- Clinical science
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.
LADME is an acronym for the important phases of pharmacokinetics:
- LADME is an acronym for the important phases of pharmacokinetics:
- and their interaction with the drug
- : deals with the effect of genetic variations on drug metabolism and drug action.
- Clinical trials: : phases of drug development, testing, and regulatory approval
|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 is concerned with the drug absorption, distribution, metabolism, and excretion!
- The process by which the drug is released from its pharmaceutical form (e.g., capsule, tablet, suppository, etc.)
- Some of the common routes of drug administration are:
- Injection; (the drug is introduced directly into the bloodstream or into tissue)
- Peroral administration
- Dermal administration
- Rectal administration
- Less common routes: buccal, sublingual, and intra-articular administration
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.
Bioavailability is affected by two mechanisms:
- First pass effect: Orally administered drugs are absorbed from the GI tract and reach the liver via the portal circulation: , where they undergo some degree of metabolism before they enter systemic circulation. This decreases the bioavailability of the drug.
- Ability to pass through lipid membranes: dependent on the nature of the substance (see the table below)
- Bioavailability is affected by two mechanisms:
- Bioequivalence: Two pharmaceutical forms of the same drug are said to be bioequivalent if they exhibit the same bioavailability when administered in equal doses.
|Chemical nature||Clinical significance||Example|
Local anesthetics, e.g., lidocaine
After the drug reaches the bloodstream, it is initially distributed in the most vascularized organs!
Distribution coefficient: = C (drug concentration in the organic solvent)/ C (drug concentration in water)
- Measure of polarity/hydrophilicity of a drug
- Volume of distribution: VD (usually expressed in liters/kg body weight) = M (amount of drug administered)/C (plasma concentration of the drug)
Binding to plasma proteins: Different drugs have different affinities to bind to plasma proteins (e.g., albumin).
- Only the unbound fraction of the drug exerts a pharmacological effect.
- Different drugs may compete to bind to plasma proteins
Biotransformation reactions take place in the liver; and affect both endogenous and exogenous substances. The main purpose of biotransformation is to detoxify a drug and alter its chemical structure to facilitate its elimination.
Types of drug kinetics
- Zero order kinetics: : The rate of metabolism and/or elimination remains constant and is independent of the concentration of the 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), sulphates, amino acids (e.g., glycine), or glutathione
- Clinical significance
- 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., )
- Half-life (T½): the time taken for the plasma concentration of a drug to reach half of its initial value
After 4 half-lives, more than 90% of the drug is eliminated!
Drugs and/or their metabolites may be excreted from the body in one or more of the following ways:
Renal elimination: mostly hydrophilic drugs
- Glomerular filtration
- Tubular secretion
- Tubular reabsorption
- Biliary elimination: lipophilic and hydrophilic substances
- Pulmonary elimination: This applies primarily to .
- Definition: The amount of an initial dose of a certain drug needed to reach a target plasma concentration.
- Formula: loading dose = (Cp * Vd) / F
- Definition: The amount of a certain drug needed to achieve a steady target plasma concentration.
- Formula: maintenance dose = (Cp * Cl * τ) / F
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:
- Interaction with receptors
- Interaction with enzymes
- Interaction with DNA (E.g., cytostatics)
- A physical/chemical effect (E.g., osmotic diuretics, antacids)
- Affinity: a measure of the tendency of a drug to bind to its receptor
- 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
- 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.
- 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)
- 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
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The following terms are used to describe dose-response relationships:
Potency (ED50): The potency of a drug is measured as the dose required to produce a pharmacological response of a specified intensity. Potency is a property that is dependent on both drug affinity and drug efficacy.
- Emax = the maximum drug response that can be achieved
- ED50 = the dose required to produce 50% of the maximum possible response (Emax)
- Lethal dose: (LD50): LD50 is determined through animal experiments and is defined as the dose that is lethal in 50% of the test population.
- Therapeutic index: = LD50/ED50 → the greater the therapeutic index, the safer the drug
The effect of a drug can decrease with repeated dosing:
- Drug tolerance
- The underlying mechanism is depletion of the body's stores of an endogenous mediator
- Tachyphylaxis develops quickly (within a few hours of dosing)
- Tachyphylaxis cannot be overcome by increasing the drug dose.
- Examples include nitrates; , indirect sympathomimetic drugs (e.g. phenylephrine), niacin, LSD, MDMA
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
- CYP2D6 polymorphism
- N-acetyltransferase polymorphism
- Pseudocholinesterase is responsible for the breakdown of succinylcholine through ester hydrolysis.
Thiopurine-methyltransferase polymorphism (TPMT)
- TPMT is involved in the breakdown of azathioprine
- 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 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