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2 :: KEy processes
ABSORPTION
>> Movement of a drug from the administration site to the bloodstream.
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Route of administration
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e.g. oral, intravenous, subcutaneous
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Physicochemical properties of the drug
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e.g. solubility, lipophilicity & ionisation, etc.
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Formulation factors
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Immediate-release vs. extended-release
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Gastrointestinal (GI) environment & drug-food interactions
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For orally administered drugs, bioavailability is often reduced due to first-pass metabolism.
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FIRST-PASS METABOLISM: a pharmacological phenomenon in which a medication undergoes metabolism at a specific location in the body.
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Bioavailability: The extent and rate at which the active moiety (drug/metabolite) enters the systemic circulation, thereby accessing the site of action
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e.g. Propranolol.
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DISTRIBUTION
>> Reversible transfer of a drug between the blood and tissues (fat, heart, brain, etc).
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Distribution can affect how much drug ends up in the active sites and thus,
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A drug will move from the absorption site to tissues around the body, such as brain tissue, fat, and muscle.
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drug efficacy and toxicity.
The extent of distribution is governed by:
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Drug lipophilicity
For example, a drug like warfarin is highly protein-bound, which means only a small percentage of the drug is free in the bloodstream to exert its therapeutic effects. If a highly protein-bound drug is given in combination with warfarin, it could displace warfarin from the protein-binding site and increase the amount that enters the bloodstream.
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Plasma protein binding
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Physiological barriers.
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(e.g. blood-brain barrier)
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Tissue perfusion and capillary permeability
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Distribution can affect how much drug ends up in the active sites and thus, drug efficacy and toxicity.
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A drug will move from the absorption site to tissues around the body, such as brain tissue, fat, and muscle.
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Drug efficacy refers to the ability to produce a desired or intended result.
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Volume of Distribution
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The volume of distribution (Vd) quantifies how extensively a drug distributes beyond the plasma compartment.
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High Vd values suggest significant tissue binding or sequestration.
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(e.g. Warfarin is highly protein-bound (>99%), so only a small fraction is pharmacologically active. Displacement interactions can increase the free drug concentration, potentially leading to toxicity.)
(ditki, 2019) (jove, 2021)
METABOLISM
>> Converts lipophilic compounds into more hydrophilic metabolites for easier excretion.
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Distribution can affect how much drug ends up in the active sites and thus,
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A drug will move from the absorption site to tissues around the body, such as brain tissue, fat, and muscle.
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drug efficacy and toxicity.
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Genetic polymorphisms
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Age
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Disease states
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Enzyme inhibition/induction by concomitant drugs
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Enzyme induction is the increased synthesis of enzymes, often triggered by substances like drugs or hormones. This raises enzyme levels and boosts catalytic activity, typically through gene activation.
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Enzyme inhibition reduces or blocks enzyme activity and may be reversible or irreversible.
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Reversible inhibition involves temporary binding and includes:
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Competitive: inhibitor competes for the active site,
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Non-competitive: inhibitor binds elsewhere, altering the enzyme’s shape,
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Uncompetitive: inhibitor binds only to the enzyme-substrate complex.
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Irreversible inhibition involves permanent binding that inactivates the enzyme.
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CONCOMITANT DRUGS: Concomitant drugs are two or more drugs used or given at or almost at the same time.
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Drug metabolism, or biotransformation, primarily occurs in the liver and involves converting lipophilic compounds into more hydrophilic metabolites for easier excretion.
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Phase I reactions (functionalisation):
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Oxidation, reduction, hydrolysis — mainly mediated by Cytochrome P450 (CYP450) enzymes (e.g. CYP3A4, CYP2D6).
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Phase II reactions (conjugation):
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Glucuronidation, sulfation, acetylation — increase water solubility.
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Inactive Metabolites
(e.g. diazepam → desmethyldiazepam)
Inactive metabolites are chemical compounds formed when a drug is metabolised by the body but do not have any significant biological effects.
These compounds are usually less potent than the original drug as they have been broken down and may have lost some of their original structure. These compounds are eliminated from the body through the urine or feces and typically do not contribute to the overall pharmacological effects of a drug. In most cases, drugs are mainly metabolised into inactive compounds.
Active Metabolites
(e.g. morphine → morphine-6-glucuronide)
Active metabolites can produce significant biological effects in the body. They can interact with the body’s receptors and even be more potent than the original drug. Active metabolites can be formed through various metabolic processes, such as oxidation, reduction, and hydrolysis.
An example of a drug that produces active metabolites is codeine. When the body metabolises codeine, it is converted into morphine, a potent opioid analgesic.
Prodrug Activation
(e.g. codeine → morphine via CYP2D6)
Pro-drugs are inactive compounds that are converted into active drugs by the body.
EXCRETION
>> The process of eliminating the parent drug and its metabolites from the body, primarily through the kidneys (renal excretion), and to a lesser extent via bile, feces, sweat, and breath.
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Distribution can affect how much drug ends up in the active sites and thus,
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A drug will move from the absorption site to tissues around the body, such as brain tissue, fat, and muscle.
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drug efficacy and toxicity.
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Renal function
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Urine pH
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Drug polarity
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Protein binding
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Impaired renal clearance can prolong drug half-life and necessitate dose adjustments.
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e.g. Drugs like aminoglycosides are eliminated renally and require close monitoring in patients with reduced kidney function to avoid accumulation and toxicity.
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Drug excretion is the removal of drugs from the body, either as a metabolite or unchanged drug.
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There are many different routes of excretion, including urine, bile, sweat, saliva, tears, milk, and stool.
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By far, the most important excretory organs are the kidney and liver.
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SUMMARY:
ABSORPTION
Refers to the movement of a drug from its site of administration into systemic circulation.
DISTRIBUTION
Describes the reversible transfer of a drug between the blood and tissues.
METABOLISM
Primarily occurs in the liver and involves converting lipophilic compounds into more hydrophilic metabolites for easier excretion.
EXCRETION
The process of eliminating the parent drug and its metabolites from the body, primarily through the kidneys (renal excretion).