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What Happens to Drugs Inside the Body?

The wise nootropic user knows how to use nootropics to achieve his or her goals. Learn how to use pharmacologic principles to design the perfect stack.

The wise nootropic user knows two things: his goals with nootropic use, & how to use nootropics to achieve those goals. The latter is an area not well explored by many nootropics users. Knowledge of how individual agents work guides the design of stacks. Certain drugs may work synergistically (both together produce a greater effect than either alone), additively (both agents work in combination), or antagonistically (counteract each other). Thus, it is essential to understand what exactly happens after a drug is ingested.

The science of pharmacology serves to explain how the ultimate pharmacodynamic effect is produced (the end result of a drug, e.g. improved long-term memory). This is accomplished by studying two aspects of what happens to drugs within the body: mechanisms & pharmacokinetics.

Mechanisms

The most common way in which all drugs work is by modulating a receptor. The body is full of thousands of different types of receptors. These receptors are usually small proteins embedded in the surface of cells. There are 3 types of receptors:

  • Enzyme-linked receptors include enzymes & receptors that lead to the direct activation of enzymes.
  • Ion channel-linked receptors are regulated by concentrations of positively & negatively charged ions, such as Ca2+ & Cl. Na+ channels play a central role in neurotransmission.
    • Lidocaine, a Na+ channel blocker, suppresses conduction of action potentials between neurones, resulting in nullification of pain signals, hence its use as a local anaesthetic.
Receptors exhibit selectivity for ligands like locks & keys. The degree of compatibility between a ligand & a receptor is referred to as affinity.
  • G-protein-coupled receptors (GPCRs) receive signals by binding with ligands.
    • A ligand is something that binds to a receptor & produces an effect. Some examples are hormones, neurotransmitters, & drugs. When a ligand binds a receptor, it can produce any of 4 effects:
      • A receptor agonist is a ligand which produces stimulatory effects upon binding, triggering or potentiating a biochemical pathway ultimately leading to a response in the body.
        • When histamine binds H1 receptors, it triggers the immune system in such a way that symptoms of an allergic reaction are produced.
      • A receptor antagonist is a ligand which does not exert an effect upon binding, leading to the extinguishment of a somatic response as the stimulating ligand is unable to make contact with the occupied receptor. Antagonists can be competitive (meaning they reversibly bind to the receptor) or non-competitive (irreversibly bind receptors). Non-competitive receptor antagonists are more potent.
        • Aspirin is an irreversible COX-enzyme antagonist. Its inhibitory effects on platelets are permanent– following discontinuation, normal platelet function does not return for ~10 days- the lifespan of a platelet. For this reason, aspirin should be held for at least 1 week prior to major surgeries.
      • A partial agonist is a ligand which has properties of both an agonist & an antagonist ultimately producing a mild stimulatory effect.
        • Aripiprazole (Abilify) is an antipsychotic with partial agonist activity. Aripiprazole’s mild modulation at the D2 receptor produces modest reductions in some psychotic symptoms but avoids undesirable side effects due to over-antagonism of dopamine activity caused by other antipsychotics.
      • An inverse agonist is a ligand which exerts the opposite effect upon binding to a receptor, reversing a somatic process.
        • When an antihistamine drug such as diphenhydramine (Benadryl) binds H1 receptors, it does not merely occupy the receptor, preventing histamine from binding, but actually promotes the opposite biochemical pathway, actively countering the allergic reaction.

Visualised dose-response curves for various ligand-receptor interactions.
Visualised dose-response curves for various ligand-receptor interactions.

 

Pharmacokinetics

Pharmacokinetics (PK) refers to what happens to the drug after it has been ingested in the body. It is divided into 5 major areas, denominated by the acronym ADME-Tox:

  1. Absorption is the first phase of pharmacokinetic interest. Here we consider aspects of the drug’s transit into the bloodstream.
    • The route of administration (oral, sublingual, inhalation, intravenous, etc.)
    • Foods, as well as most drugs that are taken by mouth, are absorbed in the small intestine
    • How long a drug takes to be absorbed
    • The maximum amount that is absorbed (peak concentration, CMAX) & the time it takes to achieve CMAX (TMAX)
    • The onset, which is the time it takes for drug’s effects to begin
  2. Distribution is where we examine where the drug goes in the body.
    • The bioavailability (F), which refers to the concentration of the drug at the site of action (for nootropics, this would be the brain)
    • The volume of distribution (VD) which represents the degree of absorption into fat tissue. This is important because the amount of available drug is that which is present in the blood
    • Protein binding refers to the amount of drug in the blood that is bound to proteins such as albumin where it is inactive. These proteins act as carriers of the drug, preventing it from degradation. When drugs compete for binding proteins, or chronic malnutrition leads to decreased production of plasma proteins, there is a potential for increased levels of drug in the blood
  3. Metabolism has to do with biochemical pathways of breakdown or altering the structure of the drug molecule.
    • The liver is the major site of drug metabolism
    • Cytochrome P450 is a key group of enzymes in the liver that is responsible for the degradation of many drugs. Individual enzymes include 2C9, 2D6, 3A4, & so on. When 2 drugs happen to compete for the same enzyme, there is potential for a drug interaction. Understanding CYP450 is understanding the majority of drug interactions (will be covered later!)
    • Other drugs are able to undergo alternate pathways of hepatic (via the liver) metabolism (e.g. oxidation) or non-hepatic metabolism (e.g. proteolysis)
    • Prodrugs are parent compound which are inactive when ingested but become activated when undergoing metabolism. Usually, this is through the cleavage of a portion of the molecule. Active compounds, too, may have active metabolites. Keep these in mind as the metabolites can continue to contribute to the pharmacodynamic effect of the drug.
  4. Elimination is how the parent compound of the drug & its metabolites are removed from the body. There are two major pathways of elimination: hepatic (faecal) & renal (via the kidneys; urination).
    • Dysfunction of either system could lead to accumulation of drugs that are excreted by that pathway, possibly worsening side effects
    • Some drugs can be excreted via alternate pathways if the major pathway of removal is compromised
The ideal dosage of a drug achieves levels above the MEC but does not exceed the MTC.
The ideal dosage of a drug achieves levels above the MEC but does not exceed the MTC.
  • Toxicology is the propensity of a drug to cause harm & via which mechanisms.
    • «The dose makes the poison»: every agent has the ability to cause harm given the correct amount.
    • The minimum toxic concentration (MTC) is the level at which a drug’s toxicity becomes clinically significant. This is often compared with the minimum effective concentration (MEC), where a drug’s desired effects start to work. The difference between MTC & MEC is the therapeutic range. The narrower the therapeutic range, the higher the risk of toxicity.
    • Some mechanisms by which antidotes can work include binding the toxic molecule, preventing it from triggering receptors or promoting recovery processes (e.g. antioxidants)

Pharmacokinetic
Pharmacokinetic pathways & major organs.

 

Summary

  • Mechanisms are how drugs produce their effect. Most drugs work by affecting a receptor.
  • Pharmacokinetics is the study of the changes that happen to the drug after it is introduced into the body. It is broken down into 5 major areas: absorption, distribution, metabolism, elimination, & toxicology.
  • Pharmacodynamics is the outcome effect of a drug, such as reduced depressive symptoms.
  • An understanding of mechanisms & pharmacokinetics of drugs can be useful in designing stacks which exploits the characteristics of each agent for an optimised pharmacodynamic effect.

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