RECEPTORS

Proteins

What are the specific molecules that drugs bind to trigger biochemical events and alter function?

Drug-receptor binding

What mechanism accounts for about 60% of all drugs' effects and produces a predictable response?

Changes the conformation of the receptor molecule

What effect does active binding of a drug to its ligand have on the receptor molecule?

Converts the receptor to its resting state

What happens to a receptor when a drug is released from its ligand?

Selectivity

What feature describes a drug's capability to selectively or preferentially bind to a targeted receptor to produce effects?

Specificity

What feature describes the interaction with a receptor that produces a specific effect?

Saturation of receptors

What state is reached when a drug's effect can no longer increase despite increasing concentrations?

Emax

What term refers to the effective concentration to produce a maximal effect, used as a measure of efficacy?

EC50

What term refers to the concentration to produce 50% of the maximal effect, used as a measure of relative potency?

Kd (dissociation constant)

What value quantifies the ability of a drug-receptor interaction to dissociate, and measures the stability of the drug and its ability to produce an effect?

Lower Kd

What indicates a more potent drug effect in relation to the dissociation constant?

Agonist

What type of drug binds to a receptor and leads to its full activation or maximal efficacy?

Antagonist

What type of drug competes for a receptor site in the presence of an agonist, leading to the lowering of the maximal efficacy of a drug?

Competitive antagonist

What type of antagonist binds reversibly to a receptor, allowing the same maximal effect to be achieved with increased doses?

Non-competitive antagonist

What type of antagonist binds irreversibly to an agonist receptor or a different site, leading to a decreased Emax that cannot be overcome by increasing agonist concentration?

Inverse agonist

What type of drug induces a decrease in the receptor's effects upon docking?

Partial agonist

What type of drug produces a less than maximal effect upon docking on a receptor?

Physiological antagonism

What type of antagonism results when two drugs produce opposite effects by interacting with two separate receptor systems?

Pharmacological antagonists

What type of antagonists bind to receptor sites but inhibit them instead of transmitting signals?

Chemical antagonists

What type of antagonism occurs when the effect of a drug is antagonized by another agent due to chemical interaction?

Ligand-gated ion channel

What type of receptor is a nicotinic cholinoceptor?

Rapid effects

What characteristic speed of effect do nicotinic cholinoceptors, as ion channels, produce?

Maintaining the dipole moment

What is important for nicotinic cholinoceptors to achieve normal functioning?

Nicotine, Acetylcholine

Name two common ligands for nicotinic cholinoceptors.

Heteropentamer composed of four subunit types

What is the subunit composition of the nicotinic cholinoceptor in the neuromuscular junction?

Heteropentamer or a homopentamer composed of two subunit types

What is the subunit composition of the nicotinic cholinoceptor in the brain?

Acetylcholine

What common ligand is described as "promiscuous" because it can attach to both nicotinic and muscarinic ion channels?

G protein-coupled receptors (GPCRs)

What type of receptors are muscarinic cholinoceptors?

Membrane-bound and found at the cytosol surface

Where are muscarinic cholinoceptors located?

Half of all known drugs

What proportion of all known drugs target GPCRs?

7-pass protein

What is the unique protein configuration of GPCRs?

Ca2+, cAMP, inositol-3-phosphate (IP3)

Name three different second messengers that may be involved with GPCRs.

Amplify the signal to 100 million times

What is the potential amplification capability of a signal produced by a single GPCR molecule?

Widespread response of the body

What does the amplification of a single GPCR allow for?

Neutralize the fight or flight response of the sympathetic nervous system

What is the necessary function of the massive wave of GPCR second messengers in the parasympathetic system?

Gi

What type of GPCR is responsible for cycling of cAMP by inhibiting adenylyl cyclase?

Gq

What type of GPCR is responsible for the production of phospholipase C, involving diacylglycerol (DAG), inositol-3-phosphate (IP3), and calcium (Ca2+) as second messengers?

Dimeric enzyme receptors

What type of receptors are tyrosine kinases?

Intrinsic enzyme activity

What activity do kinase receptors possess?

Scaffolding

What do RTKs use to keep signaling modules near each other?

Insulin receptor (IR), IL-2 receptor

Name two examples of receptor tyrosine kinases.

Insulin Receptor (IR)

What RTK is described as highly specific to ensure that the target cell takes up glucose?

Dimerization upon binding insulin, autophosphorylation of the IRS complex, activation of the PI3K/Akt pathway

What are the basic mechanisms triggered by the Insulin Receptor upon insulin binding?

Translocation of GLUT transporters to the plasma membrane

What is one of the final outcomes triggered by the Insulin Receptor pathway?

Interleukin-2 (IL-2) Receptor

What RTK is associated with cytokine receptors and uses the JAK/STAT pathway?

JAK/STAT pathway

What pathway is used by the IL-2 receptor as an expressway from the extracellular environment to the nucleus for a quicker and more direct effect?

Hematopoiesis, especially white blood cell differentiation

What biological process is mediated through the JAK/STAT pathway of the IL-2 receptor?

Receptors found on cell surface

Where are IL-2 receptors typically found?

In the nucleus

Where are nuclear receptors located?

Transcription factors

What unique property do nuclear receptors possess, allowing them to directly identify and bind to DNA sequences?

Pass through the cell membrane and nuclear membrane

What must a drug do to reach nuclear receptors?

Dimerization

What process must nuclear receptors undergo, along with activation by molecules, to produce specific outcomes?

Not specific; generalized and broad

What is a characteristic of the outcomes produced by nuclear receptors?

Hormones (e.g., Growth hormones)

What type of molecules activate nuclear receptors, leading to generalized outcomes like protein synthesis, calorie intake, or mitotic activity?

Development of certain cancers

What negative outcome has been linked to the non-specificity of nuclear receptor outcomes?

Aldosterone, spironolactone, estrogen, testosterone, retinoids

Name four examples of hormone drugs that act on nuclear steroid hormone receptors.

Allow movement across barriers

What is the general function of ion channels and transporters?

Rapid

What is the onset of action for drugs targeting ion channels?

Voltage-gated, Ligand-gated, Tension-gated

What are the three types of ion channels mentioned?

Voltage-gated

What type of ion channels do not bind directly but are affected by membrane potential?

Lidocaine, Tetrodotoxin

Name two molecules that target voltage-gated channels.

Ligand-gated

What type of ion channels are stimulated by a specific molecule or drug and are important for homeostasis?

Acetylcholine, Serotonin, GABA, Glutamate

Name four examples of molecules that stimulate ligand-gated ion channels.

Tension-gated

What type of ion channels are targets of molecules like streptomycin, gadolinium, and tarantula venom?

Alter the form and function of other structures

What is the general action of enzymes as drug targets?

Initiation, Transition state facilitation, Termination

What are the three basic steps in an enzymatic reaction?

Isoniazid

What drug inhibits enoyl reductase, an enzyme produced by M. tuberculosis?

Acetylsalicylic Acid (Paracetamol)

What drug inhibits cyclooxygenase (COX), also known as prostaglandin endoperoxide synthase, to inhibit pain?

Beta-lactams (e.g., penicillin)

What type of drugs directly inhibit bacterial serine protease?

Acetazolamide

What diuretic drug inhibits carbonic anhydrase, an enzyme in the eye that maintains fluid balance?

Heparins

What drugs activate human antithrombin to maintain the liquid phase of blood and prevent clotting?

Lipid-soluble (hydrophobic)

What property must a drug have to pass through cell membranes, regarding solubility?

Water-soluble (hydrophilic)

What property must a drug have to dissolve in aqueous fluids like gastric juice and bloodstream?

Weak acids or weak bases

How are most drugs administered to allow fluctuation between charged and uncharged states at physiologic pH?

Un-ionized drugs

Which form of a drug is highly lipid soluble and readily crosses biologic membranes?

Ionized drugs

Which form of a drug is poorly lipid soluble and doesn't readily cross lipid membranes, but dissolves well in aqueous media?

pKa of the drug and the pH of the surrounding tissues or fluids

What two factors determine the ratio of ionized versus un-ionized fraction of a drug?

The pH at which 50% of the drug is ionized and 50% is un-ionized

What is the definition of a drug's pKa?

Acidic conditions (pH below pKa)

Under what pH conditions are weak acids preferentially absorbed?

Alkaline pHs (above their pKa)

Under what pH conditions are weak bases preferentially absorbed?

Duodenum (proximal areas of the small intestine)

What is the major site of absorption for most drugs, including weak acids?

CYP3A4/5

What is the main enzyme family that mediates most metabolic reactions (50% of Phase 1 reactions)?

UDP-Glucuronosyltransferase (UGT)

What is the most active enzyme in conjugation reactions (Phase 2)?

CYP3A4/5 and UGT

What two major enzyme types metabolize 75% of drugs used today?

Oxidation-reduction

What are the main types of reactions in Phase 1 metabolism?

Cytochrome P450 (P450)

What is the main enzyme involved in the oxidative cycle of drug metabolism in the liver?

NADPH

What molecule donates electrons to P450 Reductase to oxidize the drug?

Functionalization reactions

What type of reactions are Phase I reactions?

Hydroxyl (-OH), Amine (-NH2), Sulfhydryl (-SH)

Name three functional groups that Phase I reactions introduce or unmask to convert parent drugs into more polar metabolites.

Aromatic hydroxylation

What Phase I reaction involves the addition of a hydroxyl group to an aromatic compound?

Oxidative reactions

What type of Phase I reaction involves the addition of a hydroxyl group, often making the metabolite more inactive and polar?

Flavin monooxygenase

What acts as an oxidizing agent in CYP450-independent oxidation?

Reduction

What Phase I reaction involves the removal of oxygen or addition of hydrogen?

Deamination

What Phase I reaction involves the removal of an amine group?

Hydrolysis

What Phase I reaction involves the addition of water, resulting in the breakdown of the molecule?

Oxidative dealkylation

What Phase I reaction involves the removal of an alkyl group?

Transferases

What main class of enzymes is required for Phase 2 (conjugation) reactions?

UDP glucuronosyltransferase (UGT)

What is the most dominant transferase in Phase 2 reactions?

Glucuronidation

What Phase 2 reaction involves adding a glucuronosyl group to the drug?

Acetaminophen (paracetamol), diazepam, morphine, digoxin

Name four substrates for glucuronidation.