Pharmacodynamics and Autacoids

Pharmacodynamics

• Pharmacodynamics is the study of the biochemical, cellular, and physiological effects of drugs, including the molecular mechanisms by which these actions are achieved.
• Effect on the body: Mechanism of Action (MOA)
• Integration of molecular actions into the overall response of the body.
• Quantitative terms, including:
  • Dose-response relationship
  • Relationship between drug concentration and pharmacological response
  • Largely based on the concept of drug–receptor binding
  • Therapeutic and toxic effects of drugs —interaction with receptors

Must-Know Terminologies

• Drug: A chemical substance of known structure that produces a biological effect.
• Receptor: A molecule (usually a protein) that a drug binds to in order to bring about a change in function of the biological system.
• Affinity: The strength of attraction between a drug and its receptor.
• Intrinsic Activity / Efficacy: The ability of a drug, once bound to the receptor, to elicit the pharmacologic response.
• Potency: A relative measure of the amount of a drug required to produce a specific level of response.
  • Determined by the affinity.
• Selectivity / Specificity: The measure of a receptor’s ability to respond to only one/single ligand.
• Ligand: A substance that forms a complex with a biomolecule to serve a biological function.

Types of Drugs

• Functional Modifiers
  • Purpose: Alter normal physiological processes in the body.
  • Example: NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) that relieve pain sensation.
• Replenishers
  • Purpose: Supplement the existing endogenous compounds that are deficient or lacking in concentration.
  • Example: Insulin for Type 1 Diabetes Mellitus; Oral Rehydration Solutions (ORS) for dehydration.
• Diagnostics
  • Purpose: Used to determine the presence or absence of disease.
  • Example: Tensilon test for diagnosing Myasthenia Gravis; Barium sulfate for gastrointestinal (GIT) disorders.
• Chemotherapeutics
  • Purpose:
    • Anti-neoplastics: Kill or inhibit the growth of cancer cells.
    • Anti-microbials: Kill or inhibit the growth of microbes (bacteria, fungi, viruses).
  • Example: Chemotherapy drugs for cancer treatment; Antibiotics for bacterial infections.

Drug Action: Cellular Level

• John Newport Langley
  • "There are some substances in the nerve endings or gland cells with which atropine and pilocarpine are capable of forming compounds." — Receptive substance
• Paul Ehrlich
  • “…a drug could have a therapeutic effect only if it has the right sort of affinity.” — In 1909, introduced the term “Receptor"

The Receptor Concept

• A component of the biological system to which a drug binds to bring about a change in the system's function.
• A molecule that interacts with a ligand (drug) to mediate a pharmacologic effect.
• DRUG + RECEPTOR → DRUG-RECEPTOR COMPLEX → ALTERED FUNCTION
• Mostly proteins (can also be nucleic acids like DNA or RNA).
• Can change function by modifying the rate of ongoing processes, but do not introduce new functions.
• Receptors largely determine the quantitative relationship between the dose or concentration of a drug and its pharmacologic effects.
• Receptors are responsible for the selectivity of drug actions, often working in a LOCK AND KEY fashion.
• Receptors mediate the actions of pharmacologic agonists and antagonists.
• Receptors act as regulatory proteins and components of chemical signaling mechanisms that target important drugs.
• They are key determinants of the therapeutic and toxic effects of drugs in patients.

Main Receptor Functions

• Recognition: The receptor protein must allow for the sensing, recognition, and binding of a compound.
• Transduction: The receptor must be able to transmit the message into the cell to elicit a functional response (biological or physiological).

1) Ligand Binding (Recognition)

• Affinity: Describes how strongly the drug and the receptor interact.
• Forces Mediating Ligand-Receptor Binding:
  • Van der Waals forces
  • Ionic bonds
  • Hydrogen bonds
  • Hydrophobic interactions
  • Covalent bonds
• Specificity: Refers to the selectivity a receptor has for a particular drug.
  • Chemical nature
  • Dosage
  • Routes of administration
  • Special features of the recipient (e.g., patient’s profile)

2) Activation of Effector Mechanism (Transduction)

• Effectors are components of the biological system that accomplish the biological effect after being activated by the receptor.
• Effectors are molecules that translate the drug-receptor interaction into a change in cellular activity.
• Example: Adenylyl cyclase

General Properties of Receptors

• Saturability: Receptors exist in finite numbers.
• Selectivity: Receptors must be selective in their ligand-binding characteristics (so as to respond to the proper chemical signal and not to meaningless ones).
• Stereoselectivity
• Modifiability of Conformational State: (so as to bring about the functional change).

How Do Cells Communicate? Cell Signaling

• Cells can communicate with one another.
• Cells can influence the behavior of another cell.
  • Example: Yeast cells communicate and influence one another’s proliferation in preparation for sexual mating by secreting several kinds of small peptides.
• Cells can respond sensitively to small changes in the concentration of an extracellular signaling molecule.

Forms of Cell Signaling

1. Endocrine

• A chemical messenger is released into the circulation to produce effects distant from the point of release.
• Also referred to as a hormone.
• Originally, hormones were considered a product of a ductless gland; however, many organs are now considered "endocrine."

2. Paracrine

• A chemical messenger is released from one cell to produce effects on a neighboring cell.
• Examples include neurotransmitters, cytokines, morphogens, and many growth factors which exert paracrine effects.

3. Autocrine

• A chemical messenger that exerts actions on the same cell from which it is released.
• Many endocrine and paracrine factors also play roles in autocrine signaling, exerting negative or positive feedback on their own release. This is especially important in neuronal and cytokine signaling.

4. Juxtacrine

• A chemical messenger that remains affixed to the cell in which it is produced and exerts actions on a physically juxtaposed cell.
• An example of juxtacrine signaling is the mechanism by which a T cell and an antigen-presenting cell establish an immunological "synapse."

5. Synaptic

• A neurotransmitter is released and acts on the postsynaptic target cell.
• Example: Cholinergic and adrenergic transmission.

Types of Receptors: Overview

• Ligand-regulated ion channel
  • Example: Nicotinic cholinergic receptor
• G protein-coupled receptors
  • Example: Beta-adrenergic receptor (Gs)
  • Example: Muscarinic cholinergic receptor (Gq)
• Receptor protein kinases (receptors on membrane-spanning enzymes)
  • Example: Tyrosine Kinase/Insulin Receptor
• Receptors with separate protein kinases
  • Example: Cytokine receptors
• Intracellular receptor
  • Example: Steroid hormone receptor

Energy-Independent Carrier Molecules

• Function: Facilitate the passage of ions or molecules across cell membranes by altering their conformation from a rested state to an activated state.
• Classes:
  • Uniporters
  • Symporters
  • Antiporters

Uniporters

• Transport proteins that move a substance from one side of the membrane to the other.

Symporters

• Transport proteins that simultaneously move two substances across the membrane in the same direction.

Antiporters

• Transport proteins that move one substance across the membrane in one direction while simultaneously transporting a second substance in the opposite direction.
• Example: $Na^{+}/Ca^{2+}$ exchanger.

Pumps

• Translocate their passenger through altered conformation, where proteins are converted into an enzyme that hydrolyzes ATP (energy-dependent).
• Example: $Na^{+}/K^{+}-ATPase$.

Drug-Receptor Interaction Must-Know Terminologies

Agonist

• Agonists are drugs capable of binding to and activating a receptor.
• Example: Loxapine directly stimulates cholinergic receptors and is thus an agonist.

Full Agonist:

• Occupies receptors to cause maximal activation.
• Intrinsic activity = 1 (this means it causes the maximum possible response when binding to the receptor).
• EXAMPLE: MORPHINE (Full Agonist)

Partial Agonist:

• Occupies receptors but cannot elicit a maximal response.
• Has an intrinsic activity of <1.
• EXAMPLE: NALBUPHINE (Nubaine) - analgesic but has no bradycardic effect

Antagonist

• Bind to the receptor but do not initiate a response.
• Function: They block the action of an agonist or an endogenous substance that normally works through the receptor (prevents agonist binding).

Inverse Agonist

• A drug that binds to the inactive state of receptor molecules and decreases constitutive activity.

Constitutive Activity

• Refers to the baseline activity of receptors or enzymes in the absence of any ligand (activating substance).
• This activity can be affected by drugs, such as inverse agonists, which can decrease the baseline activity.
• GPCRs (G-protein coupled receptors) can be active even without a ligand (constitutive activity).
• Inverse agonists reduce this self-activation.

Receptor Properties

• Proteins:
  • Most receptors are proteins.
• Regulatory Proteins:
  • These mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones.
  • (Autacoids = locally acting signaling molecules) Histamine / Prostaglandin
• Enzymes:
  • Receptors can also be enzymes, which may be inhibited (or less commonly activated) by binding a drug.
  • Example: Dihydrofolate reductase.
• Transportation Proteins:
  • Example: Sodium/Potassium ATPase (affected by digoxin, a cardiac glycoside).
• Structural Proteins:
  • Example: Tubulin (affected by colchicine, which inhibits tubulin polymerization).

Receptor Theories

Dose-Response Theory (Clark, 1933):

• "The increase in response to a drug depends on the increased binding of the drug to receptors."
• Dose & Efficacy:
  • Drug response is proportional to the number of receptors occupied.
  • It is assumed that all drug-receptor interactions are reversible.
  • It is assumed that drug binding to receptors represents only a fraction of the available drug.
  • It is assumed that each receptor binds only one drug.

Ariens and Stephenson (1956)

• AKA: Occupancy Theory
• Drug response depends on both the affinity of a drug for its receptors and the drug's efficacy.
• They described spare receptors.
• They proposed that a maximal response can be achieved even if a fraction of the receptors are unoccupied.
• This theory is generally accepted.

Paton’s Theory (Rate Theory)

• The intensity of the pharmacological effect is directly proportional to the total number of encounters between the drug and its receptor per unit time.
• It focuses on how fast a drug associates and dissociates from the receptor, rather than just the number of receptors bound.
• Each encounter elicits a response.
• Limitation:
  • Does not explain the maximum effect

Lock & Key Theory (Induced-fit Theory)

• The three-dimensional shape of the drug molecule acts like a key, which must fit precisely into the structure of the target (the lock) to activate it.
• Just like a lock and its key, the interactions between drugs and their targets are highly specific and based on physical shape interactions.
• The interaction is influenced by the physicochemical properties of both the drug and the receptor.

Drug-Receptor Interaction

• Receptors are modeled as having active and inactive conformational states.
• Ligands/drugs bind to specific receptors and affect their conformational states, with one state being favored over the other.
  • Agonist: Favors the active receptor conformation.
  • Antagonist: Favors the inactive receptor conformation.

Must-Know Concepts: Efficacy

• The degree to which a drug is able to induce maximal effects.
• Example:
  • Drug A reduces blood pressure by 20 mmHg.
  • Drug B reduces blood pressure by 10 mmHg.
  • Drug A has higher efficacy in this case.
• Efficacy is used to compare drugs with different mechanisms of action.
• Example:
  • Ketorolac (NSAID) has equal efficacy to morphine in controlling post-operative pain.

Potency

• The amount of drug required to produce 50% of the maximal response that the drug is capable of inducing.
• Example:
  • Both morphine and codeine are capable of relieving postoperative pain.
  • However, a smaller dose of morphine is required to achieve the same effect as codeine.
• Potency is used to compare drugs within a chemical class.
• Example:
  • Narcotic analgesics and corticosteroids often have similar efficacy if a high enough dose is given, but they differ in potency.

Agonist

• Bind to receptors and activate effector mechanisms, eliciting biological responses.
• Types of Agonists:
  • Partial Agonist
  • Full Agonist

Drug-Receptor Interaction

• Full Agonist:
  • Drugs that produce 100% of the maximum biological response.
  • They are not dependent upon potency to achieve their effect, regardless of:
    • Dosage strength
    • Potency
    • Protein dependence

Key Graph Interpretation

• X-axis = Dosage of the drug.
• Y-axis = Percent of maximum response.
• Example Dosages:
  • Partial Agonist → 0.0125
  • Full Agonist → 0.15
  • Regardless of dosage, the full agonist always reaches 100% response.

Partial Agonist

• Drugs that produce less than 100% of the maximum biological response, no matter how high the concentration is.
• Not dependent on potency to achieve their effect.

Partial Agonist Limitation

• Even with increased dosage, a partial agonist can never reach 100% response.
• Key Difference → Partial agonists have a ceiling effect, while full agonists do not.
• Potency ≠ Maximum Effect → Even if a drug is more potent, it doesn’t guarantee full activation.

Inverse Agonist

• Inactivates constitutively active receptors (receptors that can be activated even without an agonist).
• Inverse agonists bind to these receptors, stabilize them, and reduce their activity (negative intrinsic activity).

G-Protein Coupled Receptors (GPCRs):

• Some GPCRs are constitutively active, meaning they activate without a ligand (agonist).
• Inverse agonists block or reduce this spontaneous activation.
• Example: Beta-carbolines (e.g., beta-blockers)
  • Baroreceptor reflex: Regulates blood pressure, and beta-blockers protect this reflex.

Example Drug:

• Propranolol (a beta-blocker) can affect the baroreceptor reflex and regulate blood pressure.

Antagonist

• Bind to receptors but do not activate effector mechanisms (they do not produce biological effects).

Types of Antagonism:

• Competitive (Pharmacologic) Antagonism:
  • Equilibrium Competitive (Reversible)
  • Nonequilibrium Competitive (Irreversible)
• Noncompetitive Antagonism
• Functional (Physiologic) Antagonism
• Chemical Antagonism

Competitive Antagonism

• AKA: Pharmacologic Antagonism
• Combine with the same site on the receptor as the agonist, but their binding does not activate the receptor (i.e., intrinsic activity = 0).

Equilibrium Competitive:

• Bind reversibly to receptors at the same site as the agonist.
• Competitively prevent the agonist from binding to the receptor, causing a blockade of its effects.
• Graphically: This results in a rightward shift of the dose-response curve.
• Effects of the competitive antagonist can be overcome by increasing the concentration of the agonist.
• Lower potency but have no effect on efficacy because they produce the same maximum response as the agonist alone.

Non-Equilibrium Competitive

• Bind irreversibly to either the same site as the agonist or an alternative site, causing a blockade of the agonist's effects.
• Graphically: This is observed as a downward shift of the dose-response curve, with no potential for achieving the maximum response.
• Increasing concentrations of the agonist have no effect because the interaction is irreversible, and bound drugs are no longer available for activation.
• Lowers efficacy, but has no effect on potency.

Non-Competitive Antagonism

• The antagonist acts at a site beyond the receptor for the agonist.
• Difference between Non-Competitive and Non-Equilibrium Competitive Antagonist:
  • Non-Competitive Antagonist: Antagonizes agonists acting through more than one receptor system.
  • Non-Equilibrium Competitive Antagonist: Antagonizes agonists acting through one receptor system only.

Functional Antagonism

• AKA: Physiologic Antagonism
• It is not a molecular action of an antagonist.
• Describes the ability of an agonist (rather than an antagonist) to inhibit the response to a second agonist via activation of different receptors that are physically separate.
• Example:
  • Histamine promotes acid secretion, while Proton Pump Inhibitors (PPI) block acid secretion.
  • Pharmacologic antagonism → Same receptor, same site, different effects
  • Physiologic antagonism → Different receptors, different targets, alternate effects
• Example: Norepinephrine vs. Acetylcholine in the Heart
  • Norepinephrine (NE)
    • Receptor: Beta-1 (β1) adrenergic receptor
    • Effect: Increases heart rate (Tachycardia)
  • Acetylcholine (ACh)
    • Receptor: Muscarinic-2 (M2) receptor
    • Effect: Decreases heart rate (Bradycardia)
  • NE stimulates metabolism → increases heart rate (tachycardia).
  • ACh binds to M2 receptors → decreases heart rate (bradycardia).
  • This shows how different receptors can produce opposite physiological effects, making it an example of functional antagonism.

Chemical Antagonism

• Refers to an uncommon situation where two substances combine in solution, causing the effect of the active drug to be lost.
• Goal:
  • Change the chemical nature of the agonist or poison.
  • Prevent the binding of the agonist to its target.
• Mechanism of Action (MOA):
  • Chelation or Neutralization reaction.
• Example:
  • Dimercaprol binds to heavy metals (e.g., arsenic, mercury) and reduces toxicity.

Drug-Drug Interactions

Drug Action: Organism Level

Dose-Response Relationship

• The response to a drug is proportional to the concentration of the receptors that are bound (occupied) by the drug.
• Can be determined from blood concentration levels after a single dose administration.
• Two major types of dose-response relationships:
  • Graded Dose-Response
  • Quantal Dose-Response

Graded Dose-Response Curve

• The graded dose-response curve expresses an individual's response to increasing doses of a given drug.
• The magnitude of a pharmacologic response is proportional to the number of receptors with which a drug effectively interacts.
• The curve typically shows a sigmoidal shape, with the response increasing as the dose increases, and eventually reaching a plateau (maximum response).
• x-axis: $log_{10}(dose)$
• y-axis: % of maximum response
• $ED_{50}$: Dose that produces 50% of the maximum response
• Curve shape: Sigmoid (S-shaped)

Graded Dose-Response Relationship Characteristics

• Onset of Action:
  • Occurs when the drug is sufficiently absorbed to reach an effective blood level and is adequately distributed to elicit a therapeutic response.
• Peak Concentration ($C_{max}$):
  • Reached when the absorption rate equals the elimination rate.
    Time of Peak Concentration ($T_{max}$):
• The time to reach maximum concentration, which is not always comparable to the time of peak response.
• Duration of Action:
  • The time period during which the therapeutic effect continuously occurs.
• Potency
  • The relative amount of a drug needed to produce the desired response.
• Slope
  • Reflects the ability of the drug to produce an effect; steeper slopes indicate a greater response for a given dose.
• Biologic Variability
  • Varies among individuals in their intensity of response to the same concentration of a drug.
  • For example, fast acetylators vs slow acetylators bring about different responses to a drug.
• Maximal Efficacy ($E_{max}$)
  • The maximal effect that can be produced by a drug when the dose is increased, beyond which no further response is observed.
• Efficacy (Intrinsic Activity)
  • Measured along the y-axis of the dose-response curve.
  • Determined by the ability of the drug-receptor interaction to activate effector mechanisms.
  • Measured by $E_{max}$
• Potency
  • Determined by the affinity of the receptor for the drug.
  • Measured along the x-axis of the dose-response curve.
  • Measured by $ED_{50}$, the dose at which 50% of the maximal response is achieved.

Values That Can Be Obtained in Graded Dose Relationship:

• Maximal Efficacy ($E_{max}$):
  • The maximum effect that can be produced by a drug, regardless of dose increase.
• $EC<em>{50}$ ($ED</em>{50}$):
  • The concentration (or dose) of a drug that produces 50% of the maximum possible response.
• $K_D$ (Dissociation Constant):
  • The concentration of drug yielding 50% occupancy of the receptor.
  • Dependent on the affinity of a drug for its receptor.
  • High Affinity: Low $K_d$ – Drugs cannot be easily dissociated or removed from the receptor.
  • Low Affinity: High $K_d$ – Drugs can be easily dissociated or removed from the receptor.

Types of Interaction

Spare Receptors:

• Receptor Reserve: The proportion of receptors that are not required for the production of the maximal response.
• Exist if the maximal drug response is obtained at less than maximal.
• Determination is usually made by comparing the concentration for 50% of maximal effect ($EC<em>{50}$) with the concentration for 50% of maximal binding ($К</em>d$).
• $K_d$ = concentration of ligand at which 50% of the available receptors are bound.
• Spare receptors are said to exist if the $EC<em>{50}$ is less than the $K</em>d$.
• No receptors are said to exist if the $EC<em>{50}$ and the $K</em>d$ are equal.

Drug Action: Population Level

• Quantal Dose-Response Curve:

  • Relates the dosage of a drug to the frequency with which a designated response occurs within a population.
  • The response may be an “all-or-none” phenomenon (e.g., individuals either do or do not fall asleep after receiving a sedative) or some predetermined intensity of effect.

• $ED_{50}$ (Median Effective Dose)

  • The concentration or dose that causes a specified response in 50% of the population under study.

• $TD_{50}$ (Median Toxic Dose)

  • The dose required to produce a particular toxic effect in 50% of animals.

• $LD_{50}$ (Median Lethal Dose)

  • The dose required to produce a particular toxic effect in 50% of animals; the toxic effect being death of the animal.

• Therapeutic Index (TI)

  • A measure of a drug’s relative safety.
  • $TI = \frac{TD<em>{50}}{ED</em>{50}}$
    • Lower TI: Higher probability of toxicity and loss of efficacy.
    • Higher TI: Less likely to cause adverse effects.

• Therapeutic Window

  • A measure of a drug’s clinical safety.
  • The dosage range at which a drug is both safe and effective.

• Risk-Benefit Ratio

  • Used to describe the adverse effects of a drug in relation to its beneficial effects.
  • A greater risk would be accepted in the treatment of an otherwise fatal disease than in the treatment of a less serious one.
  • What is acceptable depends on the severity of the disease being treated.
  • “Clinical judgment”

• Post test:
  * Functional Antagonism
  * Epinephrine & Histamine
  * Norepinephrine & Acetylcholine
  * Isoproterenol & Acetylcholine
  * Glucocorticoid & Insulin
  * Propranolol & Epinephrine
  * Insulin & Glucagon
  * Receptor Antagonism
  * Acetylcholine & Atropine
  * Morphine & Naloxone
  * Flumazenil & Diazepam
  * Chemical Antagonism
  * Protamine Sulfate & Heparin
  * Calcium & Magnesium
  * BAL & heavy metals

Autacoids Introduction:

• Autacoids (or "autocoids") are biological factors that act like local hormones. They have a short duration of action and typically exert their effects near the site of synthesis.
• The term autacoid is derived from the Greek words “autos” (self) and “acos” (remedy or medicinal agent).
• These compounds are produced, act, and are metabolized locally. Although their effects are primarily localized, large quantities can sometimes enter systemic circulation.
• Autacoids influence various biological activities, including modulation of smooth muscle, glands, nerves, platelets, and other tissues.
• Autacoids are chemical mediators synthesized in specific tissues or areas where they also exert their effects. They play a role in physiological and pathophysiological responses to injury, often described as having a paracrine effect (acting locally).
• Autacoid modulators may interfere with autacoid synthesis, inhibit their release, or block the receptors on which they act.
• Examples of autacoids include serotonin, bradykinin, histamine, and eicosanoids, all of which are involved in processes like vasoconstriction, vasodilation, and inflammation.

Amino Acid Derivatives: Histamine

• Histamine was first synthesized in 1907 and later isolated from mammalian tissues.
• In humans, histamine is a key mediator of immediate allergic reactions (e.g., urticaria) and inflammatory responses, although it plays only a minor role in anaphylaxis.
• It also plays important roles in:
  * Gastric acid secretion
  * Chemotaxis
  * Neuromodulation
• Most tissue histamine is sequestered in granules (vesicles) within mast cells or basophils. The histamine content in tissues correlates with their mast cell density.
• In its bound form, histamine is biologically inactive.
• Mast cells are concentrated in areas prone to injury such as:
  * Nose, mouth, and feet
  * Internal body surfaces
  * Blood vessels—especially at pressure points and bifurcations

Storage & Release Immunologic Release:

• The primary pathophysiologic mechanism for histamine release from mast cells and basophils.
• This process is central to Type I hypersensitivity reactions (e.g., hay fever, urticaria).
• Released histamine contributes to:
  * Local vasodilation
  * Plasma leakage carrying mediators of inflammation and antibodies

Chemical/Mechanical Release:

• Certain amines and drugs (e.g., morphine, tubocurarine) can displace histamine from its bound, inactive form within cells.
• This release:
  * Does not require energy
  * Is not associated with mast cell injury or explosive degranulation
• Histamine release can also occur due to granule loss from mast cells, triggered by the rapid displacement of histamine by sodium ions in the extracellular fluid.

Histamine: Pharmacodynamics Major Physiologic Actions

Drugs: Histamine Agonists

• Histamine Phosphate – Used for diagnostic purposes in testing gastric acid secretion and pheochromocytoma.
• Betazole – An analog of histamine; an H2-receptor agonist with 10-fold selectivity for stimulating gastric acid production over vasodilation. Pentagastrin is also used for this purpose.
• Impromidine – Has 10,000-fold greater selectivity for H2 receptors.

Histamine Antagonists: Classification

• Antihistamines-Inverse agonists (competitive antagonists)
• Prevent mast cell degranulation by binding to IgE/Fc receptor complex
  * Example: Cromolyn Sodium
• Drugs that functionally counteract the effects of histamine
  * Example: Epinephrine

Drugs: H1-Antihistamines

• H1-antihistamines were the first type of antihistaminic drugs discovered; referred to as the “classical antihistaminics.”
• Traditionally believed to act as competitive antagonists of histamine receptors.
• Recent findings show that most, if not all, H1- antihistamines act as inverse agonists rather than receptor antagonists.

Pharmacokinetics: H1-Antihistamines

• Rapidly absorbed (oral administration; nasal spray)
• Peak blood concentrations: 1–2 hours
• Widely distributed throughout the body

Distribution & CNS Penetration

• First Generation: Enters the CNS readily
• Second Generation:
  * Less lipid-soluble
  * Substrates of P-glycoprotein transporter in the blood-brain barrier

Metabolism

• First Generation: Extensively metabolized in the liver by microsomal enzymes
• Second Generation: Metabolized by the CYP3A4 system
• Many H1 antagonists have active metabolites:
  * Hydroxyzine → Cetirizine
  * Terfenadine → Fexofenadine
  * Loratadine → Desloratadine

Duration of Action

• Most antihistamines: 4–6 hours
• Second-generation agents: 12–24 hours (also applies to meclizine)

Excretion

• Primarily excreted in the urine
• Cetirizine and Levocetirizine are excreted unchanged

Pharmacologic Effects of H1-Antihistamines

1. Sedation

• Intensity varies among chemical subgroups and among patients
• Unsuitable for daytime use
• Children (at normal doses): may show excitation instead of sedation
• Toxic doses: stimulation, agitation, seizures, coma

2. Antinausea and Antiemetic Effects

• Prevention of motion sickness
• Ineffective if nausea/vomiting is already present
• Doxylamine – used for N/V during pregnancy (BendectinⓇ; withdrawn in the US)

3. Anti-parkinsonism Effects

• Diphenhydramine – used to suppress extrapyramidal symptoms due to antipsychotic use
• Effective for acute dystonic reactions

4. Antimuscarinic Effects

• Seen in ethanolamine and ethylenediamine subgroups
• Atropine-like actions
• Useful in nonallergic rhinorrhea

5. Adrenoreceptor-Blocking Actions

• Phenothiazine subgroup → α-receptor blocking
• Can lead to orthostatic hypotension

6. Serotonin-Blocking Actions

• Cyproheptadine → blocks serotonin receptors
• Promoted as an anti-serotonin agent

7. Local Anesthesia

• Block sodium channels in excitable membranes
• Diphenhydramine and Promethazine → more potent than procaine
• Option for patients allergic to conventional local anesthetics