HOW DO DRUGS WORK?

WHY BE CONCERNED ABOUT HOW DRUGS WORK? AIDS MEMORIZATION OF: FDA Approved and Unapproved Uses Interactions with Other Drugs Adverse Effects and Contraindications

WHY BE CONCERNED ABOUT HOW DRUGS WORK? AIDS EVALUATION OF MEDICAL LITERATURE: Better assessment of new modalities for using drugs Better assessment of new indications for drugs Better assessment of new concerns regarding risk-benefit

WHY BE CONCERNED ABOUT HOW DRUGS WORK? AIDS PATIENT-DOCTOR RELATIONSHIP: The patient has more respect for and trust in a therapist who can convey to the patient how the drug is affecting the patient’s body. A patient who understands his/her therapy is more inclined to become an active participant in the management of the patient’s disease.

WHY BE CONCERNED ABOUT HOW DRUGS WORK? PEACE OF MIND! Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.

HOW DO DRUGS WORK? Most drugs work by interacting with endogenous proteins: Some drugs antagonize, block or inhibit endogenous proteins Some drugs activate endogenous proteins A few drugs have unconventional mechanisms of action

HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? Antagonists of Cell Surface Receptors Antagonists of Nuclear Receptors Enzyme Inhibitors Ion Channel Blockers Transport Inhibitors Inhibitors of Signal Transduction Proteins

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Definition of RECEPTOR: A macromolecular component of the organism that binds the drug and initiates the drug’s effect. Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate.

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Definition of CELL SURFACE RECEPTOR: A receptor that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment.

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Extracellular Compartment Unbound Endogenous Activator (Agonist) of Receptor Cell Membrane Inactive Cell Surface Receptor Intracellular Compartment

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Extracellular Compartment Bound Endogenous Activator (Agonist) of Receptor Cell Membrane Active Cell Surface Receptor Intracellular Compartment Cellular Response

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Displaced Endogenous Activator (Agonist) of Receptor Extracellular Compartment Bound Antagonist of Receptor (Drug) Cell Membrane Inactive Cell Surface Receptor Intracellular Compartment

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor.

HOW DO DRUGS WORK BY ANTAGONIZING 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, yet do not activate the receptors to trigger a response. When cell surface receptors bind the drug molecule, the endogenous chemical cannot bind to the receptor and cannot trigger a response. The drug is said to “antagonize” or “block” the receptor and is referred to as a receptor antagonist.

ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORS CLINICALLY USEFUL? Some important examples: Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal insufficiency (losartan [Cozaar®]; valsartan [Diovan®]) Beta-Adrenoceptor Blockers for angina, myocardial infarction, heart failure, high blood pressure, performance anxiety (propranolol [Inderal®]; atenolol [Tenormin®])

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Definition of NUCLEAR RECEPTOR: A receptor that exists in the intracellular compartment and upon activation binds to regulator regions in the DNA and modulates gene expression.

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Unbound Endogenous Activator (Agonist) of Nuclear Receptor Inactive Nuclear Receptor In Cytosolic Compartment DNA Nucleus Intracellular Compartment Inactive Nuclear Receptor In Nuclear Compartment

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Active Nuclear Receptor Bound Endogenous Activator (Agonist) of Nuclear Receptor DNA Nucleus Modulation of Transcription Intracellular Compartment

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Displaced Endogenous Activator (Agonist) of Nuclear Receptor Bound Antagonist of Receptor (Drug) Inactive Nuclear Receptor In Cytosolic Compartment DNA Nucleus Intracellular Compartment Inactive Nuclear Receptor In Nuclear Compartment

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor.

HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS? KEY CONCEPTS: Nuclear receptors exist to mediate the effects of intracellular, endogenous chemicals on gene expression. Some drugs bind to nuclear receptors, yet do not activate the receptors to translocate to the nucleus, bind DNA and alter gene expression. When nuclear receptors bind the drug molecule, the endogenous chemical cannot bind to the receptor and cannot alter gene expression. The drug is said to “antagonize” or “block” the receptor and is referred to as a receptor antagonist.

ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORS CLINICAL USEFUL? Some important examples: Mineralocorticoid Receptor Antagonists for edema due to liver cirrhosis and for heart failure (spironolactone [Aldactone®]) Estrogen Receptor Antagonists for the prevention and treatment of breast cancer (tamoxifen [Nolvadex®])

HOW DO DRUGS WORK BY INHIBITING ENZYMES? Active Enzyme Substrate Product Cellular Function

HOW DO DRUGS WORK BY INHIBITING ENZYMES? Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug)

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 the effects of enzyme inhibitors.

ARE DRUGS THAT INHIBIT ENZYMES CLINICALLY USEFUL? Some important examples: Cyclooxygenase Inhibitors for pain relief, particularly due to arthritis (aspirin; ibuprofen [Motrin®]) HMG-CoA Reductase Inhibitors for hypercholesterolemia (atorvastatin [Lipitor®]; pravastatin [Pravachol®]) Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and chronic renal insufficiency (captopril [Capoten®]; ramipril [Altace®])

HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? Ions (e.g., Ca++, Na+, K+) Open Ion Channel Intracellular Compartment [Ions] Cellular Response

HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? Ions (e.g., Ca++, Na+) Blocked Ion Channel Drug that Blocks Ion Channels Ions (e.g., K+) Intracellular Compartment

HOW DO DRUGS WORK BY BLOCKING ION CHANNELS? KEY CONCEPTS: Ion channels allow ions to transverse the cell membrane through a pore and down an electrochemical gradient. Some drugs bind to ion channels and physically block the pore or cause an allosteric change that closes the pore. Changes in the intracellular concentration of ions mediates the effects of inhibitors of ion channels.

ARE DRUGS THAT BLOCK ION CHANNELS CLINICALLY USEFUL? Some important examples: Calcium Channel Blockers (CCBs) for angina and high blood pressure (amlodipine [Norvasc®]; diltiazem [Cardizem®]) Sodium Channel Blockers to suppress cardiac arrhythmias (lidocaine [Xylocaine®]; amiodarone [Cordarone®])

Cellular Response HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Membrane Impermeable Solute Active Transporter Membrane Impermeable Solute Cellular Response Intracellular Compartment

HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS? Membrane Impermeable Solute Inactive Transporter Drug that Inhibits Transporters Membrane Impermeable Solute Intracellular Compartment

HOW DO DRUGS WORK BY INHIBITING TRANSPROTERS? KEY CONCEPTS: Transporters bind to and shuttle membrane impermeable solutes across the cell membrane. Some drugs bind to transporters and cause allosteric changes that prevent proper functioning of the transporters. Changes in the intracellular concentration of specific solutes mediates the effects of inhibitors of transporters.

ARE DRUGS THAT INHIBIT TRANSPORTERS CLINICALLY USEFUL? Some important examples: Selective Serotonin Reuptake Inhibitors (SSRIs) for the treatment of depression (fluoxetine [Prozac®]; fluvoxamine [Luvox®]) Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in renal 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? (Some overlap with enzyme inhibitors) Extracellular Compartment Bound Endogenous Activator (Agonist) of Receptor Cell Membrane Active Cell Surface Receptor Intracellular Compartment Multiple Signal Transduction Proteins (each is a potential drug target) Cellular Response

HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS? (Some overlap with enzyme inhibitors) Extracellular Compartment Bound Endogenous Activator (Agonist) of Receptor Cell Membrane Active Cell Surface Receptor Intracellular Compartment Blockade or Augmentation of Signal Transduction Pathway by Drug

HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS? KEY CONCEPTS: Signal transduction proteins transmit a chemical signal from 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 or augment the signal transduction pathway and this mediates the effects of the drug.

ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINS CLINICALLY USEFUL? Some important examples: Tyrosine Kinase Inhibitors for chronic myelocytic leukemia (imatinib [Gleevec®]) Type 5 Phosphodiesterase Inhibitors for erectile dysfunction (sildenafil [Viagra®]) This is a major focus of drug development

HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS? Agonists of Cell Surface Receptors Agonists of Nuclear Receptors Enzyme Activators Ion Channel Openers

HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS? Extracellular Compartment Cell Membrane Inactive Cell Surface Receptor Intracellular Compartment

HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS? Extracellular Compartment Bound Exogenous Agonist of Receptor (Drug) Cell Membrane Active Cell Surface Receptor Intracellular Compartment Cellular Response

HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE 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 endogenous agonist to bind to or activate the receptor.

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.

ARE DRUGS THAT ACTIVATE CELL SURFACE RECEPTORS CLINICALLY USEFUL? Some important examples: Alpha1-Adrenoceptor Agonists for nasal congestion (oxymetazoline [Afrin®]; phenylephrine [Neosynephrine®]) Opioid Receptor Agonists for analgesia (morphine; meperidine [Demerol®])

HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS? Inactive Nuclear Receptor In Cytosolic Compartment DNA Nucleus Intracellular Compartment Inactive Nuclear Receptor In Nuclear Compartment

HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS? Active Nuclear Receptor Bound Exogenous Agonist of Receptor (Drug) DNA Nucleus Modulation of Transcription Intracellular Compartment

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 endogenous agonist 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 ACTIVATE NUCLEAR RECEPTORS CLINICALLY USEFUL? Some important examples: Estrogen Receptor Agonists for hormone replacement therapy in postmenopausal women (conjugated equine estrogens [Premarin®]) 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 Enzyme Activator (Drug) Cellular Function

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 the effects of enzyme activators.

ARE DRUGS THAT ACTIVATE ENZYMES CLINICALLY USEFUL? Some important examples: Activators of Guanylyl Cyclase for angina (nitroglycerin; isosorbide dinitrate [Isordil®]) Reactivators of Cholinesterase after poisoning with nerve gas or organophosphate pesticide (pralidoxime [Protopam®])

HOW DO DRUGS WORK BY OPENING ION CHANNELS? Binding Site on Ion Channel Ions (e.g., Ca++, Na+) Closed Ion Channel Binding Site on Ion Channel Ions (e.g., K+) Intracellular Compartment

HOW DO DRUGS WORK BY OPENING ION CHANNELS? Drug That Opens Ion Channel Ions (e.g., Ca++, Na+, K+) Open Ion Channel Drug That Opens Ion Channel [Ions] Cellular Response Intracellular Compartment

HOW DO DRUGS WORK BY OPENING ION CHANNELS? KEY CONCEPTS: Ion channels allow ions to transverse the cell membrane through a pore and down an electrochemical gradient. Some drugs bind to ion channels and allosterically open the ion channel or allosterically render the channel more readily opened by other endogenous chemicals. Changes in the intracellular concentration of ions mediates the effects of drugs that open ion channels.

ARE DRUGS THAT OPEN ION CHANNELS CLINICALLY USEFUL? Some important examples: Potassium Channel Openers for hair regrowth (minoxidil [Rogaine®]) GABAAChloride Channel Openers for anxiety (alprazolam[Xanax®]; midazolam [Versed®])

Disrupters of Structural Proteins Drugs that Are Enzymes 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

Drugs that Are Nutrients 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

DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS? Some important examples: Vinca Alkaloids for cancer (vincristine [Oncovin®]; vinblastine [Velban®]) Colchicine for gout

ARE SOME DRUGS ENZYMES? Some important examples: Thrombolytic therapy for acute myocardial infarction (alteplase [Activase®])

DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES? Some important examples: DNA alkylating agents for the treatment of cancer (cyclophosphamide [Cytoxan®]; chlorambucil [Leukeran®])

DO SOME DRUGS REACT CHEMICALLY WITH SMALL MOLECULES? Some important examples: Antacids that neutralize gastric acid (various preparations containing Al(OH)3, Mg(OH)2 or CaCO3)

DO SOME DRUGS BIND FREE MOLECULES OR ATOMS? Some important examples: Bile-Acid Sequestrants for hypercholesterolemia (cholestyramine [Questran®]) Chelating Agents for heavy metal poisoning (dimercaprol; penicillamine) Proteins that bind TNF-α for rheumatoid arthritis (infliximab [Remicade®]; etanercept [Enbrel®])

ARE SOME DRUGS NUTRIENTS? Some important examples: Vitamins, minerals, lipids, carbohydrates, aminoacids

DO SOME DRUGS EXERT ACTIONS DUE TO PHYSICAL PROPERTIES? Some important examples: Bulk Laxatives for constipation (psyllium [Metamucil®]; polycarbophil [Fibercon®] Osmotic Diuretics for edema (mannitol)

DO SOME DRUGS WORK VIA AN ANTISENSE ACTION? An important example: Antisense Deoxyoligonucleotides for cytomegalovirus retinitis in patients with AIDS (fomivirsen [Vitravene®] This is a major focus of drug development

ARE SOME DRUGS ANTIGENS? Some important examples: Vaccines

IS THE MECHANISM OF ACTION OF SOME DRUGS UNKNOWN? Some important examples: Inhalation Anesthetics for general anesthesia (Isoflurane [Forane®]; Sevoflurane [Ultane®]

HOW DO DRUGS WORK? Now you know!!