Pharmacology: Receptor Pharmacology

• Pharmacology studies drug-induced physiological processes
• Anesthesia necessitates a spectrum of drugs for surgical anesthesia, analgesia, amnesia, and muscle relaxation, with pain management as a clinical component.
• The patient's genetic profile impacts anesthesia outcomes
• Elderly patients show age-related receptor population declines and decreased pharmacodynamic responses.
• The focus is not only on the protein receptor site but also on its role as a regulator of the pharmacological response.
• Drug binding alters the receptor activity, either enhancing (propofol on GABA receptors), decreasing (ketamine on NMDA receptors), or triggering chain reactions (opioids on µ-opioid receptors).
• The protein's response is what causes the drug effect

Receptor Structure and Properties

• Receptors are proteins or other substances that bind to endogenous chemicals or drugs and cause an effect
• Receptors have sensitivity, selectivity, and specificity
• Drug responses occur at low concentrations, are produced by similar chemicals, and always elicit the same response from a given set of receptors.
• Drug-receptor bonds range from weakest to strongest: van der Waals, hydrophobic, hydrogen, ionic, and covalent.

Drug Receptors and Ligands

• The drug-receptor complex (DRC) involves drug alignment and attachment to a receptor
• Endogenous substances or drugs can complex with receptors and signal
• A ligand is a molecule binding with a receptor to produce a biological response, including endogenous chemicals as well as drugs.
• Six classes of drug-receptor proteins are based on genetic characteristics
• Complete receptor saturation by drug molecules is unnecessary for tissue response
• Duration from intravenous drug administration to tissue response reflects the time it takes for drug binding and conformational changes
• Receptors critical for anesthetic action reside in the lipid bilayer of cell membranes
• Intravenous anesthetics bind to membrane receptor channel proteins; GABA receptors are primary sites, except ketamine targets NMDA receptors
• Inhalation anesthetics bind to GABA-A receptors, inhibiting signal transduction by increasing chloride ion influx

Drug Bonding and Receptor Types

• Agonist drugs induce receptor proteins to fit the drug molecule, aided by van der Waals forces and ionic bonding
• Volatile anesthetics (desflurane, sevoflurane, isoflurane) and nitrous oxide bond to cell receptors using nonspecific hydrophobic bonding.
• Varieties of receptors for anesthesia include GABA, opioid, alpha, beta, acetylcholine, histamine subtypes, capsaicin, nicotinic, and muscarinic.
• Some drugs such as caffeine, insulin, steroids, theophylline, and milrinone, interact with intracellular proteins
• Some drugs like stomach antacids and chelating agents, do not act on protein receptors, but alter pH or bind cations
• Receptor numbers in cell membranes are dynamic, increasing (up-regulating) or decreasing (down-regulating) in response to stimuli

Receptor Response and Signal Transduction

• Nicotinic cholinergic receptors at the neuromuscular postsynaptic membrane are ionophore receptor complexes; ACh opens the channel, causing Na influx, action potential and muscle contraction.
• Adrenergic receptors are G protein-coupled receptors; they affect intracellular concentrations of second messengers like Ca and cAMP to transduce signals and alter behavior
• Signal transduction involves cells converting signals or stimuli
• When a drug binds to a G protein-coupled receptor, it initiates events
• Actions of common anesthetics are transduced through cell surface G protein-coupled receptors or GPCRs, linked to second messengers like cAMP or cGMP.

Drug Response Principles

• Signal transduction for GABA-A receptors involves chloride ion movement
• Drugs like ropivacaine, cisatracurium, and dexmedetomidine have selective receptor binding for better side effect profiles
• Drug Receptor Complex (DRC) = Tissue is derived from the Law of Mass Action
• Drug + Receptor = Drug Receptor Complex (DRC) = Tissue Response
• Propofol, ketamine, and epinephrine work on GABA, NMDA, and Alpha 1 receptors, respectively
• Tissue response to drugs varies by the individual due to differences in genetic and physiological state
• The extent of a drug's effect is proportional to the number of occupied receptors, according to the occupancy theory
• ED50 is the median effective dose, where 50% of the population responds
• Therapeutic index (LD50/ED50) measures drug safety margin for therapeutic effect

Drug-Receptor Interactions

• Advances in molecular receptor pharmacology shows how patient responses form from the drug-receptor interaction and leading to a response (FTR)
• Free drugs sufficiently occupy and activate receptors to create tissue response at a steady state.
• Pharmacologic agents produce physiological effects by acting with drug-specific receptors and changing cellular function
• Most receptors are cell membrane-bound proteins found in extracellular or intracellular locations

Receptor Occupancy and Drug Effects

• Percentage of receptors occupied by a drug does not equal the percentage of maximal effect produced
• Receptor systems have excess unoccupied receptors to promote drug-receptor complex formation and near-maximal drug effects at low concentrations and create safety
• Dose-Response Relationships: Dose related qualities include potency, affinity, efficacy, and population variability

Affinity, Potency, and Efficacy

• Affinity and efficacy impacts the degree of drug-receptor interaction for GABAA and propofol affecting the quantity of DRC at any moment.
• Potency distinguishes agonists that activate the same receptor and produce the same effect but require different concentrations -- potency is the lowest dose required.
• A drug's efficacy refers to its ability to produce the desired effects expected by stimulation of a given receptor population; the maximum effect achieved
• Potency correlates with affinity, increasing the receptor interaction as the receptor affinity increases
• EC50 gauges potency/affinity -- increasing EC50 reduces potency; decreasing EC50 increases potency.

Individual Variability and Drug Response

• Required dose for effect varies in patients
• Resistance means a patient requires greater (two- to threefold), variability in drug concentration and effect relationship is superimposed on pharmacokinetics.
• Pharmacokinetic analysis describes drug absorption, distribution, onset and magnitude
• Drug elimination kinetic analysis describes the duration

Drug Receptor Response Triad

• Conformational changes to the receptor protein results with drug combinations is key for tissue response
• Biosphere involvement after drug association regulates response onset-offset course
• Two-state model: receptors exist in activated or inactivated equilibrium
• Agonists balance towards activation, antagonists freeze the equilibrium and inverse agonists move toward inactivation
• Only 1% receptor occupancy is sufficient for a response to occur
• Synthesis and destruction of receptor proteins, takes minutes rather than days

Drug Interactions

• Addition effect: Combined drug effect through same mechanism equals individual actions e.g.(midazolam+diazepam)
• Synergism: Combined drug effect is greater than algebraic sum e.g. (midazolam+propofol.
• Potentiation: Enhancement through another drug, that provides no action alone e.g. (diazepam+opioid)
• Antagonism: Drug action opposes another's action e.g. (fentanyl+naloxone)

Antagonists

• Antagonists bind without activating the receptor, use ionic, hydrogen, and van der Waals interactions
• Pure pharmacologic antagonist drugs block with similar molecular structure, lack initiate receptor protein conformational shift for tissue response

Drug Receptor Binding

• Antagonists cause a rightward shift of the drug dose-response curve, as receptors are left unoccupied
• Large numbers of drug's receptors need antagonist-binding preventing pharmacologic effect
• Competitive Antagonists possess a property with weak affinity that may be displaced by an agonist (e.g., atropine, esmolol)
• High agonist concentrations override the blocking effect producing parallel shift without altered maximum effect
• Increasing concentration of agonists will shift the dose response and create a rightward relation

Noncompetitive and Agonist-Antagonists

• Noncompetitive antagonism is present when high agonist concentrations will not overcome the antagonism; either bound irreversibly or allosteric
• Noncompetitive antagonists bind irreversibly, shift dose curve, and decreases max effects
• Agonist-antagonist drugs have receptor protein affinity and activity but often less active

Antagonistic Actions

• Physiologic antagonism involves two agonist drugs binding different receptors
• Chemical antagonism drug action is blocked without receptor activity
• Protamine is positive bonds with Herparin to inactivate. e.g. Sugammadex

Agonists

• Agonists are drugs that bind, and stimulate receptors
• Differences in agonist potency show different affinity
• Most agonists attach through combining ionic hydrogen bonds making them reversible

Receptor States

• Receptors are either bound or unbound, agonist ligand will produce the effect
• Agonists shift the equilibrium toward activation
• Partial agonists activate without maximal effects even during high concentrations
• Inverses bind with agonists, can shift to inactivity

Receptor Adaptation

• Receptors adapt with environment and homeostatic control
• Constant Agonist stimulation equals desensitization decreasing the effects
• Antagonist increase sensitivity requiring higher dosage amounts to work
• Higher drug dosage equals tolerance as the effect diminishes

Grotein Signaling

• Sustained pathways will prevent G-protein to allow active become active heterotrimeric with non-G proteins receptors internalized/sequestered
• down regulation decreases number of receptors producing signal receptor inactivity
• Changes occur in concentrations (up or down)
• drug tolerance increases
• Constant exposure of drug causes the body to break the drugs efficacy.