Principles of Drug Action and Toxicity

Most drugs produce their effects by interacting with ______ within cells or on cell surfaces

Targets

A drug ______ can be a molecule such as a protein, a lipid molecule, or DNA

Target

Common ________ for drugs include receptor proteins, ion channel proteins, enzymes, and transporters

Targets

Molecules on the cell surface or inside the cell that bind to hormones, neurotransmitters, or drugs to initiate a cellular response

Receptor proteins

Pores in the cell membrane that regulate the flow of ions, which can be opened or blocked by drugs

Ion channel proteins

Proteins that catalyze biochemical reactions, which drugs can inhibit or activate

Enzymes

Proteins that actively move substances across cell membranes

Transporters

It is important to note that some drugs do not have ____ specific target and may produce their effects through less targeted mechanisms

One

These drugs produce effects by changing the physical or chemical environment of a biological system rather than binding to a receptor or enzyme

Nonspecific

Antacids act nonspecifically by neutralizing the _____

Acid

______ drugs can result in changes in pH, osmolarity, and surface tension

Nonspecific

Many drugs target ______ to either activate or inhibit their function

Enzymes

The drug (inhibitor) binds to the same active site as the natural substrate

Competitive

The drug (inhibitor) binds to a different site (allosteric site), changing the enzyme’s shape and reducing its effectiveness

Non-competitive

________ are the target for drugs most of the time; binding usually changes its activity

Receptors

These can be extracellular or intracellular

Receptors

Drugs that exert osmotic effects are typically highly _________ and cannot easily cross cell membranes

Hydrophilic

Drugs that exert osmotic effects change the osmolarity of a solution, causing _____ to shift

Fluid

A hydrophilic alcohol used as a diuretic to rapidly reduce intracranial pressure or treat cerebral edema

Mannitol

Increase urine production

Diuretic

This remains in the blood, increasing its osmolarity, which draws excess fluid from the brain tissue into the blood and then the renal tubules, increasing the excretion of water in urine

Mannitol

Mannitol doesn’t directly interact with a __________

Receptor

This mechanism involves a drug changing the structure of proteins, typically by breaking chemical bonds

Protein denaturation

Used as an inhalational agent to treat respiratory conditions; acts as a disulfide breaking agent to reduce viscosity of mucus and make it easier to expel

NAC

This is used as an oral treatment for acetaminophen overdose because it serves as a precursor to glutathione, an important detoxifying cofactor

NAC

Antacids work by chemically ________ stomach acid, thereby increasing the pH of the stomach

Neutralizing

Examples are calcium carbonate and sodium bicarbonate

Antacids

This mechanism refers to compounds that are selectively toxic to foreign organisms or cells

Selective toxicity

Examples of selective toxicity

Germicides and disinfectants

These work by altering the surface tension between a liquid and a gas or another liquid

Surfactants

A natural lung surfactant replacement given to babies burn prematurely; composed of phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C

Intrasurf

Intrasurf reduces surface tension in the ______ of the lungs, preventing them from collapsing and allowing the premature baby to breathe easier

Alveoli

Surfactant, a mixture of lipids and proteins, lowers the _______ _______ between the wet lining of the alveoli and the air inside them

Surface tension

Surfactant lowers the _______ properties of water in the alveoli which helps them remain stable by preventing collapse and bursting

Cohesive

Without adequate surfactant, the strong ______ forces of water molecules lining the alveoli create a high surface tension

Cohesive

High surface tension can lead to alveoli ________

Collapse

High surface tension makes it extremely difficult to re-_______ the lungs with each breath

Inflate

Adequate _______ allows alveoli to stay properly open at various sizes throughout the breathing cycle

Surfactant

The definition of a receptor depends on the _______

Context

The component of a cell that interacts with a drug and initiates a chain of biochemical events leading to the drug’s therapeutic or toxic effects

Receptor

Receptors cause something to _____ inside the cell in addition to binding

Change

For a drug to bind to a receptor, there must be precise _________ involving chemical groups and the there-dimensional shape

Compatibility

The three-dimensional _____ of the drug must fit precisely into the receptor site, like a lock and key

Shape

A _________ shape will not bind effectively, while a complementary shape will

Mismatched

Various types of ______ chemical bonds form between the drug and receptor including ionic bonds, hydrogen bonds, and van der waals

Weak

Strongest type of bond; involves the sharing of electrons

Covalent

Involves the electrostatic attraction between a positively charged atom and a negatively charged atom (transfer of electrons)

Ionic

A weak interaction between a hydrogen atom covalently bonded to an electronegative atom (like N or O) and another electronegative atom

Hydrogen bond

Weak interactions between non-polar groups, often involving aromatic rings

Hydrophobic

The weakest interactions, arising from temporary fluctuations in electron distribution

Van der Waals

Drug-receptor binding usually involves a combination of _______ ____ bonds, including ionic, hydrogen, hydrophobic, and Van der Waals

Multiple weak

We usually want __________ and reversible interactions for drug-receptor binding

Non-covalent

Non-covalent interactions allow the drug to eventually ________ from the receptor, terminating the drug’s effect and enabling the body to metabolize and excrete it

Unbind

Aspirin forms an irreversible _______ bond with the COX enzyme; this means the enzyme is permanently deactivated until the body synthesizes new enzyme molecules

Covalent

The _____ bond usually happens first and serves an anchor that initially positions the drug, bringing the other functional groups close enough to the surface for subsequent weaker interactions

Ionic

Often, one _______ of a drug has significantly more binding activity than another

Isomer

The specific ________ can impact the number of potential bonds that can form

Isomer

An increased number of ______ between the drug and receptor generally leads to increased activity and increased selectivity

Bonds

The most effective and safest drugs typically form many _____ bonds with their receptor

Weak

Ideal drugs have the necessary _______ with their receptor while maintaining reversibility

Strength

A receptor must bind _________ to a messenger molecule (like a hormone, neurotransmitter, or drug)

Specifically

Receptors are designed to receive and process _________ signals, a way for cells to detect changes in their environment and cause a response

Extracellular

Receptors play a primary role in _________ communication by transmitting the signal across the cell membrane via chemical messengers

Intracellular

Ultimately, binding to the receptor leads to a ________ ______, often by causing a downstream change in the activity of intracellular enzymes

Measurable response

A receptor must initiate an intracellular change ______ receiving an extracellular signal

After

Even though _______ and other macromolecules are not receptors, they are still crucial drug targets

Enzymes

Enzyme inhibited by aspirin

COX enzyme

Receptors are typically proteins that _____ the cell membrane, having both extracellular and intracellular components

Span

The part of the receptor facing the exterior of the cell; often has carbohydrate chains and binding sites

Extracellular

These contribute to overall structure of receptors and play a role in cell-cell recognition

Sugars

The receptor has specific sites to bind its natural messengers, called _________ _______

Endogenous transmitters

Upon binding to a transmitter, the receptor influences the activity of _________ _______

Intracellular enzymes

The receptor binding action initiates a chain of biochemical events called ________ ______ inside the cell, ultimately leading to the drug’s effect

Signal transduction

The receptor’s intracellular component has enzymatic activity; ligand binding causes two receptor units to dimerize and activate the enzyme, triggering a signaling cascade

Enzyme-linked receptors

These are multi subunit channels that cross the cell membrane; when the ligand binds, the channel rapidly opens, allowing ions to flow across the membrane, causing an immediate change in cell potential

Ligand-gated ion channels

The most complex and biggest target for drug development; the receptor protein threads through the membrane seven times; ligand binding causes a conformational change in the receptor, which activates a nearby guanine nucleotide binding protein, this protein that activates an effector, leading to an amplified cellular response

G protein-coupled receptors

These are also known as intracellular receptors and are located in the cytoplasm or nucleus; the ligand must be lipophilic to cross the cell membrane and enter the cell; the drug binds to the cytosolic receptor, and the complex then moves to the nucleus where it regulates gene expression and regulation of transcription

Nuclear receptors

A receptor is a macromolecular component that determines the _________ relations between dose of drug and effect

Quantitative

The number and affinity of _______ dictates how much drug is needed to produce a given effect

Receptors

Receptors have specific shapes and chemical binding sites, ensuring that a drug primarily acts on its ________ target while minimizing unwanted side effects

Intended

Receptors are the targets through which drugs exert their ________ ____, whether by mimicking a natural signal (agonist) or by blocking a natural signal (antagonist)

Primary effect

Receptors exist in ______ numbers

Finite

As the drug concentration increases, the binding increases until all receptors are ________, at which point the binding plateaus

Saturated

Drug binding relies on ______ bonds that are non-covalent

Weak

Non-covalent interactions allow the drug to _____ from the receptor, terminating the effect and allowing the drug to be metabolized and excreted

Unbind

Receptors prefer one __________ due to its precise 3D fit

Stereoisomer

If the concentration of the non-preferred stereoisomer is very ____, you may still get some binding, but the activity will be much lower than the prefererd form

High

A receptor will typically bind well to two _________ related drugs (or its natural ligand and a synthetic drug that mimics its structure)

Strucutrally

Researchers make _____ chemical changes to known active compounds to make drugs with improved binding

Small

Specific binding occurs only in the _______ sensitive to the endogenous compound and at physiologically relevant concentrations

Tissues

At very high concentrations, a drug can eventually bind _________ to many targets

Nonspecifically

True receptor-mediated binding happens at a ______ concentration where the drug binds only to its specific target

Small

Failure of a drug to satisfy saturability, reversibility, stereoselectivity, drug specificty, and tissue specificity can lead to ________ binding

Nonspecific

Drugs with nonspecific binding have _________ efficacy and increased side effects

Reduced

Any chemical that binds to receptors

Ligand

Chemicals produced naturally by the body, such as hormones and neurotransmitters

Endogenous ligands

Chemicals originating outside the body, such as drugs, environmental chemicals, or dietary compounds

Exogenous ligands

A quantitative measure of how well a ligand binds a receptor

Affinity

Affinity has nothing to do with the _____ of effect the ligand it has

Effect

Only describes how tightly or how readily the ligand binds, not whether it activates or blocks

Affinity