Pharmacodynamics: Drug Action & Receptors

Pharmacodynamics Overview

• Focuses on what drugs do to the body and the molecular mechanisms involved
• It's the study of the biochemical, cellular, and physiological actions of drugs.
• Considers the mechanism of action
• Integrates molecular actions into the effect on the body
• Uses quantitative terms like dose-response relationships and drug concentration relationships with pharmacological responses
• Therapeutic and toxic effects result from drug interactions with receptors
• Relies on the concept of drug-receptor binding

Key Terminology

• Drug: A chemical substance of known structure that produces a biological effect
• Receptor: A molecule to which a drug binds, causing a change in the biological system
• Affinity: The strength of attraction between a drug and its receptor
• Intrinsic Activity/Efficacy: A drug's ability to activate the receptor once bound eliciting a pharmacologic response
• Potency: The relative measure of the amount of drug needed for a specific response, determined by affinity
• Selectivity: The relative measurement of the amount of drug needed to produce a specific response, determined by affinity
• Specificity: A receptor's ability to respond to a single ligand
• Ligand: A substance forming a complex with a biomolecule for a biological purpose

Types of Drugs

• Functional Modifiers: Alter normal physiology, like NSAIDs relieving pain
• Replenishers: Supplement existing compounds, like insulin for Type 1 DM
• Diagnostics: Used to detect disease, such as the Tensilon test for Myasthenia gravis
• Chemotherapeutics: Kill or inhibit cancer cells (anti-neoplastics) or microbes (anti-microbials)

Cellular Level Drug Action

• John Newport Langley identified a "receptive substance" that could form compounds
• Paul Ehrlich introduced the term "receptor", therapeutic effects depend on affinity
• Receptors are components of biological systems where drugs bind
• Drug interaction with receptors leads to functional changes.
• Most receptors are proteins, but some can be nucleic acids (DNA, RNA)
• Drugs can change the rate of normal functions, but do not introduce new ones

Receptor Functions

• Receptors determine the relationship between the drug dose and its effects
• Receptors are responsible for the selectivity found in drug actions
• Receptors mediate actions of agonists and antagonists
• Serve as regulatory proteins that are part of a chemical signaling mechanism, drugs target them
• Key determinants of therapeutic and toxic effects of the drug

Main Receptor Functions

• Recognition: Receptors must recognize and bind compounds
• Ligand binding: Affinity describes the strength of drug interaction with the receptor
  • Van der Waal’s forces, ionic, hydrogen, hydrophobic, and covalent bonds mediate actions
• Specificity refers to receptor selectivity for a drug, consider the chemical nature, dosage, routes of admin, and patient specific features
• Transduction: Receptors must transmit messages to elicit a function
  • Components of the system accomplish the biological effect _ Effectors are molecules translating drug-receptor interaction into cellular activity

General Properties of Receptors

• Saturability: Receptors exist in limited quantities
• Selectivity: Specific ligand-binding characteristics must be present
  • Stereoselectivity is needed to ensure that the proper chemical signal is being transmitted
• Modifiable Conformation: There should be functional change when there is a conformational state

Cell Signaling

• Cells can communicate with each other and influence the behavior of other cells
• Cells can respond to slight changes in extracellular signaling molecules
• Endocrine: Chemical messengers are released into circulation and affect distant spots; these are traditionally hormones from ductless glands
• Paracrine: Chemical messengers released affect neighboring cells; EX: neurotransmitters, cytokines and morphogens
• Autocrine: Messengers affect the same cell that releases them and play roles in neuronal/cytokine signaling
• Juxtacrine: Messengers remain affixed to the cell and affect physically juxtaposed cells
  • Example: T cell and an antigen relationship
• Synaptic: Neurotransmitters released interact with postsynaptic cells.

Types of Receptors

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

Energy-Independent Carrier Molecules

• Facilitate ion or molecule passage across cell membranes by altering their conformation
• Uniporters: Transport a substance across the membrane in one direction
• Symporters: Transport two substances simultaneously in the same direction
• Antiporters: Transport one substance in one direction while transporting another in the opposite direction

Energy-Dependent Carrier Molecules

• Pumps: Translocate passengers via altered conformation and convert proteins into enzymes that hydrolyze ATP
  • Example: Sodium/potassium-ATPase

Drug-Receptor Interaction

• Agonists: Drugs bind to and activate receptors
  • Full agonists: cause the maximal activation, intrinsic activity = 1
  • Partial agonists: they cannot elicit the maximal response but still elicit some response, intrinsic activity < 1
• Antagonists: Bind to receptors and do not activate a response
  • They block the action of agonists
• Inverse agonists: bind to the inactive receptors stabilizing them

Receptor Properties

• Most receptors are proteins
• Regulatory proteins mediate signals like neurotransmitters and hormones
• Enzymes are either activated or inhibited by drug binding
• Transportation proteins are receptors (ex. cardioactive digitalis glycosides)
• Structural proteins include tubulin (the receptor for colchicine which is an anti-inflammatory)

Receptor Theories

• Dose-Response Theory (Clark, 1933): The increased response to the drug is dependent on increased binding of drug receptors.
  • Responses are proportional to number of receptors occupied
  • Reversible drug-receptor interactions
  • Minimal drug binding to available receptors
• Ariens and Stephenson (1956): Activity is dependent on both affinity and efficacy of drug
  • Maximal response can be achieved when only spare receptors are occupied
• Paton's Theory: Intensity of pharmacological effect is dependent on the rate that the drug encounters the receptor _ Each encounter elicits a response
• Lock & Key: 3D shape of drug molecule act as the "key" to activate the "structure" Interactions and relationships are based on physical shape

Drug-Receptor Interaction Detail

• Receptors are active and inactive conformational states
• Drugs attach to specific receptors this affects how that conformation state is affected
• An agonist favors an active receptor conformation
• And antagonist would favor the inactive conformation

Important Concepts

• Efficacy: Is the degree that a drug can induce maximal effects; used to compare if drugs have different mechanisms
  • Example: Drug A may reduce blood preesure 20mm HG while drug B reduce it by 10mm HG
• Potency: This is what quantity is required to induce 50% maximal response
  • Examples: Morphine and codeine can both relive post-operative pain, however less morphine is required

Drug-Receptor Interaction: Agonist

• Agonists: Bind to receptors and activate mechanisms
  • Partial Agonist
    • There is no matter the concentration of the partial agonist, 100% production cannot occur
• Full Agonist
  • Produces 100% of a maximum biological response

Drug-Receptor Interaction: Inverse Agonist

• Inverse agonists inactivate constitutively active receptors
  • beta-carbolines act as the inverse agonist example,

Drug-Receptor Interaction: Antagonist

• Antagonists: Bind to receptors, don't activate mechanisms (no effects)
• Has 4 types of antagonism
  • Competitive (Pharmacologic) antagonism: There are two types being equilibrium and non-equilibrium.
    • Equilibrium is the same site location and reversible, this leads to a rightward shift and increased agonist concentration
    • Non-Equilibrium does not have max response due to being irreversibly bonded
  • Noncompetitive antagonism: Antagonist binds to a different site , acting throughout any agonist
  • Functional (Physiologic) antagonism: Agonist hinders 2nd agonist in physically divided receptors
    • Example: Histamine secretes acid while PPI blocks the acid secretion
  • Chemical antagonism: Two compounds join, this hinders effectiveness
  • Example: Dimercaprol will bind to heavy metals and reduce the toxicity

Drug-Drug Interactions

• Additive: effect of two drugs equal the sum of both agents (1 + 1 = 2)
• Synergistic: Effect of combined drugs exceeds the sum (1 + 1 > 2)
• Potentiation: Accentuation of one drug's effect in presence of another drugs effect (1 + 0 = 2)
• Antagonism: Effect of the combined drugs does not meet the sum of all drags, the drugs oppose each other (1 + 1=0)

Dose-Response Relationship

• Response is proportional to occupied receptors
• Can be determined after single blood dose
• There are 2 types graded and quantal

Graded Dose-Response Curve

• It shows individuals responses to increasing doses
• The magnitude is proportional to the number of effectively interacting receptors

Graded Dose-Response Relationship

• Onset of action: Occurs when the drug can absorb efficiently so that there is distribution for eliciting the therapeutic response
• Peak concentration (Cmax): The absorption rate meet the elimination rate
• Time of peak concentration (Tmax): Time to reach maximum concentration, this is not always comparable to rate of response
• Duration of Action: The time that it creates continues affect

Graded Dose-Response Terms

• Potency: Quantity needed to produce affect
• Slope: Ability of Drug to Produce Affect
• Biologic Variability: Different bodies will responds differently base on the concentrations
• Maximal Efficacy (Emax): Max Effect Produce in the Dose
• Efficacy: measure along the y-axis; determined by the drugs ability to activate mechanisms
  • It is determined by the ability of the drug-receptor interation to activate effector mechanisms and it its measured by Emax
• Potency: Affinty between dose and it is measured along the X axis, measured by ED50

Values That Can Be Obtained from Graded Dose-Response Relationship

• Maximal efficacy (Emax)
  • EC50 (ED50) the lowest concentration that produces 50% of the maximum result
  • KD (Dissociation Constant): concentration needed for 50% to activate receptors
    • Depends on affinity (low KD = high affinity)

Relationships of Dose-Response

• Full agonist with a competitive antagnosist affect potency and efficacy
• Full agonist + Noncompetitive antagonist
  • Affects the potentcy efficacy
• Full agonist + Partial agonist
  • Potency and efficacy are both affected
  • Partial agonist will have greater effect than the full antagonist

Spare Receptors

• Receptor reserve and the Proportion of receptors isn't need needed for a maximized response
  • There must be a maximul drug response obtained with less receptors occupied Spare Receptor - spare receptors said to exist if the EC50 dose is less than the KD Determination is made by Comparing the concentration of Maximal affect EC50 is concentration of a ligand is at with 50% of receptors are bound

Quantal Dose-Response Curve

• Shows the population in which a certain dose will produce a specific affect.
• "All-or-none" affects ED50 (Median Effective Dose) - The Concentration in which causes a specified response TD50 (Median Toxic Dose)- Dose required to produced toxic affect LD50 (Median Lethal Dose) Dose to reproduce effect while killing the population
• Thearapeutic Index = TD50 / ED50, shows realitve affet and safety It its a measure of clincal safety, based on doses

Risk-Benefit Ratio

• Used to describe the adverse effects with a drug in coordination to beneficial effects, risk would be greater if there is a fatal disease.