DSI Newsletter: How Drugs Work

DSI Newsletters, Issue 36:
How Drugs Work

A drug (pill) works much like a key works on a lock; that is, the drug fits in a "receptor" in our body that functions as if it were a lock. The drug functions as if it were a key. It is the interaction of the drug with its receptor that creates a clinical effect in our body.
The narcotic class of pain medications has opiate receptors that exert their effect on. There are different types of opiate receptors with varying functions. Different opioids stimulate the different receptors to more or less degree, thus leading to difference among the narcotic opioid pain medications available.
There are four types of opiate receptors: mu1; mu2; kappa and delta. All opioid narcotics exert their effects by activating one or more of these receptors. Analgesia involves activation of mu1 receptors in the brain and the kappa receptors in the spinal cord. Mu2 receptors are involved in respiratory depression and intestinal constipation; two common side effects form opioid narcotic pain killers. The delta receptor is thought to be closely related to euphoria (to get high or inebriated).
The actions of opioids on receptors can vary depending on the location within the body. For example, a particular opioid may act as an antagonist (a key that fits in the keyhole but will not open the lock and gets in the way of future keys) at the kappa receptors in the brain, but as an agonist (does open the lock and cause the effect) at the same type of receptors in the large intestines.
So, different opioid narcotics have similarities and differences. The goal is to minimize pain, return function and avoid side effects.

Opioids Glossary
Affinity: the strength of the interaction between the ligand drug and its receptor.
Agonist: a drug compound that will bind to a receptor to form a complex which elicits a full pharmacologic response, peculiar to the nature of the receptor involved.
Antagonist: a compound that will bind to a receptor to form a complex which does not give rise to any response, as if the receptor were unoccupied.
Delta receptors = a term used collectively to refer to two characterized subtypes of opioid receptors (delta-1, delta-2) that possess numerous features in common which are not present in the mu receptors or kappa receptors.
Dynorphin = an endogenous peptide which functions as a selective agonist for the kappa opioid receptors.
Endorphin(s), beta-endorphin = an endogenous peptide which functions as a selective agonist for the mu-opioid receptors.
Endomorphin = a term which refers to two small (5 amino-acids) endogenous peptides, known as endomorphin-1 and endomorphin-2, which function as mu-agonists with greater selectivity than beta-endorphin.
Enkephalin = one of a number of endogenous peptides which function as selective agonists for the delta-opioid receptors.
Full agonist = see "agonist."
Inverse agonist = in the context of receptors which exert some basic signaling activity even the absence of an agonist (characteristic known as "constitutive activity"), an agent which binds to a receptor, suppressing this activity to some degree.
Intrinsic activity = a measure of the maximum response to an agonist. Kappa receptors = a term used collectively to refer to three characterized subtypes of opioid receptors (kappa-1, kappa-2, kappa-3) that possess numerous features in common which are not present in the mu receptors or delta receptors.
Ligand = molecule which binds to a receptor to form a complex.
Mixed agonist-antagonist = see "partial agonist."
Narcotic = literally "sleep/stupor-inducing agent." Term usually applied indiscriminately to describe any exogenous compound with a "sedating" profile. Use of the term with reference to the opioids is not recommended, due to its ambiguity, and arguably negative connotation.
Neurotransmitter = any endogenous compound that plays a role in synaptic nervous transmission.
Opiate = compound containing the fundamental morphine or thebaine structure possessing some affinity to any, or all, of the opioid receptor subtypes. Examples are heroin, buprenorphine and naltrexone.
Opioid = any compound, peptide or otherwise, which, while not containing the fundamental morphine or thebaine structure, possesses some affinity for any, or all, of the opioid receptor subtypes. Common opioids are endorphin, fentanyl and methadone. Partial agonist = a compound which possesses affinity for a receptor, but unlike a full agonist, will elicit only a small degree of the pharmacological response peculiar to the nature of the receptor involved, even if a high proportion of receptors are occupied by the compound.
Pharmacophore = the minimum functionality, or 3-D configuration of specific atoms or groups, that a molecule must have in order to exhibit biological activity.
Selectivity = the relationship between the affinity of a compound for a particular receptor and its affinity for other types of opioid receptor. For instance, a compound that will bind with high affinity to the mu-receptors, but with very low affinity to kappa and delta receptors, is said to possess high selectivity for mu.
Semi-synthetic opiate/opioid = a compound with some opioid receptor affinity, synthesized by functional modification of a product extracted from opium.
Synthetic opiate/opioid = a compound with some opioid receptor affinity, synthesized using no products extracted from opium.

Sincerely:

Joseph Saponaro, MD, DABIM, FACP, CPI, CCI, CCRI, CCRC, CCRP
Board Certified Internist, JPMC
Principal Investigator, DSI
Diplomat American Board of Internal Medicine
Fellow American College of Physicians
Certified Physician Investigator by the AAPP
Certified Clinical Investigator by the DIA
Certified Clinical Research Investigator by the ACRP
Certified Clinical Research Coordinator by the ACRP
Certified Clinical Research Professional by SoCRA
Member: The American College of Preventive Medicine

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