBs work + example drugs
They block the receptors angiotensin II binds to, therefore the adrenal gland releases less aldosterone which causes = less water/Na retention = lower blood volume and it also prevents vasoconstriction
What is the first line treatment for hypertension
Firstline = ACE inhibitors or ARBs for most people
What chemical features of ACE are crucial for its function
ACE is a METALLOENZYME that contains a Zn2+ ion at its active site
This Zinc ion helps hydrolyse the peptide bond of Angiotensin I to convert it into Angiotensin II
What are the 3 crucial points on the ACE active site
1) substrate binding site
2) zinc binding site for catalysis
3) hydrophobic pocket
How does ACE work chemically
It cleaves the C-terminus dipeptide (His-Leu) from angiotensin I (decapeptide) to produce angiotensin II (octapeptide)
The substrate’s carbonyl group (C=O) binds to zinc and h20 attacks the carbonyl group, breaking the pi bond = removal of AA
How do ACE inhibitors stop the chemical interactions between ACE and Angiotensin I
ACE inhibitors mimic the structure of Angiotensin I and competitively bind to ACE. They bind to the Zn2+ binding site preventing Angiotensin I from doing so
What feature MUST ace inhibitors have
A Zn2+ binding group e.g. -SH, -COOH, -POOH also
When creating drugs we want them to mimic what state
The TRANSITION (intermediate) state
How is cholesterol formed
The reaction uses HMG-Co A reductase and involves 2 hydride transfers
