always be kept in mind. The drug molecule must be able to withstand the pharmaceutical
and pharmacokinetic phases of drug action and must have the necessary geometric,con-
formational, stereochemical, electronic, and physicochemical properties necessary to
specifically bind with the receptor at the pharmacodynamic phase of action. The recep-
tor molecule should be unique to the pathological process under study, accessible to the
drug, and capable of stereospecific, saturable binding with a binding equilibrium con-
stant in the nanomolar range. The ultimate realization of the successful drug candidate
will require geometrically precise drug design (using quantum pharmacology calcu-
lations or experimental methods such as X-ray crystallography) and efficient drug
synthesis (using synthetic organic chemistry).
2.12 THE CLINICAL–MOLECULAR INTERFACE: THE
CONCEPT OF RATIONAL POLYPHARMACY
People who are afflicted with chronic diseases frequently find themselves taking many
drugs. Hopefully, these drugs complement each other in terms of their mechanism of
action and are not competing against each other. The capacity of a drug to either augment
or diminish the bioactivity of a co-administered drug is frequently determined at the level
of the receptor. A drug designer who is developing drugs for a disease for which thera-
peutics are already available may wish to consider developing an agent with the capac-
ity for rational polypharmacy (also called rational polytherapy). Rational polypharmacy
is usually achieved by designing drugs that work at different receptors, but which ulti-
mately are of benefit to treatment of the same disease. The treatment of Alzheimer’s dis-
ease may ultimately provide good examples of this approach: the co-administration of a
cholinesteraseenzyme inhibitor with an anti-amyloid agent would be an example of rational
polypharmacy, whereas the co-administration of two competitive cholinesterase inhibitors
simultaneously would be an example of irrational polypharmacy.
As a general rule, one drug in higher doses is better than two drugs in lower doses.
The notion that two drugs can be given together, in lower doses, to improve efficacy
while decreasing toxicity is usually a fallacy.
Case 2.1. A 76-year-old female is brought to an outpatient clinic. The family is con-
vinced that their mother has Alzheimer’s disease. On examination, she is definitely con-
fused and disoriented. She does not know the date, does not know the name of the city
in which she lives, cannot perform simple arithmetic, cannot draw simple diagrams,
cannot identify a watch, and cannot spell the word “WORLD” backwards. However, it
is also revealed that she is on lorazepam (for agitation), carbamazepine (for trigeminal
neuralgia), oxazepam (for insomnia), amitriptyline (for depression), and propranolol
for high blood pressure. When the administration of these medications was stopped, her
mental status returned to normal. She had a drug-induced reversible delirium, rather
than an irreversible dementia. She is an example of the “do not diagnose dementia while
the patient is on a dozen drugs” rule.
2.12.1 Drug–Drug Interactions in Drug DesignThe problem of drug–drug interactions is closely related to the concept of rational
polypharmacy. Drug–drug interactions frequently occur secondary to molecular
RECEPTORS: STRUCTURE AND PROPERTIES 101