Chemistry 106: Drugs in Society

Lecture 20: How do Drugs Elicit an Effect? Interactions between Drugs and

Macromolecular Targets II

5/11/18

By the end of this session, you should be able to

1. Define enzyme inhibitor and know some drugs act as enzyme inhibitors

2. Know competitive inhibition can occur at both enzymes and receptors – our 2

main targets for drugs – and that since both are proteins with

complementary binding sites for the molecules they are meant to bind, they

both show similar inhibition curves

3. Know some drugs do not fully activate receptors while they are in the

receptor binding site; these partial agonists may actually reduce the effect

of full agonists

Rationalize why Talwin should not be given to individuals with break

through pain who are on morphine

Rationalize why Buprenex might be a better choice for managing

heroin withdrawal than either methadone or Narcan

4. Of the following classes of antihypertensive drugs: ACE inhibitors, AT

blockers, and -blockers, know which work by blocking enzymes and which

work by blocking receptors

Since we now have a feel for how enzymes and receptors function naturally, let’s

consider what happens when we start raising the concentration of drug in the [non-

cellular] portion of the bloodstream the plasma (Cp).

Competitive Enzyme Inhibition

We typically block enzymes, and the percentage of the total enzyme available that

is blocked is a function of Cp, and may be described by a Ki for a given drug

mKS

SVvelocity

max

Where Km’ = Km(1 + I/Ki), and I is inhibitor concentration, Ki tells what inhibitor

concentration is necessary for inhibition – essentially how well the inhibitor binds If concentration of inhibitor I is 0 then Km’ = Km and the enzyme functions based on

the amount of substrate available

If concentration of natural substrate is huge by comparison, you compete away any

inhibiting drug

If Ki is tiny, then any concentration of I will generate a much larger Km’ and the

enzyme would stop working since S would be small by comparison

Here’s how it looks graphically…

Go figure…it looks just like the curve for inhibiting receptors on the next page.

Both are proteins, both have specific sites that bind to naturally occurring

molecules

Receptor Inhibition Considerations

For receptors the situation is a bit more complicated, since drugs can act as

full mimics of the receptor and activate it (agonist), bind and prevent the

binding of agonists and endogenous ligands (antagonists), or bind and

activate the receptor…but not very well (partial agonist)

By looking at cellular effect, we account for spare receptors and can focus

on what the drug is doing to the cell (and thus tissue, organ, system, person)

Compare the concentration that provides an effect in 50 % of the cells C

and the concentration needed with an inhibitor C’ = C(1 + I/Ki) to that for an

enzyme inhibitor in the graph below – once again, we are blocking the site

where the natural molecule would bind

o If one where to consider the binding of inhibitor to a receptor as

temporarily removing the receptor, then this would be akin to

instantaneous receptor down-regulation (though there are no

instances I know of where antagonizing a receptor acts to raise the

number of those receptors…odd, eh?)

If concentration of inhibitor I is 0 then C’ = C and the receptor functions

based on the amount of ligand available

If concentration of natural substrate is huge by comparison, you compete

away any antagonizing drug

If Ki is tiny, then any concentration of I will generate a much larger C’ and

the receptor would stop working since C would be small by comparison

The effect of adding a partial agonist is complex, but is easily understood

when you consider

o The effect on the cell should initially decrease, since you are replacing

a strongly activating molecule with a weakly activating molecule

o The effect will never be completely lost as the partial agonist will

exert an effect

Q: Pentazocine (Talwin) is a partial opioid agonist that can be used in the

treatment of pain. Why should pentazocine not be administered with a strong

opioid agonist such as morphine?

Q: Buprenorphine (Buprenex) is a partial opioid agonist that has been shown to be

effective in the treatment of heroin withdrawal. Why would this compound be a

better choice than an antagonist such as naloxone?

Q: Methadone is considered a full opioid mu receptor agonist. Which do you think

would be a better choice for opioid succession, buprenorphine or methadone?

As an example of drugs that act on receptors and enzymes, let’s return to the

problem of hypertension (high blood pressure) and its treatment

Not only does cortisol promote hypertension, so does adrenaline, and is useful in

treating patients who are suffering a hypotensive crisis (blood pressure too low).

It constricts the smooth muscle of the cardiovascular system by activating the -

adrenergic receptor (which we used as an example of receptor desensitization)

However, with the prevalence of hypertension (blood pressure too high) in western

societies, some of the most widely prescribed drugs are the -blockers, such as

atenolol (Tenormin®), metoprolol (Lopressor®), and propranolol (Inderal®)

Clearly, appropriate use of drugs is circumstance dependant – give someone

who is having a hypertensive crisis (sustained systolic blood pressure > 180 mm

Hg, or diastolic blood pressure > 120 mm Hg) adrenaline and you could kill them

In keeping with our previous discussion on receptor reregulation, one of the

main causes for hypertensive crisis is discontinuation of antihypertensive

medications (another is the use of stimulant drugs – as a rule, adrenergic

agonists)

What do you think would happen if you gave someone stimulants (or

adrenaline) and -blockers?

More recently, we have learned how intercede in the main regulatory pathway for

the regulation of fluid balance, as shown below

Angiotension Converting Enzyme (ACE) Inhibitors

ADH = anti-diuretic hormone; blocking this system results in lowering of blood

pressure

The angiotensins are peptide signaling molecules, with angiotensin II producing the bulk

of the effects, they bind to AT receptors of which there are 2 flavors, AT1 & AT2

o So there is a potential to block the enzyme that converts angiotensin I to

angiotensin II - Enalapril (Vasotec®) does this - or to directly block the

receptors angiotensin II binds - Losarten (Cozaar®) does this. In either case,

the signaling pathway leading to the release of ADH is inhibited, more fluid is

excreted, and blood pressure goes down

ACE (B below) belongs to the (large) family of enzymes known as the serine

proteases, Carboxypeptidase (A below) being a classic, well defined member and

very similar

The ACE inhibitors are able to act as transition state mimics; as such ACE binds

them tightly

There are other drugs that are routinely used to affect hypertension by acting

directly on the [calcium channel receptors in] heart (e.g.’s diltiazem (Cardizem®),

amlodipine (Norvasc®), Nifedipine (Procardia®) and some that promote fluid loss

directly from the kidney such as furosemide (Lasix®). All represent attempts to

intervene on the major cause of morbidity and mortality in western civilization,

heart attack and stroke.

The question then becomes “have we become overly reliant on these medications since

we know they are available?” Recall how Ayurvedic medicine and the Asclepiads

empirically administered changes to diet, exercise, meditation and rest - after all

this time, lifestyle changes are still some of the best advice medicine has to offer