04/11/23

HOW DO DRUGS WORK?

04/11/23

WHY BE CONCERNED ABOUT HOW DRUGS WORK?

• FDA Approved and Unapproved Uses

• Interactions with Other Drugs

• Adverse Effects and Contraindications

AIDS MEMORIZATION OF:

04/11/23

WHY BE CONCERNED ABOUT HOW DRUGS WORK?

• Better assessment of new modalities for using drugs

• Better assessment of new indications for drugs

• Better assessment of new concerns regarding risk-benefit

AIDS EVALUATION OF MEDICAL LITERATURE:

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WHY BE CONCERNED ABOUT HOW DRUGS WORK?

The patient has more respect for and trust in a therapist whocan convey to the patient how the drug is affecting the

patient’s body.

AIDS PATIENT-DOCTOR RELATIONSHIP:

A patient who understands his/her therapy is more inclined to become an active participant in the management

of the patient’s disease.

04/11/23

WHY BE CONCERNED ABOUT HOW DRUGS WORK?

Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately.

PEACE OF MIND!

04/11/23

HOW DO DRUGS WORK?

• Some drugs antagonize, block or inhibit endogenous proteins

• Some drugs activate endogenous proteins

• A few drugs have unconventional mechanisms of action

Most drugs work by interacting withendogenous proteins:

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HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBITENDOGENOUS PROTEINS?

• Antagonists of Cell Surface Receptors

• Antagonists of Nuclear Receptors

• Enzyme Inhibitors

• Ion Channel Blockers

• Transport Inhibitors

• Inhibitors of Signal Transduction Proteins

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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

A macromolecular component of the organism that binds the drug and initiates the drug’s effect.

Definition of RECEPTOR:

Most receptors are proteins that have undergone various post-translational modifications such as covalent

attachments of carbohydrate, lipid and phosphate.

04/11/23

HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

A receptor that is embedded in the cell membrane and functionsto receive chemical information from the extracellular

compartment and to transmit that information to the intracellular compartment.

Definition of CELL SURFACE RECEPTOR:

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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Cell Membrane

Unbound Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

Cellular Response

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HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS?

Cell Membrane

Displaced Endogenous Activator (Agonist) of Receptor

Inactive Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

Bound Antagonist of Receptor (Drug)

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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?

04/11/23

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 activatethe 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 andis referred to as a receptor antagonist.

04/11/23

ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORS

CLINICALLY USEFUL?

• Angiotensin Receptor Blockers (ARBs) for high blood pressure, heart failure, chronic renal insufficiency(losartan [Cozaar®]; valsartan [Diovan®])

Some important examples:

• Beta-Adrenoceptor Blockers for angina, myocardial infarction, heart failure, high blood pressure, performance anxiety

(propranolol [Inderal®]; atenolol [Tenormin®])

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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

A receptor that exists in the intracellular compartment and uponactivation binds to regulator regions in

the DNA and modulatesgene expression.

Definition of NUCLEAR RECEPTOR:

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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

Unbound Endogenous Activator (Agonist) of Nuclear Receptor

Inactive Nuclear ReceptorIn Cytosolic Compartment

Intracellular Compartment

Nucleus

DNA

Inactive Nuclear ReceptorIn Nuclear Compartment

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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

Intracellular Compartment

Nucleus

DNA

Modulation ofTranscription

Active Nuclear Receptor

Bound Endogenous Activator (Agonist) of Nuclear Receptor

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HOW DO DRUGS WORK BY ANTAGONIZING NUCLEAR RECEPTORS?

Displaced Endogenous Activator (Agonist) of Nuclear Receptor

Intracellular Compartment

Nucleus

DNA

Bound Antagonist of Receptor (Drug)

Inactive Nuclear ReceptorIn Cytosolic Compartment

Inactive Nuclear ReceptorIn Nuclear Compartment

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HOW DO DRUGS WORK BY ANTAGONIZINGNUCLEAR 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.

04/11/23

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 activatethe 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 andis referred to as a receptor antagonist.

04/11/23

ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORS

CLINICAL USEFUL?

• Mineralocorticoid Receptor Antagonists for edema due toliver cirrhosis and for heart failure

(spironolactone [Aldactone®])

Some important examples:

• Estrogen Receptor Antagonists for the prevention and treatmentof breast cancer (tamoxifen [Nolvadex®])

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HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

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HOW DO DRUGS WORK BY INHIBITING ENZYMES?

Inactive Enzyme

Substrate

Bound Enzyme Inhibitor (Drug)

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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.

04/11/23

ARE DRUGS THAT INHIBIT ENZYMESCLINICALLY USEFUL?

• Cyclooxygenase Inhibitors for pain relief,particularly due to arthritis (aspirin; ibuprofen [Motrin®])

Some important examples:

• Angiotensin Converting Enzyme (ACE) Inhibitors for high blood pressure, heart failure, and

chronic renal insufficiency(captopril [Capoten®]; ramipril [Altace®])

• HMG-CoA Reductase Inhibitors for hypercholesterolemia(atorvastatin [Lipitor®]; pravastatin [Pravachol®])

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HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?

Open Ion Channel

Intracellular Compartment

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

[Ions]

Cellular Response

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HOW DO DRUGS WORK BY BLOCKING ION CHANNELS?

Blocked Ion Channel

Intracellular Compartment

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

Drug that Blocks Ion Channels

Ions (e.g., K+)

04/11/23

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.

04/11/23

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®])

04/11/23

HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?

Active Transporter

Intracellular Compartment

Membrane Impermeable Solute

Cellular Response

Membrane Impermeable Solute

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HOW DO DRUGS WORK BY INHIBITING TRANSPORTERS?

Inactive Transporter

Intracellular Compartment

Membrane Impermeable Solute

Membrane Impermeable Solute

Drug that Inhibits Transporters

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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.

04/11/23

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®])

04/11/23

HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS?

(Some overlap with enzyme inhibitors)

Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

Cellular Response

Multiple Signal Transduction Proteins(each is a potential drug target)

04/11/23

HOW DO DRUGS WORK BY INHIBITING SIGNAL TRANSDUCTION PROTEINS?

(Some overlap with enzyme inhibitors)

Cell Membrane

Bound Endogenous Activator (Agonist) of Receptor

Active Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

Blockade or Augmentation of Signal Transduction Pathway by Drug

04/11/23

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.

04/11/23

• 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?

04/11/23

HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS?

• Agonists of Cell Surface Receptors

• Agonists of Nuclear Receptors

• Enzyme Activators

• Ion Channel Openers

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HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?

Cell Membrane Inactive Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

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HOW DO DRUGS WORK BY ACTIVATING CELL SURFACE RECEPTORS?

Cell Membrane Active Cell Surface Receptor

Extracellular Compartment

Intracellular Compartment

Bound Exogenous Agonist of Receptor (Drug)

Cellular Response

04/11/23

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?

04/11/23

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.

04/11/23

•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?

04/11/23

HOW DO DRUGS WORK BY ACTIVATING NUCLEAR RECEPTORS?

Inactive Nuclear ReceptorIn Cytosolic Compartment

Intracellular Compartment

Nucleus

DNA

Inactive Nuclear ReceptorIn Nuclear Compartment

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HOW DO DRUGS WORK BY ACTIVATINGNUCLEAR RECEPTORS?

Intracellular Compartment

Nucleus

DNA

Modulation ofTranscription

Active Nuclear Receptor

Bound Exogenous Agonist of Receptor (Drug)

04/11/23

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.

04/11/23

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.

04/11/23

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®])

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HOW DO DRUGS WORK BY ACTIVATING ENZYMES?

Inactive Enzyme

Substrate

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HOW DO DRUGS WORK BY ACTIVATING ENZYMES?

Active Enzyme

Substrate Product

Cellular Function

Enzyme Activator (Drug)

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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.

04/11/23

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®])

04/11/23

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

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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

04/11/23

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.

04/11/23

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®])

04/11/23

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

04/11/23

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

04/11/23

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

Some important examples:

• Colchicine for gout

DO SOME DRUGS DISRUPT STRUCTURAL PROTEINS?

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ARE SOME DRUGS ENZYMES?

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

Some important examples:

04/11/23

DO SOME DRUGS COVALENTLY LINK TO MACROMOLECULES?

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

Some important examples:

04/11/23

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:

04/11/23

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®])

04/11/23

ARE SOME DRUGS NUTRIENTS?

• Vitamins, minerals, lipids, carbohydrates, aminoacids

Some important examples:

04/11/23

DO SOME DRUGS EXERT ACTIONSDUE TO PHYSICAL PROPERTIES?

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

Some important examples:

• Osmotic Diuretics for edema(mannitol)

04/11/23

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

04/11/23

ARE SOME DRUGS ANTIGENS?

Some important examples:

• Vaccines

04/11/23

IS THE MECHANISM OF ACTIONOF SOME DRUGS UNKNOWN?

• Inhalation Anesthetics for general anesthesia(Isoflurane [Forane®]; Sevoflurane [Ultane®]

Some important examples:

04/11/23

HOW DO DRUGS WORK?

Now you know!!