Análisis e interpretación de los datos obtenidos de las encuestas aplicadas

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 cholinesterase enzyme 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 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 Design

The problem of drug–drug interactions is closely related to the concept of rational polypharmacy. Drug–drug interactions frequently occur secondary to molecular

interactions between two co-administered drugs, and are a common clinical problem.

Table 2.2 shows a partial listing of drugs with which cimetidine interacts; a number of these interactions are clinically relevant.

When designing drugs for a chronic disease, the possibility of drug–drug interactions should be taken into consideration: some may be beneficial, but most are not. Drug–drug interactions may be classified as follows:

1. Pharmacodynamic drug–drug interactions a. Competitive homotopic molecular targets

Same site on the same receptor (e.g., diazepam and lorazepam are both ben-zodiazepines working at the same site on the GABA-A receptor).

b. Non-competitive homotopic molecular targets

Different sites on the same receptor (e.g., diazepam and phenobarbital both bind to the GABA-A receptor, but at different sites: benzodiazepine site versus barbiturate site).

c. Convergent heterotopic molecular targets

Different receptors targeting the same biochemical process (e.g., diazepam plus vigabatrin: diazepam is an agonist for the GABA-A receptor, upregu-lating GABA function; vigabatrin is a GABA transaminase enzyme inhibitor that upregulates GABA function by increasing concentrations of GABA in the brain).

d. Divergent heterotopic molecular targets

Different receptors targeting different biochemical processes, but affecting the same disease process (e.g., diazepam plus phenytoin: diazepam is an agonist for the GABA-A receptor, while phenytoin is an antagonist of the voltage-gated Na⁺channel receptor; both drugs work to prevent seizures, but by entirely different mechanisms).

2. Pharmacokinetic drug–drug interactions

a. A—Absorption competition (similar structures compete for absorption in gut).

b. D—Distribution competition (competitive binding on albumin within bloodstream).

c. M—Metabolism competition (competition for same enzymes in liver).

d. E—Elimination competition (similar structures are competitive for kidney excretion).

3. Pharmaceutical drug–drug interactions

Chemical reaction in gut (e.g., co-administration of valproic acid with an antacid).

4. Adjunctive polypharmacy

Two different drugs targeting completely different aspects of a common disease (e.g., giving an antiplatelet agent and an antihypertensive agent to a person with a stroke; one agent treats platelet clots that may cause stroke, the other agent treats the high blood pressure that also may cause strokes).

Selected References General References on Receptors

D. R. Burt (1985). Criteria for receptor identification. In: H. T. Yamamura, S. J. Enna, M. J. Kuhar (Eds.). Neurotransmitter Receptor Binding, 2nd ed. New York: Raven Press, pp. 41–60.

P. Ehrlich (1897). Klin Jahr. 6: 299.

R. Flower (2002). Drug receptors: a long engagement. Nature 415: 587.

B. G. Katzung (Ed.) (2001). Basic and Clinical Pharmacology, 8th ed. New York: Lange.

A. Korolkovas (1970). Essentials of Molecular Pharmacology. New York: John Wiley.

J. Langley (1878). J. Physiol. (London) 1: 367.

H. Lullmann, K. Mohr, A Ziegler, D. Bieger (2000). Color Atlas of Pharmacology. New York: Thieme.

J. Parascandola (1980). Origins of the receptor theory. Trends Pharmacol. Sci. 1: 189–192.

D. F. Smith. (Ed.) (1989). CRC Handbook of Stereoisomers: Therapeutic Drugs. Boca Raton:

CRC Press.

Drug–Receptor Interaction Forces

P. Andrews (1986). Functional groups, drug–receptor interactions and drug design. Trends Pharmacol. Sci. 7: 148–151.

A. Ben-Nairn (1980). Hydrophobic Interactions. New York: Plenum.

P. H. Doukas (1975). The role of charge-transfer processes in the action of bioactive materials.

In: E. J. Ariëns (Ed.). Drug Design, vol. 5. New York: Academic Press, pp. 133–167.

P. A. Kollman (1980). The nature of the drug–receptor bond. In: M. F. Wolff (Ed.). The Basis of Medicinal Chemistry, 4th ed. Part 1. New York: Wiley-Interscience, pp. 313–329.

J. B. Stenlake (1979). Foundations of Molecular Pharmacology, vol. 2. London: Athlone Press, chapter 2.

Quantifying Receptor Binding

A. De Lean, D. Rodbard (1979). Kinetics of cooperative binding. In: R. D. O’Brien (Ed.). The Receptors. New York: Plenum Press, pp. 140–192.

D. G. Haylett (2003). Direct measurement of drug binding to receptors. In: Textbook of Receptor Pharmacology, 2nd ed. Boca Raton: CRC Press, pp. 153–180.

J. M. Klotz, D. L. Hunston (1971). Properties of graphical representation of multiple classes of binding sites. Biochemistry 10: 3065–3069.

P. M. Laduron (1982). Towards a unitary concept of opiate receptor. Trends Pharmacol. Sci. 3:

351–352.

K. E. Light (1984). Analyzing non-linear Scatchard plots. Science 223: 76–77.

Receptor Binding Terms

E. J. Ariëns (1983). Intrinsic activity: partial agonists and partial antagonists. J. Cardiovasc.

Pharmacol. 5: S8–SI5.

F. J. Barrantes (1979). Endogenous chemical receptors: some physical aspects. Annu. Rev.

Biophys. Bioeng. 8: 287–321.

J. M. Boeynaems, J. E. Dumont (Eds.) (1980). Outlines of Receptor Theory. New York:

Elsevier/North Holland.

J. P. Changeux (1995). The acetylcholine receptor: A model for allosteric membrane proteins.

Biochem. Soc. Trans. 23: 195.

D. Colquhoun (1973). The relation between classical and cooperative models for drug action. In:

H. P. Rang (Ed.). Drug Receptors. Baltimore: University Park Press, pp. 149–182.

A. De Lean, P. J. Munson, D. Rodbard (1979). Multivalent ligand binding to multisubsite recep-tors: application to hormone–receptor interactions. Mol. Pharmacol. 15: 60–70.

A. De Lean, D. Rodbard (1979). Kinetics of cooperative binding. In: R. D. O’Brien (Ed.). The Receptors. New York: Plenum Press, pp. 143–192.

J. DiMaio, F. R. Ahmed, P. Shiller, B. Belleau (1979). Stereo-electronic control and decontrol of the opiate receptor. In: F. Gualtieri, M. Gianella, and C. Melchiorre (Eds.). Recent Advances in Receptor Chemistry. New York: Elsevier/North Holland, pp. 221–234.

M. D. Hollenberg, P. Cuatrecasas (1979). Distinction of receptor from non-receptor interaction in binding studies. In: R. D. O’Brien (Ed.). The Receptors. New York: Plenum Press, pp. 193–214.

P. M. Laduron (1984). Criteria for receptor sites in binding studies. Biochem. Pharmacol. 33:

833–839.

D. E. Macfarlane (1984). On the enzymatic nature of receptors. Trends Pharmacol. Sci. 5: 11–15.

H. G. Mautner (1980). Receptor theories and dose–response relationships. In: M. E. Wolff (Ed.).

The Basis of Medicinal Chemistry, 4th ed., vol. 1. New York: Wiley-Interscience, pp. 271–284.

M. Poo (1985). Mobility and localization of proteins in excitable membranes. Annu. Rev.

Neurosci. 8: 369–406.

D. Rodbard (1980). Agonist versus antagonist. Trends Pharmacol. Sci. 1: 222–225.

K. Starke (1981). Presynaptic receptors. Annu. Rev. Pharmacol. Toxicol. 21: 7–30.

R. P. Stephenson (1956). A modification of receptor theory. Br. J. Pharmacol. 11: 379–393.

D. J. Triggle, C. R. Triggle (1976). Chemical Pharmacology of the Synapse. New York: Academic Press, chapter 2.

Receptor Metabolism

J. L. Carpentier, P. Gorden, A. Roberts, L. Orci (1986). Internalization of polypeptide hormones and receptor cycling. Experientia 42: 734–744.

R. B. Dickson (1985). Endocytosis of polypeptides and their receptors. Trends Pharmacol. Sci.

6: 164–167.

I. A. Hanover, R. B. Dickson (1985). The possible link between receptor phosphorylation and internalization. Trends Pharmacol. Sci. 6: 457–459.

M. D. Hollenberg (1985). Receptor regulation, Parts 1 and 2. Trends Pharmacol. Sci. 6: 242–245;

299–302.

J. A. Koenig, J. Edwardson (1997). Endocytosis and recycling of G protein receptors. Trends Pharmacol Sci. 18: 276.

Molecular Structure of Receptors

A. A. Abdel-Latif (1986). Calcium-mobilizing receptors, polyphosphoinositides, and the generation of second messengers. Pharmacol. Rev. 38: 227–272.

M. J. Berridge (1985). The molecular basis of communication within the cell. Sci. Am. 253: 142–152.

H. R. Bourne (1997). How receptors talk to trimeric G proteins. Curr. Opin. Cell Biol. 9: 134.

R. Flower (2002). Drug receptors: a long engagement. Nature 415: 587.

J. C. Garrison (1985). Possible roles of protein kinase C in cell function. Annu. Rep. Med. Client.

20: 227–236.

A. G. Gilman (1995). G proteins and regulation of adenylyl cyclase. Biosci. Rep. 15: 65–97.

D. G. Grahame-Smith, J. K. Aronson (2002). Textbook of Clinical Pharmacology and Drug Therapy, 3rd ed. New York: Oxford University Press.

H. Hamm, A. Gilchrist (1996). Heterotrimeric G proteins. Curr. Opin. Cell Biol. 8: 189–196.

L. E. Hokin (1985). Receptors and phosphoinositide-generated second messengers. Annu. Rev.

Biochem. 54: 205–235.

P. W. Majerus, T. M. Conolly, H. Deckmyn, T. S. Ross, T. E. Bross, H. Ishii, V. S. Bansal, D. B. Wilson (1986). The metabolism of phosphoinositide-derived messenger molecules.

Science 234: 1519–1526.

S. R. Nahorski, D. A. Kendall, I. Batty (1986). Receptors and phosphoinositide metabolism in the central nervous system. Biochem. Pharmacol. 35: 2447–2453.

E. J. Neer (1995). Heterotrimeric G proteins: organizers of transmembrane signals. Cell 80: 249–257.

Y. Nishizuka (1986). Studies and perspectives of protein kinase C. Science 233: 305–312.

P. J. Parker, L. Coussens, N. Totty, L. Rhea, S. Young, E. Chen, S. Stabel, M. D. Waterfield, A. Ullrich (1986). The complete primary structure of protein kinase C, the major phorbol ester receptor. Science 233: 853–859.

E. Pfeuffer, R. M. Dreher, H. Metzger, T. Pfeuffer (1985). Catalytic unit of adenylate cyclase:

purification and identification by affinity cross binding. Proc. Natl. Acad. Sci. USA 82:

3086–3090.

T. Schneidere, P. Igelmund, J. Hescheler (1997). G protein interaction with K⁺and Ca²⁺channels.

Trends Pharmacol. Sci. 18: 8–11.

H. Schulman (1984). Calcium-dependent protein kinases and neuronal function. Trends Pharmacol.

Sci. 5: 188–192.

R. K. Sunahara, C. W. Dessauer, A. Gilman (1996). Complexity and diversity of mammalian adenylyl cyclases. Ann. Rev. Pharmacol. Toxicol. 36: 461–480.

K. Wickman, D. Clapham (1995). Ion channel regulation by G proteins. Physiol. Rev. 75: 865–885.

106

3