• Clinical science

Fundamentals of pharmacology

Summary

The action of a drug depends on multiple factors. Pharmacokinetics concerns what the body does to the drug. Pharmacodynamics, on the other hand, concerns what the drug does to the body. Furthermore, when a drug is administered in combination with other drugs, a variety of drug interactions may take place that synergistically or antagonistically modify the effect of the given drug (e.g., the activation or inhibition of cytochrome p450 enzymes by certain medications). The knowledge of drug interactions and the pharmacokinetic properties of a drug help to determine the ideal route of administration (topical, oral, IV). Drugs that are eliminated by the liver may attain high serum concentrations when hepatic function is impaired, which increases the risk of drug toxicity. The same principle applies to drugs that are eliminated via the kidneys.

Overview

Clinical trial phase Purpose Study population
Phase 0 trial Evaluate pharmacodynamic and pharmacokinetic properties of the drug Small number of healthy individuals (∼ 10–15)
Phase I trial Evaluate safety Small number of healthy individuals (∼ 15–30)
Phase II trial Evaluate efficacy against placebo or the gold standard Small number of patients with a specific disease (∼ 10–100)
Phase III trial Final confirmation of efficacy and safety Randomized control trial with a large number of patients with a specific disease (∼ 100–1000)
Phase IV trial Safety studies following approval Large number of patients with a specific disease after drug approval
Phase V trial Post-marketing surveillance: compares the real-life effectiveness to the efficacy found in research studies

Pharmacokinetics

Pharmacokinetics is concerned with the drug absorption, distribution, metabolism, and excretion!

Liberation

  • The process by which the drug is released from its pharmaceutical form (e.g., capsule, tablet, suppository, etc.)
  • The most common routes of drug administration are:
    • Injection; (the drug is introduced directly into the bloodstream or into tissue)
    • Inhalation
    • Peroral administration
    • Dermal administration
    • Rectal administration
    • Less common routes: buccal, sublingual, and intra-articular administration

Absorption

The process by which the drug reaches the bloodstream. The following factors affect drug absorption:

  • Bioavailability describes the rate and concentration at which the drug appears in circulation. It is expressed as a percentage of the dose that was initially administered.
  • Bioequivalence: Two proprietary preparations of a drug are said to be bioequivalent if they exhibit the same bioavailability when administered in equal doses.
Chemical nature Clinical significance Example
Lipophilic
  • Predominantly nonpolar compounds
  • The drugs can easily diffuse across the lipid bilayer of the cell membrane.
    • These drugs can be administered topically.
    • CNS penetration: free diffusion across the blood-brain barrier
  • These drugs are biotransformed in the liver and then excreted through the bile duct.
Hydrophilic
  • Predominantly polar compounds
Amphiphilic

Local anesthetics, e.g., lidocaine

Distribution (pharmacology)

After the drug reaches the bloodstream, it is initially distributed in the most vascularized organs!

  • Distribution coefficient: measure of hydrophobicity/hydrophilicity of a drug
    • C (drug concentration in the organic solvent)/ C (drug concentration in water)
  • Volume of distribution: VD (usually expressed in liters/kg body weight) = M (amount of drug administered)/C (plasma concentration of the drug)
    • This value measures the tendency of the drug to be distributed in plasma rather than body tissues.
    • Lipophilic substances tend to have a large volume of distribution
  • Binding to plasma proteins: Different drugs have different affinities to bind to plasma proteins (e.g., albumin).
    • Only the unbound fraction of the drug has a pharmacological effect.
    • Different drugs may compete to bind to plasma proteins
  • Redistribution: transfer of a drug between the different compartments within the human body
    • Lipophilic substances (e.g., inhalation anesthetics) are redistributed from plasma into fat tissue → initially decreased action of the applied drug
    • Drug is stored but over time is released again from fat tissue into plasma → delayed elimination and prolonged action of the specific drug ).

Metabolism (biotransformation)

Biotransformation is the chemical alteration of substances (e.g., drugs) within the body by the action of enzymes and mainly takes place in the liver. Biotransformation detoxifies drugs and facilitates their elimination.

  • Types of drug kinetics
    • Zero order kinetics: : The rate of metabolism and/or elimination remains constant and is independent of the concentration of a drug (e.g., metabolism of alcohol)
    • First order kinetics: : The rate of metabolism and/or elimination is directly proportional to the plasma concentration of the drug (applies to most drugs)
  • Phases of biotransformation
    • Phase I reaction: The drug is transformed into a polar metabolite (mostly through oxidation by the cytochrome P450 system) → allows phase II reactions to take place
    • Phase II reactions (conjugation reaction): involves coupling the metabolite with glucuronic acid (most common coupling reaction), acetyl groups : (e.g., metabolism of isoniazid), sulfates, amino acids (e.g., glycine), or glutathione
  • Clinical significance
    • Detoxification: In most cases, the drug is inactivated and modified into a hydrophilic metabolite → allows the drug to be excreted by the kidneys or in bile
    • Activation; : Certain drugs are transformed in the liver from their inactive prodrug state into active forms.
    • Formation of toxic metabolites

Excretion

  • Clearance: a measure of the rate of drug elimination. It is defined as the plasma volume that can be completely cleared of the drug in a given period of time (e.g., creatinine clearance)
  • Half-life (T½): the time required for the plasma concentration of a drug to reach half of its initial value

After 4 half-lives, more than 90% of the drug will be eliminated!

Drugs and/or their metabolites are excreted from the body in one or more of the following ways:

Loading dose

  • Definition: The amount of an initial dose of a certain drug needed to reach a target plasma concentration.
  • Formula: loading dose = (Cp x Vd) / F

Maintenance dose

  • Definition: The amount of a certain drug needed to achieve a steady target plasma concentration.
  • Formula: maintenance dose = (Cp x Cl * τ) / F
    • Cp = target plasma concentration at steady state (mg/L)
    • Cl = clearance (L/h)
    • τ = dosing interval (hours)
    • F = bioavailability

References:[1]

Pharmacodynamics

Pharmacodynamics is concerned with the effect of a drug at its site of action, the dose-response relationship of the drug, and the influence of other factors on the drug effect!

Types of receptors

Every functioning molecule in an organism is a potential site of action for a drug. Some of the means through by which drugs act include:

Drug-receptor interactions

Basic principles

  • Affinity: a measure of the tendency of a drug to bind to its receptor
    • Most drug-receptor bonds are reversible
    • Covalent drug-receptor bonds, which are encountered less frequently, are almost always irreversible (e.g., the binding of aspirin to cyclooxygenase enzyme).
  • Efficacy: the degree to which drugs activate receptors after binding and lead to a cell response
  • Residence time: : the lifespan of a drug‑receptor complex

Types of drug-receptor interactions

  • Agonist: : a drug that has a similar effect to that of the endogenous receptor activator (e.g., β2 agonists)
  • Antagonist: a drug that binds to a receptor and prevents its activation. Types of antagonism include:
    • Competitive antagonist: The agonist and the antagonist compete to bind to the same receptor; . Inhibits the effect of the agonist in a dose-dependent fashion → higher concentration of the agonist is needed to achieve same efficacy (e.g., there is a decrease in potency)
      • Reversible competitive antagonists
      • Irreversible competitive antagonists
    • Non-competitive antagonist: The drug binds at a site other than the agonist-binding site (also called allosteric site) and changes the structure of the agonist binding site and decreases the affinity of the agonist
    • Functional (physiological); antagonist: In this type of antagonism, two different molecules working through separate receptors produce physiologically opposite effects.
  • Partial agonist: a substance that has some agonistic action at a receptor but does not elicit the complete response of a true agonist.
  • Inverse agonist: Binds to the same receptor as an agonist, but not to the same active site. It elicits a response that is opposite of the agonistic response and has a negative efficacy.
  • Allosteric modulator: Binds at a different site than the agonist and initiates conformational changes that induce modulation of ligand-binding.
  • Allosteric activator: Binds at a site other than the agonist-binding site (also called allosteric site) and changes the structure of the active binding site to increase affinity to the substrate

Please see enzymes and biocatalysis for more information enzyme kinetics.

Dose-response relationship

The following terms are used to describe dose-response relationships:

The effect of a drug can decrease with repeated dosing:

Pharmacogenetics

Pharmacogenetics deals with genetic variation in the expression of enzymes that metabolize drugs. These genetic differences can cause the observed drug response to deviate from the expected response and/or increase the risk of side effects:

  • If the enzyme in question is responsible for the breakdown of a drug, the following effects are possible:
    • A hyperactive variant of the enzyme decreases the drug response.
    • A hypoactive variant of the enzyme can cause cumulative drug effects and thus increase the risk of side effects.
  • The reverse is true if the enzyme is responsible for the activation of a drug.

Examples of clinically relevant variations

Drug interactions and the cytochrome p450 system

Drug interactions

  • Drug interactions can cause an increase or decrease in the potency of a drug or result in additional side effects.
  • The greater the number of coadministered drugs, the greater the chance of drug interaction
  • The most common form of drug interaction results from the induction of the cytochrome P450 enzyme system. Interactions as a result of drug inhibition are less common.

Cytochrome-P450 system

  • Basic principles
    • Cytochrome P450 is a superfamily of heme-containing, primarily oxidative enzymes; that take part in phase 1 reactions.
    • They are divided into families and subfamilies based on the similarity of amino acid sequences.
    • Nomenclature: the prefix "CYP" (which stands for cytochrome P450)- + family number + a letter representing the subfamily + isoenzyme number
    • There are 200 cytochrome P450 enzymes, which are classified into 43 subfamilies and 18 families. Of these 200, only 12 are involved in drug metabolism. They belong to the first three families:
    • The highest concentration of CYP enzymes is found within the centrilobular hepatocytes
    • CYP induction increases the rate of metabolism of the substrate, while CYP inhibition decreases it.
      • The effects of drugs that are activated by CYP enzymes are increased by enzyme induction and decreased by enzyme inhibition.
      • The effects of drugs that are broken down by CYP enzymes are decreased by enzyme induction and increased by enzyme inhibition.
      • Ultrarapid metabolizers: The activity of CYP2D6 is increased in individuals with a duplication on chromosome 22. Such individuals require a significantly higher dose for the desired effect to be achieved!
  • Role in carcinogenesis

Carbamazepine acts as both substrate and inducer of CYP3A4!

Rifampicin and carbamazepine are some of the strongest inducers of cytochrome P450 enzymes and can thus interact with many drugs!

CYP Substrate
Inhibitors Inducers
CYP1A2
  • Smoking
CYP2C CYP2C19
CYP2C9
CYP2D6
CYP2E1
  • Ethanol

CYP3A4

References:[2][3][4][5][6][7][8][9]

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  • 4. Bui VN, Nguyen TT, Mai CT, et al. Procarcinogens - Determination and evaluation by yeast-based biosensor transformed with plasmids incorporating RAD54 reporter construct and cytochrome P450 genes. PLoS ONE. 2016; 11(12): p. e0168721. doi: 10.1371/journal.pone.0168721.
  • 5. Smela ME, Currier SS, Bailey EA, Essigmann JM. The chemistry and biology of aflatoxin B(1): from mutational spectrometry to carcinogenesis. Carcinogenesis. 2001; 22(4): pp. 535–45. pmid: 11285186.
  • 6. Hukkanen J, Jacob P 3rd, Peng M, Dempsey D, Benowitz NL. Effect of nicotine on cytochrome P450 1A2 activity. Br J Clin Pharmacol. 2011; 72(5): pp. 836–8. doi: 10.1111/j.1365-2125.2011.04023.x.
  • 7. Mozayani A, Raymon L. Handbook of Drug Interactions. Springer Science & Business Media; 2011.
  • 8. UpToDate. Cimetidine: Drug Information. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/cimetidine-drug-information. Last updated January 1, 2018. Accessed November 11, 2018.
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  • National Comprehensive Cancer Network. Phases of Clinical Trials. https://www.nccn.org/patients/resources/clinical_trials/phases.aspx. Updated January 1, 2019. Accessed January 20, 2019.
last updated 07/11/2019
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