Pharmacology: Key Terms and Agents

Pharmacology and Key Terms

• Pharmacology studies substances interacting with living systems via chemical processes (binding)
• Pharmacology involves the regulation/interaction with regulatory or structural molecules, and activating or inhibiting normal body processes
• Medical pharmacology uses these substances to prevent, diagnose, and treat disease
• Toxicology studies the undesirable side effects of chemicals on living systems, from cells to ecosystems
• Environmental pollutants, industrial chemicals, and drugs can have hazardous effects via molecular & cellular mechanisms

Pharmacotherapeutic Agents

• A prototype is a representative agent for a drug class
• Isoproterenol serves as a prototype for β2-adrenoceptor agonists
• Ibuprofen is a prototype for non-steroidal anti-inflammatory drugs (NSAIDs)
• A pharmacophore is the drug portion responsible for its biological action
• A single drug can have multiple pharmacophores
• Drugs are often classified based on their pharmacophore, such as beta-lactam antibiotics
• An agonist binds to a receptor, producing a biologic response (receptor activators)
• Responses can be similar to or different from the endogenous ligand
• An antagonist decreases or opposes the action of another drug or endogenous ligand
• Antagonists have an effect only when an agonist is present

Binding Forces in Drug-Receptor Interactions

• Binding involves forces that drive the drug near and ensure exact fit
• These forces include ionic (long-range) and van der Waals forces
• Covalent bonds involve sharing electrons by a pair of atoms
• Covalent Bonds are not usually seen in drug-receptor interactions
• Covalent bonds, when they do occur, are irreversible which determines duration based on turnover rate
• A drug response may last for days to weeks due to covalent bonds
• Ionic bonds involve electrostatic attraction between ions of opposite charge
• Ionic bonds are relatively weak in aqueous environments
• Many drugs, charged at physiological pH, form ionic bonds with ionized groups in the receptor sites
• Ionic bonds operate at greater distances, initiating drug-receptor complexes
• Cation-π interactions involve the electron cloud of aromatic compounds binding positive ions
• Amino acids like phenylalanine, tyrosine, and tryptophan, having aromatic side groups, can do this
• These interactions are common in receptors and neurotransmitter binding (e.g., ACh, DA, NE, 5-HT)
• Interactions between multiple aromatic amino acids and a single cationic moiety strengthen a drug-receptor interaction
• Hydrogen bonds exist between polar molecules
• Hydrogen is bound to an electronegative atom (O or N) making the electronegative atom partially negative and H partially positive.
• Hydrogen bonds are weaker than ionic bonds, but they are common in drug-receptor interactions
• Multiple hydrogen bonds can stabilize forces as strongly as or stronger than a single ionic bond
• Van der Waals forces are weak interactions developing when two atoms are in close proximity
• They are important for the specificity of drugs to their receptors
• Van der Waals forces account for the "exact fit" differentiating stereoisomers

Hydrophobic Interactions and Allostery

• Hydrophobic interactions play a major role in stabilizing drug-receptor binding
• Water prefers forming hydrogen bonds within itself and with many solutes
• A drug binds a receptor via hydrophobic interaction, increasing binding and decreasing its affinity to aqueous environments
• Many receptors have hydrophobic pockets
• Cooperation of binding forces involves initial ionic attractions followed by cationic-π attractions, orienting the drug
• Intermolecular interactions within the ligand weaken, resulting in hydrophobic, hydrogen bonding, and van der Waals forces becoming more prominent
• Lack of a right fit results in drug not binding long enough leading to no change in response
• Allostery involves modulators binding to an allosteric site while ligands bind to the orthosteric site
• This can lead to positive or negative cooperativity, depending on the direction of the change observed
• Allosteric site ligands allow for more finely tuned control of cellular processes compared to drugs acting on the orthosteric site of a receptor

Cooperativity and GPCR Activation

• Some receptors need two ligand molecules to bind
• The first molecule binding makes it easier and faster for the second
• GPCR activation involves Gα and Gβγ activating second messengers and downstream phosphokinase (PKA, PKC)
• G protein-coupled receptors include α and β adrenoceptors
• Hydrophilic ligands interact with receptors on the cell surface via extracellular domains in ligand-gated ion channels, G protein-coupled receptors, and enzyme-linked receptors

Pharmacodynamics vs. Pharmacokinetics

• Pharmacodynamics (PD) is the relationship between drug concentration at receptor sites and pharmacological response
• PD addresses what the drug does to the body
• It involves the biochemical and physiological actions of a drug, correlating the magnitude of effect with chemical structure and concentration
• Pharmacokinetics (PK) is the quantitative description of the relationship between dose, drug concentration in body fluids, and time
• PK addresses what the body does to the drug, allowing for understanding temporal and spatial distribution patterns

Receptor Families and Ligand Properties

• Four receptor families exist with varying ligand properties
• These receptors include ligand-gated ion channels, G protein-coupled receptors, enzyme-linked receptors, and intracellular receptors
• Hydrophilic ligands interact with cell surface receptors via extracellular domains
• Hydrophobic ligands interact with intracellular receptors, crossing lipid bilayer membranes
• Transmembrane ligand-gated ion channels open upon binding of a ligand, such as acetylcholine binding to nicotinic ACh receptors
• This binding triggers sodium influx, action potential, and contraction of skeletal muscle
• The duration of response here is very rapid, lasting only a few milliseconds
• These receptors are vital for neurotransmission, cardiac conduction, and muscle contraction
• Transmembrane voltage-gated ion channels open in response to changes in membrane voltage
• Lidocaine blocks neuronal depolarization by binding to voltage-gated Na+ channels
• GPCRs are the most abundant receptor type, including adrenergic and opioid receptors
• GPCRs couple to G proteins, which are heterotrimers of α, β, and γ subunits
• Enzyme-linked receptors, like insulin receptors, commonly involve tyrosine kinases
• Intracellular receptors, like steroid receptors, cannot be used for emergency/immediate response in anaphylaxis
• Epinephrine, which binds to GPCRs, must be used instead

Signal Transduction

• Signal transduction is the process of cells receiving and responding to signals from their environment
• This process involves a series of molecular events converting external stimuli into specific cellular responses, like second messengers
• GPCR activation involves both Gα and Gβγ activating second messengers, including adenylate cyclase and phospholipase c
• This activation leads to downstream protein kinase activation and phosphorylation events
• A second messenger is a molecule in the cascade translating ligand binding into a cellular response
• Second messengers are often mediated by enzymes called kinases
• GPCR signal transduction involves Adenylate Cyclase (AC) via Gα subunit, Phospholipase C (PLC) via Gα subunit, and Gβγ subunit
• GPCR signaling leads to activation and inhibition using Adenylate cyclase, and activation for Phospholipase C
• Gβγ subunits can increase the activity of inwardly rectifying potassium channels
• They can also increase the phosphatidyl inositol-3-kinase enzyme (PI3K)
• Non-GPCR second messengers include Nitric Oxide (NO) and Cyclic Guanosine mono-phosphate (cGMP) -NO is synthesized from arginine by 3 isoforms of nitric oxide synthase and is a vasodilator -cGMP is a vasodilator, NO activates GC, and PDE V inhibitors increase cGMP

Signal Amplification and Receptor Theory

• Ligand binding involves Affinity, Kd, and Bmax
• Affinity is strength of the interaction/binding between the ligand and its receptor, defined as KA = 1/Kd
• Kd is the drug concentration required to occupy 50% of available receptor sites
• Bmax is the maximum number of receptors that can be bound by a drug
• When Bmax is achieved, receptors in the system are saturated

Dose-Response Curves

• Dose vs. Ligand binding curves will differ
• A Dose-response curve is a graph plotting response magnitude against drug dose increases
• Threshold concentration refers to the minimum concentration required to elicit a measurable response
• Ceiling effect refers to the fact that at very high concentrations, receptors become saturated, and further drug administration has no additional effect
• EC50 is the half maximal effective concentration
• Potency measures the amount of drug needed to produce a given effect magnitude
• EC50 represents the concentration with 50% of the maximum effect
• Efficacy is the drug's ability to elicit a response upon binding to a receptor
• Emax represents the maximal response
• Drug X is more potent than Drug Y if its EC50 value is lower
• Drug X is more effective than Drug Y if its Emax value is higher

Agonists and Antagonists

• Intrinsic efficacy/activity describes a drug's ability to activate a receptor after forming a drug-receptor complex
• It's usually determined by the drug's molecular structure and varies, denoted by α
• A full agonist has α of 1, while an antagonist has a value of 0
• A partial agonist ranges between 0 and 1 while an inverse agonist ranges between -1 and 0
• A full/strong agonist binds to a receptor and produces a maximal biological response, mimicking the endogenous ligand's effect
• This can cause a ceiling effect at high concentrations
• Full agonists have strong affinity, intrinsic activity of 1, and stabilize the receptor in active conformation
• A partial/weak agonist has intrinsic activity between 0 and 1
• Even occupying 100% of receptors, it does not produce Emax like a full agonist, resulting in a lower ceiling effect
• Affinity levels of a partial agonist can vary
• Inverse agonists preferentially bind to the inactive state of the receptor, reducing constitutive activity
• These agonists have intrinsic activity between -1 and 0
• Inverse agonists convert constitutively active receptors (R*) into inactive receptors (R)
• Inverse agonists exert opposite pharmacological effects compared to agonists
• Competitive antagonists: Both agonist & antagonist bind same site causing competition with each other
• An antagonist stabilizes the receptor in inactive state R.
• This causes a shift in the agonist's dose-response curve that increases the EC50
• ↑ agonist → overcome comp. antagonist effect.
• Non-Competitive / Irreversible antagonists use two mechanisms: -Bind covalently to active site of receptor or bind to an “allosteric site” other than the agonist binding site
• Non-Competitive antagonists cause a downward shift in the Emax
• Adding more agonists will generally reverse/overcome the effect of a competitive antagonist

Therapeutic Index

• Therapeutic Index (TI) = TD50/ ED50 -TD50 is the drug dose producing a toxic effect in half the population -ED50 is the drug dose producing a therapeutic or desired response in 50% of the population
• In some cases, only a fraction of total receptors must be occupied to elicit a maximal response from a cell, called concept of spare receptors
• E.g. insulin receptors → 99% of receptors are spare (1% used)
• On another end, e.g. human heart has about 5-10 % of β-adrenoceptors as spare receptors
• Little functional reserve in failing heart such that must occupy most receptors to obtain maximum contractility
• High intrinsic activity → EC50 << Kd
• Only can be seen with full agonists; no spare receptors with partial agonists

Receptor Desensitization

-Receptor desensitization involves receptors showing reduced ability to be activated again by their respective drug -The stages of desensitization can involve Phosphorylation, Internalization, and Down-regulation (Degradation)

• Pharmacotherapeutic agents: tolerance, desensitization, tachyphylaxis using slow regeneration of inactive receptor, formation of endogenous inhibitor, or negative cooperativity
• Desensitization is phosphorylation of receptor leading to receptor internalization down-regulation along with depletion of endogenously released factor or increased metabolism

Drug Action Course

• The graph of drug concentration in plasma as a function of time after dose administration follows curves determined by rates of appearance and elimination -Rate of appearance into plasma is by dose administration and absorption -Rate of elimination from plasma involves metabolism and excretion
• Oral Drug administration involves dissolution from dosage form and Dissolving in GI fluids before absorption in GI tract -Rate & Extent of absorption depend on route of administration and drug properties
• IV drug administration: No absorption
• Rate of administration in IV bolus: drug in plasma instantaneously & IV infusion: slowly dripped into vein -Plasma concentrations increase gradually
• Absorption Rate Constant: Rate at which absorption occurs is dependent on the amount of drug available for absorption. -At low concentrations, some drugs are absorbed by carriers in a first-order process with Michaelis-Menten kinetics -At high concentrations, transporters are saturated becoming zero-order with Absorption rate = Vmax = constant

Drug Half-Life

• After 5 half-lives have passed, drug's concentration in the plasma is only 3% of the absorbed dose since 97% eliminated
• Half life is property of the drug that represents the time required for plasma conc to decrease by 1½ of its value After 5 half-lives have passeddrug's concentration in the plasma is only 3% of the absorbed dose (97% eliminated).
• Half life requires elimination and completion, therefore 5 half lives typically use

Time Course of Drug Action

• MEC: Minimum Effective Concentration in relation to Onset of Action and MSC: Maximum Safety concentration

Drug Tolerance

• Drug tolerance and physical dependence has three types including: Innate, Learned, and Acquired
• Innate Tolerance genetics unchangeable, polymorphisms in receptors or proteins, low levels of proteins (Alcohol dehydrogenase) Metabo morphine

Mechanism of Addiction

• More dopamine hormone goes through CNS through the mesolimbic dopaminergic pathway being activated for euphoric feeling