HOW DO DRUGS WORK BY INHIBITING ENZYMES?KEY CONCEPTS:

• Enzymes catalyze the biosynthesis of products from substrates.

• Some drugs bind to enzymes and inhibit enzymatic activity.

• Loss of product due to enzyme inhibition mediates theeffects of enzyme inhibitors.

HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? KEY CONCEPTS:

• Ion channels allow ions to transverse the cell membranethrough a pore and down an electrochemical gradient.

• Some drugs bind to ion channels and physicallyblock the pore or cause an allosteric change

that closes the pore.

• Changes in the intracellular concentration of ions mediatesthe effects of inhibitors of ion channels.

ARE DRUGS THAT BLOCK ION CHANNELSCLINICALLY USEFUL?

• Calcium Channel Blockers (CCBs) for angina and high blood pressure(amlodipine [Norvasc®]; diltiazem [Cardizem®])

Some important examples:

• Sodium Channel Blockers to suppress cardiac arrhythmias(lidocaine [Xylocaine®]; amiodarone [Cordarone®])

HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?

Active Transporter

Intracellular Compartment

Membrane Impermeable Solute

Cellular Response

Membrane Impermeable Solute

HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?

Inactive Transporter

Intracellular Compartment

Membrane Impermeable Solute

Membrane Impermeable Solute

Drug that Inhibits Transporters

HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS?KEY CONCEPTS:

• Transporters bind to and shuttle membrane impermeablesolutes across the cell membrane.

• Some drugs bind to transporters and cause allosteric changesthat prevent proper functioning of the transporters.

• Changes in the intracellular concentration of specific solutes mediatesthe effects of inhibitors of transporters.

ARE DRUGS THAT INHIBIT TRANSPORTERSCLINICALLY USEFUL?

• Selective Serotonin Reuptake Inhibitors (SSRIs) for thetreatment of depression

(fluoxetine [Prozac®]; fluvoxamine [Luvox®])

Some important examples:

• Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) inrenal epithelial cells to increase urine and sodium

output for the treatment of edema (furosemide [Lasix®]; bumetanide [Bumex®])

HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS?

KEY CONCEPTS:

• Signal transduction proteins transmit a chemical signalfrom a receptor to the final biological target.

• Some drugs bind to and inhibit key signal transduction proteins.

• Inhibition of key signal transduction proteins may block oraugment the signal transduction pathway and this

mediates the effects of the drug.

• Tyrosine Kinase Inhibitors for chronic myelocytic leukemia(imatinib [Gleevec®])

Some important examples:

• Type 5 Phosphodiesterase Inhibitors for erectile dysfunction(sildenafil [Viagra®])

• This is a major focus of drug development

ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINS

CLINICALLY USEFUL?

HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS?

• Agonists of Cell Surface Receptors

• Agonists of Nuclear Receptors

• Enzyme Activators

• Ion Channel Openers

Footnote:

Most agonists attach to binding site on receptor for endogenous agonist and trigger a response.

However, agonists may bind to remote site on receptor and cause

allosteric effects that increase the ability of an endogenousagonist to bind to or activate the receptor.

HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?

HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?

KEY CONCEPTS:

• Cell surface receptors exist to transmit chemical signals from the outside to the inside of the cell.

• Some drugs bind to cell surface receptors and trigger a response.

• Drugs in this group are called receptor agonists.

• Some drug agonists are actually the endogenous chemical signal,whereas other drug agonists mimic endogenous chemical signals.

•Alpha1-Adrenoceptor Agonists for nasal congestion (oxymetazoline [Afrin®]; phenylephrine [Neosynephrine®])

Some important examples:

• Opioid Receptor Agonists for analgesia(morphine; meperidine [Demerol®])

ARE DRUGS THAT ACTIVATE CELL SURFACE RECEPTORS

CLINICALLY USEFUL?

HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?

Footnote:

Most agonists attach to binding site on receptor for endogenous agonist and trigger a response.

However, agonists may bind to remote site on receptor and cause

allosteric effects that increase the ability of an endogenousagonist to bind to or activate the receptor.

HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?

KEY CONCEPTS:

• Nuclear receptors exist to mediate the effects of intracellular,endogenous chemicals on gene expression.

• Some drugs bind to nuclear receptors and trigger a response.

• Drugs in this group are called receptor agonists.

• Some drug agonists are actually an endogenous chemical,whereas other drug agonists mimic an endogenous chemical.

ARE DRUGS THAT ACTIVATENUCLEAR RECEPTORSCLINICALLY USEFUL?

• Estrogen Receptor Agonists for hormone replacement therapy in postmenopausal

women (conjugated equine estrogens [Premarin®])

Some important examples:

• Glucocorticoid Receptor Agonist for inflammation (hydrocortisone[Cortef®]; dexamethasone [Decadron®])

HOW DO DRUGS WORK BY ACTIVATING ENZYMES?

Inactive Enzyme

Substrate

HOW DO DRUGS WORK BY ACTIVATING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

Enzyme Activator (Drug)

HOW DO DRUGS WORK BY ACTIVATING ENZYMES? KEY CONCEPTS:

• Enzymes catalyze the biosynthesis of products from substrates.

• Some drugs bind to enzymes and increase their enzymatic activity.

• Increased biosynthesis of product mediates theeffects of enzyme activators.

ARE DRUGS THAT ACTIVATE ENZYMESCLINICALLY USEFUL?

• Activators of Guanylyl Cyclase for angina (nitroglycerin; isosorbide dinitrate [Isordil®])

Some important examples:

• Reactivators of Cholinesterase after poisoning with nerve gasor organophosphate pesticide

(pralidoxime [Protopam®])

HOW DO DRUGS WORK BY OPENING ION CHANNELS?

Closed Ion Channel

Intracellular Compartment

Ions (e.g., Ca++, Na+)

Ions (e.g., K+)

Binding Site on Ion Channel

HOW DO DRUGS WORK BY OPENING ION CHANNELS?

Open Ion Channel

Intracellular Compartment

Ions (e.g., Ca++, Na+, K+)

[Ions]

Cellular Response

Drug That Opens Ion Channel

HOW DO DRUGS WORK BY OPENING ION CHANNELS? KEY CONCEPTS:

• Ion channels allow ions to transverse the cell membranethrough a pore and down an electrochemical gradient.

• Some drugs bind to ion channels and allosterically openthe ion channel or allosterically render the

channel more readily opened by other endogenous chemicals.

• Changes in the intracellular concentration of ions mediatesthe effects of drugs that open ion channels.

ARE DRUGS THAT OPEN ION CHANNELSCLINICALLY USEFUL?

• Potassium Channel Openers for hair regrowth(minoxidil [Rogaine®])

Some important examples:

• GABAAChloride Channel Openers for anxiety(alprazolam[Xanax®]; midazolam [Versed®])

HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION?

• Disrupters of Structural Proteins

• Drugs that Are Enzymes

• Drugs that Covalently Link to Macromolecules

• Drugs that React Chemically with Small Molecules

• Drugs that Bind Free Molecules or Atoms

HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)?

• Drugs that Are Nutrients

• Drugs that Exert Actions Due to Physical Properties

• Drugs that Work Via an Antisense Action

• Drugs that Are Antigens

• Drugs with Unknown Mechanisms of Action

• Vinca Alkaloids for cancer(vincristine [Oncovin®]; vinblastine [Velban®])

Some important examples:

• Colchicine for gout

DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS?

ARE SOME DRUGS ENZYMES?

• Thrombolytic therapy for acute myocardial infarction(alteplase [Activase®])

Some important examples:

DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES?

• DNA alkylating agents for the treatment of cancer(cyclophosphamide [Cytoxan®]; chlorambucil [Leukeran®])

Some important examples:

DO SOME DRUGS REACT CHEMICALLY WITH SMALL MOLECULES?

• Antacids that neutralize gastric acid(various preparations containing Al(OH)3, Mg(OH)2 or CaCO3)

Some important examples:

DO SOME DRUGS BIND FREE MOLECULES OR ATOMS?

• Bile-Acid Sequestrants for hypercholesterolemia(cholestyramine [Questran®])

Some important examples:

• Chelating Agents for heavy metal poisoning(dimercaprol; penicillamine)

• Proteins that bind TNF-α for rheumatoid arthritis(infliximab [Remicade®]; etanercept [Enbrel®])

ARE SOME DRUGS NUTRIENTS?

• Vitamins, minerals, lipids, carbohydrates, aminoacids

Some important examples:

DO SOME DRUGS EXERT ACTIONSDUE TO PHYSICAL PROPERTIES?

• Bulk Laxatives for constipation(psyllium [Metamucil®]; polycarbophil [Fibercon®]

Some important examples:

• Osmotic Diuretics for edema(mannitol)

DO SOME DRUGS WORK VIA AN ANTISENSE ACTION?

• Antisense Deoxyoligonucleotides for cytomegalovirus retinitisin patients with AIDS

(fomivirsen [Vitravene®]

An important example:

• This is a major focus of drug development