Glossary

11.2 Drug categories and mechanisms of action

8 min read•august 14, 2024

Drugs interact with our nervous system in complex ways, affecting neurotransmitters and receptors. Understanding how they work helps us use them safely and effectively. From pain relievers to antidepressants, each drug has a unique mechanism of action.

Classifying drugs by how they work in the brain helps us predict their effects and side effects. Some drugs mimic natural brain chemicals, while others block or enhance their actions. This knowledge guides doctors in choosing the right medication for each patient's needs.

Drug classification by mechanism

Classifying drugs based on their primary mechanism of action

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  • Drugs can be classified based on their primary mechanism of action in the nervous system, which involves interacting with specific systems or receptors
  • Major classes of drugs based on their mechanisms of action include:
    • Agonists: Drugs that bind to and activate receptors, mimicking the effects of endogenous neurotransmitters (, )
    • Antagonists: Drugs that bind to receptors and block the effects of endogenous neurotransmitters or agonists (, )
    • Reuptake inhibitors: Drugs that block the reuptake of neurotransmitters from the synaptic cleft, increasing their availability and prolonging their effects (, )
    • Enzyme inhibitors: Drugs that inhibit the enzymes involved in the synthesis, metabolism, or degradation of neurotransmitters, altering their levels in the nervous system (, acetylcholinesterase inhibitors)

Examples of drug classes and their primary mechanisms of action

  • (morphine, fentanyl) are agonists at opioid receptors, producing analgesia and
  • (diazepam, alprazolam) are agonists at receptors, producing anxiolytic and sedative effects
  • (SSRIs; fluoxetine, sertraline) block the reuptake of , increasing its availability and producing antidepressant effects
  • (haloperidol, clozapine) are antagonists at dopamine receptors, reducing the positive symptoms of schizophrenia
  • (donepezil, rivastigmine) inhibit the enzyme acetylcholinesterase, increasing the levels of acetylcholine and improving cognitive function in Alzheimer's disease

Drug-neurotransmitter interactions

Receptor binding and neurotransmitter levels

  • Drugs interact with neurotransmitter systems by binding to specific receptors or altering the levels of neurotransmitters in the synaptic cleft
  • Receptor binding: Drugs can bind to neurotransmitter receptors as agonists, antagonists, or modulators, altering the receptor's activity and downstream signaling pathways
    • Agonists activate receptors, producing effects similar to the endogenous neurotransmitter (morphine activating opioid receptors)
    • Antagonists block receptors, preventing the binding of endogenous neurotransmitters or agonists and reducing their effects (naloxone blocking opioid receptors)
    • Modulators can enhance or inhibit the effects of endogenous neurotransmitters without directly activating or blocking the receptor (benzodiazepines enhancing the effects of GABA)
  • Neurotransmitter levels: Drugs can alter the levels of neurotransmitters in the synaptic cleft by influencing their synthesis, release, reuptake, or degradation
    • Reuptake inhibitors block the reuptake of neurotransmitters, increasing their availability in the synaptic cleft and prolonging their effects (SSRIs blocking serotonin reuptake)
    • Enzyme inhibitors can inhibit the synthesis, metabolism, or degradation of neurotransmitters, altering their levels in the nervous system (MAO inhibitors increasing monoamine levels)

Effects on neuronal activity and downstream signaling

  • The effects of drugs on neurotransmitter systems can lead to changes in neuronal activity, synaptic plasticity, and downstream signaling cascades, ultimately influencing behavior, cognition, and physiological processes
  • Changes in neuronal activity: Drugs can increase or decrease the firing rate of neurons by modulating the balance of excitatory and inhibitory neurotransmission (benzodiazepines increasing inhibitory GABA signaling)
  • Synaptic plasticity: Drugs can induce long-term changes in synaptic strength and connectivity, contributing to the development of , , and addiction (opioids inducing long-term potentiation in reward pathways)
  • Downstream signaling cascades: Drugs can activate or inhibit intracellular signaling pathways, leading to changes in gene expression, protein synthesis, and cellular function (antidepressants increasing BDNF signaling and neurogenesis)

Types of receptor interactions

Agonists and antagonists

  • Agonists are drugs that bind to and activate neurotransmitter receptors, producing effects similar to the endogenous neurotransmitter
    • Full agonists maximally activate the receptor, producing the same maximal response as the endogenous neurotransmitter (morphine at opioid receptors)
    • Partial agonists partially activate the receptor, producing a submaximal response compared to the endogenous neurotransmitter (buprenorphine at opioid receptors)
  • Antagonists are drugs that bind to neurotransmitter receptors and block the effects of endogenous neurotransmitters or agonists
    • Competitive antagonists compete with the endogenous neurotransmitter or for receptor binding, reducing their effects (naloxone at opioid receptors)
    • Non-competitive antagonists bind to a different site on the receptor, preventing receptor activation regardless of the concentration of the endogenous neurotransmitter or agonist (ketamine at NMDA receptors)

Modulators

  • Modulators are drugs that can enhance or inhibit the effects of endogenous neurotransmitters without directly activating or blocking the receptor
  • Positive allosteric modulators bind to a site distinct from the neurotransmitter binding site and enhance the receptor's response to the endogenous neurotransmitter (benzodiazepines at GABA receptors)
  • Negative allosteric modulators bind to a site distinct from the neurotransmitter binding site and reduce the receptor's response to the endogenous neurotransmitter (pregabalin at voltage-gated calcium channels)
  • Allosteric modulators can provide a more subtle and targeted approach to modulating neurotransmitter signaling compared to direct agonists or antagonists
  • Examples of allosteric modulators include benzodiazepines (positive allosteric modulators of GABA receptors) and NAMs of mGluR5 receptors (negative allosteric modulators of metabotropic glutamate receptors)

Pharmacokinetic processes of drugs

Absorption, distribution, metabolism, and excretion (ADME)

  • Pharmacokinetics refers to the processes of drug absorption, distribution, metabolism, and excretion (ADME) in the body
  • Absorption: The process by which a drug enters the bloodstream from the site of administration
    • Factors influencing absorption include the route of administration (oral, intravenous, intramuscular), drug formulation, and physicochemical properties of the drug (lipophilicity, molecular size)
    • Bioavailability refers to the fraction of the administered dose that reaches the systemic circulation unchanged (oral morphine has lower bioavailability than intravenous morphine)
  • Distribution: The process by which a drug is transported from the bloodstream to various tissues and organs
    • Distribution is influenced by factors such as blood flow, tissue permeability, and drug binding to plasma proteins and tissues (highly protein-bound drugs have limited distribution)
    • The volume of distribution (Vd) describes the apparent volume in which a drug is distributed in the body (drugs with high Vd have extensive tissue distribution)
  • Metabolism: The process by which a drug is chemically modified or biotransformed by enzymes, primarily in the liver
    • Metabolism can result in the activation of prodrugs, the inactivation of active drugs, or the formation of active or inactive metabolites (codeine is metabolized to morphine by CYP2D6)
    • Cytochrome P450 (CYP) enzymes play a major role in drug metabolism, and genetic variations in CYP enzymes can influence drug response and toxicity (CYP2D6 poor metabolizers have reduced conversion of codeine to morphine)
  • Excretion: The process by which a drug and its metabolites are eliminated from the body, primarily through the kidneys and bile
    • Renal excretion involves glomerular filtration, tubular secretion, and tubular reabsorption (morphine and its metabolites are primarily excreted in urine)
    • Biliary excretion involves the transport of drugs and metabolites from the liver into the bile, which is then eliminated in the feces (some drugs undergo enterohepatic recirculation)
    • The elimination half-life (t1/2) is the time required for the plasma concentration of a drug to decrease by 50% during the elimination phase (morphine has a t1/2 of 2-3 hours)

Factors influencing pharmacokinetics

  • Route of administration: Different routes of administration (oral, intravenous, intramuscular, transdermal) can influence the absorption, bioavailability, and onset of action of drugs
  • Drug formulation: The physical form of a drug (tablet, capsule, solution, suspension) can affect its absorption and bioavailability
  • Physicochemical properties: The lipophilicity, molecular size, and ionization of a drug can influence its absorption, distribution, and excretion
  • Genetic variations: Polymorphisms in drug-metabolizing enzymes (CYP enzymes) and drug transporters (P-glycoprotein) can lead to interindividual variability in drug pharmacokinetics and response
  • Disease states: Hepatic or renal impairment can alter the metabolism and excretion of drugs, requiring dose adjustments or contraindications
  • Drug interactions: Concomitant use of drugs that induce or inhibit drug-metabolizing enzymes or transporters can affect the pharmacokinetics and efficacy or toxicity of other drugs (rifampin induces CYP enzymes, grapefruit juice inhibits CYP3A4)

Dose-response relationships

Relationship between drug dose, receptor occupancy, and effects

  • The relationship between drug dose, receptor occupancy, and therapeutic or adverse effects is a key consideration in pharmacology and drug development
  • Dose-response relationship: The relationship between the dose of a drug and its observed effects, which can be described by a dose-response curve
    • Therapeutic window: The range of drug doses that produce therapeutic effects without causing unacceptable adverse effects (a wide therapeutic window is desirable for safe and effective use)
    • Potency: The dose of a drug required to produce a specific effect, often expressed as the EC50 (the concentration that produces 50% of the maximal effect) or ED50 (the dose that produces 50% of the maximal effect) (morphine is more potent than codeine)
    • Efficacy: The maximum effect that a drug can produce, regardless of the dose (full agonists have higher efficacy than partial agonists)
  • Receptor occupancy: The fraction of receptors bound by a drug at a given concentration or dose
    • The relationship between receptor occupancy and drug effects can be described by the occupancy-response curve (higher occupancy generally leads to greater effects)
    • The occupancy required for therapeutic effects may differ from the occupancy associated with adverse effects, allowing for the separation of desired and undesired drug actions (antipsychotics aim for D2 receptor occupancy in the therapeutic range)

Therapeutic index and factors influencing dose-response relationships

  • Therapeutic index: The ratio of the dose that produces therapeutic effects to the dose that produces adverse effects, reflecting the safety margin of a drug
    • A high therapeutic index indicates a wide separation between the therapeutic and toxic doses, suggesting a favorable safety profile (acetaminophen has a high therapeutic index)
    • A low therapeutic index indicates a narrow separation between the therapeutic and toxic doses, requiring careful dosing and monitoring to avoid adverse effects (digoxin has a low therapeutic index)
  • Factors influencing the relationship between dose, receptor occupancy, and effects include:
    • Receptor density and distribution in target tissues (higher receptor density may require higher doses for effective occupancy)
    • Receptor affinity and selectivity of the drug (higher affinity and selectivity can lead to greater potency and fewer off-target effects)
    • Pharmacokinetic properties of the drug (ADME) (drugs with poor absorption or rapid metabolism may require higher doses)
    • Interindividual variability in drug response due to genetic, environmental, and pathophysiological factors (CYP enzyme polymorphisms can affect drug metabolism and response)
  • Understanding the dose-response relationship and factors influencing it is crucial for optimizing drug therapy, minimizing adverse effects, and developing new drugs with improved safety and efficacy profiles

Key Terms to Review (33)

Acetylcholine: Acetylcholine is a neurotransmitter that plays a vital role in communication between neurons and is involved in various physiological functions such as muscle contraction, memory, and attention. It is found both in the central nervous system and the peripheral nervous system, influencing numerous neural pathways and processes.
Agonist: An agonist is a substance that binds to a receptor and activates it to produce a biological response. These molecules mimic the action of naturally occurring neurotransmitters, enhancing or facilitating their effects in the nervous system. By doing so, agonists play crucial roles in various physiological processes and are integral in understanding how different drugs interact with neural pathways.
Antagonist: An antagonist is a substance that binds to a receptor and inhibits or blocks its activity, preventing the natural ligand from eliciting a biological response. By interfering with receptor activation, antagonists play crucial roles in pharmacology and neuropharmacology, as they can modulate various physiological processes and behaviors by counteracting the effects of agonists.
Antipsychotics: Antipsychotics are a class of medication primarily used to manage symptoms of psychosis, including hallucinations, delusions, and disorganized thinking. They work by altering the effects of neurotransmitters in the brain, particularly dopamine and serotonin, which play crucial roles in mood regulation and perception. Understanding how these medications interact with synaptic transmission and their mechanisms of action is essential for grasping their therapeutic roles in psychiatric disorders.
Benzodiazepines: Benzodiazepines are a class of medications primarily used to treat anxiety, insomnia, and other related disorders by enhancing the effects of a neurotransmitter called gamma-aminobutyric acid (GABA) in the brain. These drugs work by binding to specific sites on GABA receptors, leading to increased inhibitory neurotransmission, which helps reduce neuronal excitability. Their use is particularly relevant in the context of anxiety disorders and post-traumatic stress disorder, where they can provide rapid relief from acute symptoms.
Cholinesterase inhibitors: Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine, a neurotransmitter essential for communication between nerve cells. By inhibiting the enzyme acetylcholinesterase, these drugs enhance cholinergic transmission, which is crucial for memory and learning processes. They are often used in the treatment of cognitive disorders, particularly Alzheimer's disease, where impaired cholinergic signaling contributes to memory deficits.
Cognitive-Behavioral Therapy: Cognitive-behavioral therapy (CBT) is a widely used psychotherapeutic approach that focuses on changing unhelpful cognitive distortions and behaviors, aiming to improve emotional regulation and develop personal coping strategies. CBT emphasizes the connection between thoughts, feelings, and behaviors, helping individuals identify and challenge negative thought patterns that contribute to psychological distress, particularly in conditions like anxiety and depression.
David Nutt: David Nutt is a prominent British psychiatrist and neuroscientist known for his research on the effects of drugs on the brain and his advocacy for evidence-based drug policy. His work has significantly influenced the understanding of drug categories and mechanisms of action, particularly in the context of psychoactive substances and their potential therapeutic applications. Nutt's efforts have sparked discussions on the social and legal implications of drug use, highlighting the importance of scientific evidence in shaping public policy around drugs.
Dependence: Dependence refers to a state where an individual relies on a substance, such as drugs or alcohol, to function normally, often leading to compulsive use despite negative consequences. This reliance can develop through physical or psychological means, impacting the brain's reward system and resulting in withdrawal symptoms when the substance is not consumed.
Dopamine: Dopamine is a neurotransmitter that plays several important roles in the brain, influencing mood, motivation, reward, and motor control. It is critical in many neural pathways, connecting various brain regions and affecting behavior and cognitive functions.
Enzyme inhibitor: An enzyme inhibitor is a molecule that binds to an enzyme and decreases its activity, preventing it from catalyzing a reaction. This interaction can significantly impact biochemical pathways and is crucial in understanding how various drugs exert their effects on the body, as they can either enhance or block the action of specific enzymes.
Euphoria: Euphoria is a profound sense of happiness or well-being that can be triggered by various stimuli, including psychoactive substances. It often involves intense feelings of joy, excitement, or elation and can significantly influence behavior and motivation. Understanding euphoria is essential in the context of how different drugs can induce these feelings through their effects on brain chemistry and the mechanisms that underlie their action.
Flumazenil: Flumazenil is a medication primarily used as a benzodiazepine antagonist, which means it can reverse the effects of benzodiazepines in cases of overdose or sedation. This drug works by competitively inhibiting the action of benzodiazepines at their binding sites on the GABA-A receptor, leading to a restoration of normal neural activity that may have been depressed due to these sedatives. Understanding flumazenil is essential in the context of drug categories and mechanisms of action, especially for its role in treating benzodiazepine toxicity.
Functional MRI: Functional MRI (fMRI) is a neuroimaging technique that measures and maps brain activity by detecting changes in blood flow and oxygen levels. This non-invasive method allows researchers and clinicians to observe brain functions in real-time, making it essential for understanding various neural processes related to cognition, emotion, and motor control.
GABA: GABA, or gamma-aminobutyric acid, is the primary inhibitory neurotransmitter in the brain that plays a crucial role in reducing neuronal excitability throughout the nervous system. It helps maintain a balance between excitatory and inhibitory signals, influencing various functions such as mood, motor control, and cognitive processes.
Hallucination: A hallucination is a perception of something that is not present in reality, experienced as if it were real. This phenomenon can occur in various forms, including auditory, visual, tactile, or olfactory experiences, and is often associated with alterations in brain function or sensory processing. Hallucinations are commonly linked to certain drug categories and their mechanisms of action, which can affect neurotransmitter systems and brain regions involved in perception.
Harm reduction: Harm reduction refers to a set of strategies aimed at minimizing the negative health, social, and legal impacts associated with drug use. This approach recognizes that while substance use can pose significant risks, completely eliminating drug use may not be feasible for everyone. Instead, harm reduction seeks to reduce the harmful consequences of drug use through various means, including education, access to clean needles, and safe consumption spaces, which all connect deeply with understanding drug categories, their mechanisms of action, and the brain's response to psychoactive substances as well as addiction and substance abuse disorders.
Mao inhibitors: MAO inhibitors are a class of medications that block the activity of monoamine oxidase (MAO), an enzyme responsible for breaking down neurotransmitters such as serotonin, dopamine, and norepinephrine in the brain. By inhibiting this enzyme, these drugs increase the levels of these neurotransmitters, which can help alleviate symptoms of depression and anxiety. This mechanism is important in understanding how different drug categories function and interact with neurotransmitter systems.
Naloxone: Naloxone is a medication used to rapidly reverse opioid overdose by acting as an opioid antagonist. It works by binding to the same receptors in the brain that opioids do, effectively displacing them and blocking their effects, which can help restore normal breathing and consciousness in individuals experiencing an overdose. Understanding naloxone is crucial in the context of drug categories and mechanisms of action as it highlights the therapeutic potential of antagonists in opioid-related emergencies.
Neuropharmacology: Neuropharmacology is the study of how drugs affect the nervous system and behavior. This field focuses on the interactions between chemical substances and neural mechanisms, which includes understanding how different drug categories influence neurotransmission and neuroreceptors. By examining these connections, neuropharmacology helps identify potential therapeutic targets for treating neurological disorders and mental health issues.
Neuroplasticity: Neuroplasticity is the brain's ability to reorganize itself by forming new neural connections throughout life, allowing it to adapt to changes, learn new information, and recover from injuries. This concept is fundamental to understanding how the brain develops and functions, emphasizing that it is not a static organ but rather a dynamic system capable of change in response to experience and environment.
Neurotoxicity: Neurotoxicity refers to the damaging effects of substances on the nervous system, leading to dysfunction or destruction of nerve cells. This can occur due to exposure to various drugs, environmental toxins, or other harmful agents that disrupt normal neural function, impacting everything from cognitive abilities to motor skills. Understanding neurotoxicity is crucial for identifying how certain drugs and chemicals can adversely affect brain health and contribute to neurological disorders.
Neurotransmitter: A neurotransmitter is a chemical messenger that transmits signals across a synapse from one neuron to another, playing a crucial role in communication within the nervous system. They help modulate various functions including mood, memory, and motor control, and their mechanisms of action are fundamental to understanding how drugs affect brain activity.
Oliver Sacks: Oliver Sacks was a renowned neurologist and author known for his compelling case studies of individuals with neurological disorders. His work brought attention to the human side of neuroscience, illustrating how brain conditions affect patients' lives and perceptions, and he often explored themes of identity and consciousness in relation to drug effects and treatment mechanisms.
Opioids: Opioids are a class of drugs that include both natural and synthetic compounds that bind to opioid receptors in the brain, producing pain-relieving effects. These substances are often used medically to manage pain but can also lead to significant addiction and misuse. Understanding their mechanisms of action is crucial for recognizing their impact on the brain and behavior.
Reuptake inhibitor: A reuptake inhibitor is a type of drug that blocks the reabsorption of neurotransmitters by neurons, leading to increased levels of these chemicals in the synaptic cleft. This mechanism enhances neurotransmission and is commonly utilized in treating various mental health disorders, such as depression and anxiety. By preventing the uptake of neurotransmitters like serotonin, dopamine, or norepinephrine, reuptake inhibitors promote greater availability of these critical signals between neurons.
Sedation: Sedation is a medical process used to calm or relax a patient, often through the administration of drugs that depress the central nervous system. This term is closely tied to the effects of various drug categories, particularly those used in anesthesia and anxiolytics, which help reduce anxiety and induce a tranquil state, facilitating medical procedures or aiding in treatment.
Selective Serotonin Reuptake Inhibitors: Selective serotonin reuptake inhibitors (SSRIs) are a class of medications commonly prescribed to treat depression and anxiety disorders by increasing the levels of serotonin in the brain. They work by selectively blocking the reabsorption (reuptake) of serotonin in the synaptic cleft, making more serotonin available to bind to receptors and enhance mood and emotional regulation. SSRIs are crucial in the field of neuropharmacology, illustrating how drug mechanisms can target specific neurotransmitter systems to address mood disorders and anxiety-related conditions.
Serotonin: Serotonin is a neurotransmitter that plays a key role in regulating mood, emotions, and various physiological processes in the body. It's involved in functions like sleep, appetite, and digestion, and is often linked to feelings of well-being and happiness.
SNRIs: SNRIs, or serotonin-norepinephrine reuptake inhibitors, are a class of antidepressant medications that work by increasing the levels of serotonin and norepinephrine in the brain. These neurotransmitters play a crucial role in regulating mood and emotional responses, making SNRIs effective for treating major depressive disorder, anxiety disorders, and other mood-related conditions. By inhibiting the reuptake of both serotonin and norepinephrine, SNRIs enhance neurotransmission and can help alleviate symptoms associated with depression and anxiety.
SSRIs: Selective Serotonin Reuptake Inhibitors (SSRIs) are a class of medications commonly used to treat depression and anxiety by increasing levels of serotonin in the brain. They work by blocking the reabsorption (reuptake) of serotonin in the synaptic cleft, making more serotonin available for neurotransmission. By enhancing serotonin signaling, SSRIs help alleviate mood disorders and improve emotional well-being, highlighting their role in synaptic transmission and neuropharmacology.
Tolerance: Tolerance refers to the body's decreased response to a drug after repeated use, requiring higher doses to achieve the same effect. This phenomenon occurs due to physiological adaptations in the brain and body, impacting how drugs interact with receptors and neurotransmitter systems over time. Understanding tolerance is crucial in examining how different drug categories work and their various mechanisms of action, as well as recognizing the profound effects of psychoactive substances on brain function.
Withdrawal: Withdrawal refers to the physical and psychological symptoms that occur when a person reduces or stops the intake of a substance they have become dependent on. This process can result in a range of unpleasant effects, highlighting the body's adaptation to the presence of drugs, especially in cases of prolonged use. The severity and nature of withdrawal symptoms can vary based on the substance involved, the duration of use, and individual differences in metabolism and neurochemistry.
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