2Pharm III Flashcards by Tim Agee

Adaptive immunity, Cell mediated:

Humoral:

T-lymphocytes

B lymphocytes

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Where does the body learn to recognize “self” antigens?

Thymus gland

*central tolerance

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What are the 3 specialized forms of T lymphocytes?

*which do we believe is involved in autoimmunes?

Helper

Cytotoxic

*Suppressor

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T/F
Suppressor T cells regulate/dampen helper and cytotoxic T cells, preventing immune rxns from damaging the self

*this is Self Tolerance

True

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When the immune system properly recognizes self/non-self antigens:

When this fails:

Immunologic tolerance

Autoimmunity

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T/F

Autoimmunity is in 2% of the pop and the majority are women (and elderly, genetically susceptible)

True

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Hypothesis of Autoimmunity is that T and B lymphocytes escape central tolerance mechanisms in the ______ gland

Thymus

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What 2 major factors are necessary to develop autoimmmune disease?

Inherited susceptibility genes

Environmental triggers

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What genes predispose to autoimmune disease?

MHC - major histocompatibility complex

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What is the function of MHC genes?

encode cytokines

are recognized by T-lymphocytes for antigen processing

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What are 3 common environmental triggers for autoimmune disease?

infection

high fever

trauma

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Possessing an autoimmune gene doesn’t mean an individual will always develop the disease, but what are 5 diseases that show familial autoimmunity?

thyroid disease

lupus

Type I diabetes

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Foreign antigens release cytokines that can activate T-lymphocytes and _______ T-lymphocytes

self-reactive

*infection as a trigger

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What self-antigens can deposit in various places of the body, causing vasculitis, joint damage, and kidney damage?

Autoantibodies

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What autoimmune disease is initiated by the alteration/inhibition of receptor function without tissue damage?

What receptor is inhibited?

Myasthenia gravis

acetylcholine (results in paralysis)

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What autoimmune disease is initiated by autoantibodies that stimulate receptors that would normally only be stimulated by a hormone?

Hyperthyroidism

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Organ specific autoimmune disease is mediated by what?

What is the Tx?

T-lymphocytes

reduce inflammation with coriticosteroids, anticytokines

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What is the effect of a large dose of corticosteroids when targeting organ specific autoimmune disease?

lymph tissue atrophy

*this decreases T/B cell production, increases susceptibility to infection

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Immunosuppressive drugs target what cells?

T cell responses

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The goals for Pharmacologic interventions in autoimmune disease are generally what?

Palliative

*address inflammation with Aspirin/NSAIDS

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What is a sign of toxicity to aspirin?

Tinnitus

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T/F

GI, kidney, resp system, tinnitus are all adverse effects of Aspirin use

True

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What are 2 oral complications of Aspirin/NSAID use?

Bleeding

Aphthous stomatitis

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What is used to Tx RA when Aspirin/NSAIDS aren’t working?

Mechanism?

sulfasalazine (Azulfidine)

prostaglandin inhibitor

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sulfasalazine (used for RA) has what (4) side effects?

headache photosensitivity GI Anorexia

COX-2 inhibitor:

celebrex (Celecoxib)

T/F | Do not use celebrex with low dose aspirin

False *ok to use

If a pt is using celebrex and antihypertensives, what should we do? *why?

Monitor BP *celebrex decreases BP med efficacy

2 side effects of celebrex:

CV (Increased risk for stroke/heart attack) bleeding

2 Contraindications for celebrex:

if aspirin/NSAID allergic if allergic to sulfonamides

DMARDS: used for:

Disease-modifying anti-rheumatic drugs RA and if pts don't respond to COX-2 inhibitor (celebrex)

What intervention can slow the course of RA disease progression, may induce remission, and prevents further destruction of joints/tissues?

DMARDS

T/F | DMARDS have fast onset

False *takes 3-4 months to see effects

4 classes of DMARDS:

Immune modulators (...mab) Antimalarials Penicillamine Gold compounds

What DMARD is also a heavy metal antidote?

Penicillamine

2 DMARD immune modulating drugs:

methotrexate leflunomide

What is the drug of choice for severe RA or psoriatic arthritis that is unresponsive to NSAIDS?

methotrexate

T/F | methotrexate, being a DMARD, takes 3 to 4 months to kick in

False 3-6 weeks, faster than other DMARDS

What are the 2 uses of methotrexate?

High dose - chemo Low dose - immune modulator for autoimmune (RA)

What is the (2) most common side effects of methotrexate? 3 others?

mucosal ulcerations, nausea cytopenias, cirrhosis, acute pneumonia-like syndrome

What DMARD inhibits pyrimidine synthesis, reduces pain/inflammation, and slows structural damage?

leflunomide

T/F Since leflunomide messes with the immune system by blocking pyrimidine synth, it has a whole lot of side effects (including teratogenicity)

True

What are 2 proinflammitory cytokines involved in RA?

IL-1b TNF-alpha

What secretes IL-1b and TNF-alpha involved in RA? What does this further stimulate?

synovial macrophage synovial cells secrete collagenase

3 TNF-alpha blockers: 1 IL-1b receptor antagonist:

etanercept infliximab adalimumab anakinra

What TNF alpha blocker binds TNF molecules, risks activation of hepatitis and TB in carriers, and has Upper Respiratory infections as side effects?

etanercept

What TNF alpha blocker is associated with developing antibodies against the Drug w/ long term use? *side effects: pneumonia, cellulitis, dyscrasias

infliximab

What TNF alpha blocker is a recombinant monoclonal antibody that binds to receptor sites? (used if inadequate response to other DMARDS)

adalimumab

What drug is typically used if other cytokine drugs fail?

anakinra *IL-1b receptor antagonist

anakinra (IL-1b receptor antagonist) mechanism:

slows degradation of cartilage/bone loss

2 Antimalarials that treat RA unresponsive to NSAIDS:

chroroquine hydroxychloroquine

How do antimalarials help with RA? 2 severe side effects:

slows erosive bone lesions, may induce remission eye damage, blue/black intraoral pigmentation (kind of Kaposi's sarcoma looking)

What chelating agent slows the progression of bone destruction and RA?

Penicillamine

2 mechanisms for Penicillamine:

depresses IgM rheumatoid factor depress T-cells

What drug for RA is used after gold, but before corticosteroids?

Penicillamine

4 oral complications to Penicillamine:

infection delayed healing prolonged bleeding ulcerations

Gold compounds used to treat RA decrease inflammation and slows bone/articular destruction via multiple....

mechanisms

Why does gold require intensive monitoring?

very toxic

4 side effects of gold compounds:

Dermatitis w/ mucosal ulcerations Proteinuria Neutropenia Thrombocytopenia

There are all kinds of complications with Gold, including blue-black intraoral pigmentation and _____

aphthous stomatitis

What 2 drugs cause blue-black intraoral pigmentation as a side effect to combating RA?

Antimalarials Gold

What are 3 immunosuppressive drugs used for Refractory RA *refractory = doesn't respond to normal Tx

azathioprine cyclophosphamide cyclosporine

What immune suppressant used for Refractory RA is also used in Dentistry for severe erosive lichen planus (and 3 other mouth diseases)? What drug is it used in combination with?

azathioprine prednisone

4 oral diseases azathiprine + prednisone is used for:

severe erosive lichen planus major aphthous stomatitis erythema multiforme benign mucous membrane pemphigoid

What immunosuppressant used for severe RA is also an antineoplastic? *side effects: alopecia, infertility, GI, dyscrasias

cyclophosphamide

What immunosuppressant for RA is primarily used to prevent organ rejection in transplants?

cyclosporine

When is cyclosporine used to treat RA?

if methotrexate doesn't work

What drug combats RA by inhibiting production/release of IL-II (and IL-II induced T cells)?

cyclosporine

cyclosporine is contraindicated for RA in what 3 cases?

abnormal renal function uncontrolled hypertension malignancies

16% of cyclosporine users will have what?

Gingival hyperplasia

3 used for Synthetic Glucocorticoid meds | steroids

Autoimmune Immunosuppressive transplant therapy Respiratory disease

Glucocorticoids (steroids) have anti-inflammatory effects and profound effects on number, distribution, and function of ________ What do they inhibit that decreases production of prostaglandins and leukotrienes from arachidonic acid?

peripheral leukocytes phospholipase A

Steroids increase what peripheral leukocyte? Decrease what peripheral leukocytes?

increase neutrophils decrease T/B cells, monocytes, eosinophils, basophils

Steroid suppress the immune system and the adverse rxns are proportional to the _____. Tx is considered ______

dose palliative

With Sjogren's Syndrome _____ % of the glandular cells remain intact, allowing for ______

50% salivary stimulating meds

An elevated BP can always be due to what?

Chronic pain

Stress =

cortisol

What does natural cortisol regulate? maintain? cortisol also has _____ effects

metabolism of carb, fat, and protein vascular reactivity anti-inflammatory

What is the most potent activator of cortisol?

Surgery

Excessive production of cortisol: Insufficient production of cortisol:

Cushing's disease Addison's disease

A medication induced adrenal insufficiency (taking steroids will suppress own production) is what kind of disorder?

Secondary

What adrenal insufficiency is more common than Addison's disease?

Secondary insufficiency *associated with chronic steroid use

What is a RARE, life-threatening emergency that exacerbates symptoms like sweating, hypotension, weak pulse, dyspnea, and cyanosis?

Adrenal crisis

6 systemic disease categories for which Steroids can be used?

Replacement therapy Arthritis Rheumatic Carditis Renal diseases Collagen diseases (lupus) Allergic diseases

T/F | Steroids function intracellularly

True *bind receptor, come inside, regulate gene expression

How is the potency of a steroid measured?

Against Hydrocortisone

Corticosteroids are characterized by what?

Duration of action *shore/intermediate/long

Prednisone has how much more of an anti-inflammatory effect than hydrocortisone?

Equivalent doses of steroids are based on the amount normally secreted in an adult w/o stress, which is...

20 mg

3 short acting steroids: 2 intermediate: 2 long:

hydrocortisone (cortisol), prednisone, methylprednisone triamcinolone, prenisolone dexamethasone, betamethasone

Steroids are usually taken what time of day? When is steroid use taken at alternate days?

morning if taking longer than 1 month

What type of steroid therapy increases the risk for adrenal suppression?

Daily *that's why alternate

Any medication that exceeds _____ mg hydrocortisone equivalent may cause adrenal suppression

20-30 mg *normal daily output

Normal cortisol output is 20 mg/day. What is max during stress?

300 mg/day

What happens if combine Chronic Steroid use w/ aspirin/NSAIDS?

Peptic ulceration

What are 3 major adverse events with Chronic Steroid use?

Moon face Cataracts Osteoporosis

4 oral side effects of Steroids:

Candidiasis Poor wound healing Mask oral infections Xerostomia

4 contraindications to using steroids:

Systemic fungal infections Viral infections TB Allergy

2 ways steroids are used in Dentistry:

reduce pain/swelling Tx inflammatory pathologies oral mucosa

What is the most common delivery route of Steroids in Dentistry?

Topical

High potency topical steroids should only be used for how long?

2 weeks only

Using high potency topical steroids for longer than 2 weeks requires what? What is the risk?

physician consult adrenal suppression

What oral topical steroid is mixed with tissue adhesive?

triamcinolone

What oral topical steroid is a 0.5% gel for mild lichen planus and recurrent aphthous stomatitis?

fluocinonide

What oral topical steroid is a 0.5% gel for oral inflammation?

clobetasol proprionate

What oral topical steroid is 0.1%?

betamethasone

What are the 2 topical steroid rinses used in dentistry? used 2-4x/day, rinse 30 secs, spit

dexamethasone elixer prenisolone syrup

What are the 2 types of injected steroid uses?

Intralesional Intra-articular (3 week intervals)

What are the 2 Oral preparations of steroids used before, during, after oral surgery?

methylprednisolone prenisone

What 3 populations require special consideration when using steroids? *but there are many more (glaucoma, hypertension, peptic ulcer, osteoporosis, diabetes, TB)

Pregnant/lactating pediatric geriatric (liver/kidney function = lower dose)

What type of dental procedures require steroid used before/during/after?

Only major *routine procedures won't stimulate cortisol production

When do cortisol levels increase in dental pts?

1-5 hrs post procedure | pain response, loss of local anesthesia

What BP levels are hypotensive?

Systolic: less than 100 mm Hg Diastolic: less than 60 mm Hg

T/F | For a routine dental procedure, if the pt has a past history of steroid use, supplementation is necessary

False *no supplementation necessary

3 types of lab tests to determine if pt needs steroids:

ACTH in plasma Urine test Stimulation test

For a pt currently taking steroids, the protocol for diagnostic/minimally invasive procedures: (4 things)

Pt takes usual dose Schedule in morning Stress reduce (pain/anxiety) monitor BP

T/F For major invasive procedures like oral surgery a physician consult, lab testing, and steroid supplementation as needed is protocol

True

T/F Pts either currently taking steroids (topically or orally) or with a history of taking steroids should be given no additional steroids with routine Tx

True

Schedule in morning, monitor BP - What are 2 anxiety control interventions for pts on steroids?

nitrous oxide benzodiazepines (Valium)

Target dose of hydrocortisone for Minor oral/perio surgery: Target dose of hydrocortisone for major oral surgery involving general anesthesia:

25 mg 50-100 mg

3 mechanisms used by Antivirals:

Alter uncoating of virus Polymerase inhibitors Inhibit viral protein synth

2 drugs used for Influenza A? *Mechanism

amantadine rimantidine *blocks viral uncoating

Drug for either Influenza A or B: This is a classic example of what? This drug inhibits what enzyme

oseltamivir (Tamilflu) Prodrug Neuraminidase inhibitor

Neuraminidase does what?

Cuts viral progeny from cellular envelope prior to release *inhibiting prevents viral release

What drug is used for respiratory syncytial virus?

ribavirin (Rebetol, Virazole)

Mechanism of ribavirin (drug used for respiratory syncytial virus):

Prevents synth of viral proteins encoded by viral mRNA

3 side effects to using ribavirin (messes with mRNA)

Mutagenic Teratogenic Carcinogenic

What drug is indicated for herpes simplex keratitis (In the eye) *mechanism involves incorporating into viral DNA in place of what?

trifluridine Thymidine

What drug is used for Herpes zoster, genital HSV, immunocompromosed primary and recurrent herpes, and is the IV drug of choice for HSV encephalitis?

acyclovir (Zovirax)

Acyclovir must be used every ____ hours

3 | Consistent with cycle phases of virus

CMV - human cytomegalovirus (and CMV retinitis) is treated with what drug? Mechanism?

ganciclovir Inhibits viral DNA synth

What 2 classic Prodrugs are used for genital herpes? What do they turn into when they pass through the intestinal wall?

famcyclovir - penciclovir valacyclovir - acyclovir

A family of naturally occurring inducible glycoproteins that interfere with viral ability to infect cells:

Interferons

3 Interferon actions:

Antiviral Cytotoxic Immunomodulatory

3 types of interferons:

Alpha Beta Gamma

T/F the antiviral mechanism of interferons isn't completely understood

True

Though not well understood, we know that Interferons inhibit viral ________

RNA translation | Degrades both mRNA and tRNA

Interferons appear to have many mechanisms, including affecting gene transcription, cell growth, differentiation, surface antigen expression, increasing phagocytic and cytotoxic activity - and interfering with what particular gene expression?

Oncogene

Interferons are used to combat some cancers, but what are the 2 most common indications?

Heb B and C MS

What are the adverse effects of Interferons?

Wide ranging *it's really hard to be on

There are new, and VERY expensive, drugs for Hepatitis C

True

What is the main challenge to Antiretroviral drugs?

Toxic to host cells

When does a viral infection technically begin?

When virus attaches to host cell *mediated by viral proteins and host membrane receptors

What are 3 general mechanisms Antiretrovirals use to inhibit disease?

Inhibit attachment Alter viral genome replication Immunization

T/F There is a new drug that inhibits HIV from entering host cells - the first of its kind (Fusion protein inhibitor) *vaccine could do this too

True

What type of drug alters retroviral genome expression?

Polymerase inhibitors

Antiretroviral immunization provides antibodies against what?

Viral envelope proteins

Retroviridae all use what enzyme? *this is essential for HIV replication

reverse transcriptase

Reverse transcriptase is a ______ polymerase

DNA | RNA to DNA

The targets of antiretroviral drugs is what?

Reverse transcriptase

What happens after a retrovirus undergoes reverse transcription?

Integration *virus incorporates into host DNA

What is the integrated DNA segment of a retrovirus called? What can it do?

Provirus Produce new RNA - protein synth for new viruses

Another name for a compete virus:

Virion

What are the 3 Primary classes of Antiretroviral drugs for HIV?

Nucleoside reverse transcriptase inhibitors Protease Inhibitors Non-nucleoside reverse transcriptase inhibitors

Aside from the 3 primary classes of Antiretroviral drugs for HIV, what are 3 additional classes?

Nucleotide reverse transcriptase inhibitors Fusion protein inhibitor Integrase inhibitor

Integrase inhibitors block viral integration into host ____. Protease inhibitors ______ of certain long peptide chains

DNA Cleavage

What is the anti-HIV drug combination therapy called?

HAART - Highly Active AntiRetroviral Therapy *usually 3 different drugs

A typical anti-HIV antiretroviral cocktail will include what 3 classes of drugs?

nucleoside reverse transcriptase inhibitor non-nucleoside transcriptase inhibitor protease inhibitor *these are the 3 primary classes

When are antiretrovirals used for HIV-infected pts?

CD4 less than 500

5 side effects to Antiretrovirals:

Anemia Leukopenia/granulocytopenia Hepatotoxicity Peripheral neuropathy Pancreatitis

EBV, Cytomegalovirus, and other Viral infections associated with immunocompromised HIV pts are treated how?

antivirals

Pneumocystis carinii (pneumonia associated with HIV) is treated with oral trimethoprimsulfamethoxazole (Bactrim), which is a ____ drug

Sulfa

Candidiasis, Cryptococcus, and Histoplasma in HIV pts are treated with the azoles and _______. *If you see this drug you can pretty much assume the pt is HIV positive

amphotericin B

T/F | TB from HIV is treated with isoniazid and rifampin

True

Nucleoside reverse transcriptase inhibitors must be ______ to be integrated into ______

biotransformed/bioactivated reverse transcriptase (a DNA polymerase ***end result is inhibition of reverse transcriptase

Nucleoside reverse transcriptase inhibitors work because the enzyme reverse trascriptase in HIV is _____ times more susceptible to inhibition than are normal human cells. What is the downside to these drugs?

1100 NO effect in cells already containing HIV

2 Nucleoside reverse transcriptase inhibitors:

didanosine zidovudine (Retrovir) ***(AZT)

AZT, zidovudine, is very toxic - pts are often required to have transfusions why? Also causes Oral and CNS effects and ______

bone marrow depression Nausea

Oral effects of AZT: 4 of them

altered taste tongue edema bleeding gingiva mouth ulcers

Acetominophen, aspirin, indomethacin (NSAID) have DDI's that inhibit the metabolism of ______ This potentiates _____ of both agents

AZT - zidovudine toxicity

How do non-nucleoside RT inhibitors differ from nucleoside?

Do NOT require bioactivation inhibits catalytic rxn of RT independent of nucleotide binding

T/F | Resistance to non-nucleoside RT inhibitors is uncommon

False *happens quickly if used alone

Protease inhibitors affect the enzyme responsible for cleaving viral precursor peptides, thus preventing _____ of HIV infected cells

maturation

3 Protease inhibitors:

indinavir nelfinavir saquinavir

What prevents a proviral gene inserting into human DNA?

Integrase inhibitor

What is a new combo drug containing 3 meds in 3 different classes for HIV?

Complera

T/F | Linear gingival erythema, NUP, and perio can all result from HIV

True

The range of responses per dose:

Biological variation

Greater than normal reaction to a drug:

Hypersusceptibility

Qualitatively different response to a drug | stimulant = sleep

Drug idiosyncrasy

Lower doses for what 2 groups?

Young Old

In most cases of Liver disease drug metabolism is affected by what system failing?

cytochrome P-450 *reduce doses

In cases or renal disease dosing must be modified based on excretory function of renal _______

clearance

A rapid development of tolerance:

Tachyphylaxis

The study of deleterious effect of phyisical, chemical or biological substances (toxins)

Toxicology

LD50: ED50:

50% of lethal dose effective dose - shows effect in 50% mice receiving

LD50/ED50 =

Margin of Safety

Acceptable margin of safety is _____ or more

2000

Daily dosing to rats/dogs from 3 months to 2 years:

Long-term (chronic) toxicity studies

The range of doses (concentrations) of a drug that elicits a therapeutic response (withouth unacceptable side effects in a population)

Therapeutic Window

TD50: ED50:

toxic response, 50% pop. therapeutically effective, 50% pop.

Therapeutic Index = *what does a large therapeutic index suggest?

TD50/ED50 Large therapeutic window

T/F | body doesn't distinguish drugs from toxic foreign substance (xenobiotics) and handles them the same way

True ``` pharacokinetics = toxicokinetics pharmacodynamics = toxicodynamics ```

The study of the absorption, distribution, metabolism and excretion of toxic compounds and metabolic products used to predict toxin concentration

Toxicokinetics

T/F | Acute toxicity usually is visible right away, and occasionally not visible for weeks/months post exposure

True

The effect of toxic insult that occurs over a prolonged period Can this manifest long AFTER the individual is no longer exposed to toxin

Chronic toxicity yes

Toxins must cross at least one epithelial layer to be systemically absorbed - what are the 3 primary sites of absorption?

GI Respiratory Skin

Benzene, tetrachloroethylene, and asbestor are absorbed into the body through what?

Lungs

T/F | Toxins must diffuse though 7 layers of skin to gain systemic exposure

True

Toxin distribution to a tissue is directly related to what 2 factors?

Amount of blood flow to the tissue Affinity of toxin to tissue

Lipid soluble toxins can cross membranes - what toxins have a difficult time crossing the BBB

water-soluble (and therefore polar)

Detoxification usually occurs where and by what enzyme system?

Liver Cytochrome P450

Cytochrome P450 creates what?

Water soluble molecules for elimination

Nontoxic material - toxic metabolite:

Toxication

Toxins go through what 3 types of changes upon metabolism:

Detoxication Toxication another toxin (active to active)

3 toxins stored in the body for a long time:

Lead - bones DDE (from DDT) - fat Inhaled macrophage engulfed particulate in lung

Toxins damage tissue by altering the structure of proteins, lipids, carbs, nucleic acids so severely that _____ is lost

Cellular integrity

Non-specific sites damaged by environmental tissue damaging agents tend to be skin, eyes, respiratory system and are

True

Because Reactive Species tend to react chemically with biologic macromolecules the site of action is _______

More specific

Example of a site-specific Reactive Species:

Carbon tetrachloride *fire extinguishers - not toxic, but metabolized into toxic free radicals that damage liver, kidney

2 types of immune responses triggered by toxins:

Hypersensitivity rxns Autoimmune rxns

What kind of toxicity alters metabolic pathways or interacts with critical receptors? *this can mess with neurotransmission, cardiac rhythm, oxygen delivery, ATP generation, or intracellular Ca balance.

Enzyme and Receptor-Mediated Toxicity

Nerve gases and pesticides are _______ inhibitors making them ____ mediated toxin

acetylcholinesterase enzyme *ACh amasses in cleft - parasympathetic

Another enzyme mediated toxin: What does Cyanide bind to? This prevents the generation of what?

heme iron in cytochrome C oxidase ATP

Carbon monoxide is a ____ mediated toxin

Receptor

Most carcinogenic initiators damage what?

DNA

Carcinogens either damage DNA or promote cancer by what means?

Damage *cirrhosis - liver cancer (causes chronic regeneration of tissues)

Substance that can induce a birth defect

Teratogen

Teratogens can alter DNA or act in what particularly potent manner?

Inhibit intracellular signals

3 types of selective toxicity:

Attack target not present in host Attack target similar but not identical to those of host Attack target shared by host, but vary by importance

When is selective toxicity least toxic? Most toxic?

When unique difference between pathogen/cancer and host target common pathways between pathogen/cancer and host

What is an indication of how selective a drug is?

Therapeutic index TD50/ED50

A narrow therapeutic index tells us what about selectivity?

Drugs less selective - affect host and pathogen/cancer

Antibacterials targeting bacterial cell wall synth (peptidoglycans) is an example of a _____ drug target

unique *minimal toxicity - safe (penicillin)

Why are antifungals not good at selective targeting?

Fungi are enveloped in lipid bilayer similar to humans *if attacks membrane, will also affect humans

When would a drug have a therapeutic window smaller than those with a unique target? An example:

similar (pathogen/host) metabolic pathways that target unique enzymes/receptors bacteria have different ribosomes, RNA, proteins

How do Macrolides work? How do aminoglycosides work?

prevent protein from coming out of bacterial ribosome disrupt mRNA decoding

Most drugs with common targets to the host have to do with what?

Cancer

3 main steps of Carcinogenesis:

Transformation Proliferation Metastasis

T/F | The genetic damage involved in the Transformation step of Carcinogenesis can be congenital or later mutations

True

Cell life cycle, synth DNA: division of 2 daughter cells:

S phase M phase (mitosis)

Most antineoplastic drugs target what?

dividing cells

What type of cells respond best to chemo?

small, rapidly dividing cells

T/F | As cancer gains mutations, responses to chemo may change and metastatic lesions may be less responsive

true

Chemotherapy works by what 2 mechanisms?

p53 - cell cycle is arrested and repaired apoptosis - bad cell dies

p53 is a ______ factor What is its function?

Transcription Tumor suppressor

p53's four anticancer mechanisms:

repair proteins G1/S arrest and repair apoptosis initiation Induce growth arrest

3 stressors that induce p53:

UV radiation oncogenes DNA damaging drugs

Tumor suppression is severely compromised if what system is damaged?

p53

3 types of cancer that express p53 and are very responsive to chemo?

leukemias lymphomas testicular cancer

What are 3 types of cancer that tend to acquire a p53 mutation and aren't very responsive to chemo?

pancreatic lung liver

Chemo has what type of kinetics?

First order: constant fraction of tumor cells killed w/ each cycle

T/F | Multiple cycles of chemo are given at the highest possible (tolerable) dose

True

Why do solid tumors not respond well to chemo? What interventions are used instead?

Slower growth/division radiation/surgery

Why is combo Chemo used?

resistance develops

Chemo that acts on differing targets, phases of cell cycle, and with different dose limiting toxicities: Some of these therapies have ____ benefits To be used how often?

Combination therapy synergistic intermittent dosing

What is the current emphasis in chemo?

Drug combination therapy

T/F | You can have cell cycle specific or non cell-cycle specific drugs

True

3 types of normally proliferating cells affected by chemo:

Marrow Skin Intestinal mucosa

3 ways chemo toxicity manifests:

Blood dyscrasias Ulcerations mucosa/GI Nausea/vomiting

T/F Alkylating agents transfer alkyl groups to sulfhydryl, carboxyl, and phosphate groups, alkylate DNA (affecting downstream RNA and protein synth) and are Cell cycle specific

False *cycle non-specific

5 classes of Chemotherapeutic alkylating agents:

nitrogen mustards alkyl sulfonates ethylenimines triazines nitrosureas

What is a common side effect of chemotherapeutic Alkylating agents?

Susceptibility to infection

3 specific Alkylating Agents:

cyclophosphamide ifosfamide (nitrogen mustard) procarbazine

Antimetabolites are specific to what cell cycle phase?

S phase

3 classes of Antimetabolites antagonize what?

Folic acid Purine Pyrimidine

An Antimetabolite Folic acid antagonist that is specific to S phase (all metabolites specific to S phase):

methotrexate

Antimetabolite Purine antagonist: *like all antimetabolites, S phase specific

mercaptopurine

2 Antimetabolite Pyrimidine antagonists: *like all, S phase specific

fluorouracil "5-FU" cytarabine "Ara-C"

2 Platinum Complexes that inhibit DNA synth/repair and are used to fight cancer:

carboplatin cisplatin

T/F | Platinum based chemo is widely used for Tx of many cancers (gyno, bladder, testes, lung, CNS, head/neck)

True

What is a major toxicity of Platinum derived compounds for cancer? (class emphasized) What are 4 others?

Myelosuppression nephrotoxic, neurotoxic, ototoxic, nausea/vomiting

What, derived from the periwinkle plant, inhibits mitotic division?

Vinca Alkyloids

Vinca Alyloids go after what phase of the cell cycle?

M and S *cell cycle specific

2 Vinca Alkyloids

vinblastine vincristine

T/F | Vinca Alkyloids have a high incidence of toxicity and may cause hearing loss (ototoxic)

True

What cell cycle phase do hormones interrupt?

G phase

Name 4 hormonal agents:

Estrogens Androgens Progestins Glucocorticoids

What is an example of a Glucocorticoid used to suppress cancer (antitumor effects)

prednisone

T/F prednisone's antitumor effects are related to glc transport inhibition, phosphorylation inhibition, or induction of cell death in immature lymphocytes

True

What is an anti-estrogen drug that competitively binds estrogen receptors? What cell cycle phases does it target?

tamoxifen G0 and G1

tamoxifen is cytocidal

False *cytostatic

5 adverse effects of tamoxifen (competitively binds estrogen receptors)

uterine cancer stroke pulmonary emboli liver osteoporosis

Why are antibiotics used for cancer therapy?

Cytotoxic - bind w/ DNA and inhibit cell division

Cell cycle specificity of antibiotics: Most effective for what type of tumor?

either non-cell cycle specific or cell cycle specific solid mass tumors

3 antibiotics used to Tx cancer:

bleomycin doxorubicin daunorubicin citrate

What Antibiotic is used for HIV-associated Kaposi's Sarcoma?

daunorubicin citrate

Cancer fighting antibiotic go after cell cycles and inhibit what?

DNA/RNA synth

What drug is the Angiogenesis inhibitor to fight cancer?

thalidomide

4 indications for thalidomide: | one investigational

leprosy Crohn's AIDS aphtous lesions multiple myeloma (investigational)

What is the classic model drug for teratogenesis?

thalidomide *morning sickness - birth defects

8 systemic effects of Chemo:

Bone marrow suppression GI Dermatologic Hepatotoxic Neurotoxic Nephrotoxic Immune deficiencies Infertility

What is the greatest consequence of the Oral complications to Chemo?

Discomfort interferes w/ eating | secondary infection risk

Chemo pts should be manages orally with plaque control, pain control (topical anethesia), salivary replacement, Fluoride, antifungals, antivirals, and antimicrobial mouthrinses/dentrifrices

True

T/F | All metals produce toxicity in animals and humans

True

Metals form coordination complexes with various ligands that have 4 consequences:

Disrupt enzymatic/transport process Loss of energy production Loss of ion regulation Potential carcinogenesis

What is the most common arsenic containing mineral? Therapeutic use:

Arsenopyrite kill amoebas/parasites

T/F | Everyone has about 3 micrograms of arsenic in the body daily, but can tolerate well

True

Arsenic effects: dermatological, vasodilation, GI, CNS, headache, coma, teratogenic, carcinogenic, and breath smells like what?

Garlic

What is given for arsenic poisoning? How does it work?

dimercaprol sulfhydryl group combines with arsenic - excreted in urine

Antimony is used to flame proof and is highly toxic

True

What is the antidote to Antimony?

domercaprol *just like arsenic - sulfhydryl combines and excreted in urine

Silver is germicidal, is used to encapsulate wounds, antiseptic for burns, cauterizes wounds - and used to be placed into newborn eyes to kill gonococcus

True

What happens when Silver is absorbed into the circ system?

Argyria *blue/gray skin pigmentation of skin/mucous membranes

T/F | Pure gold is toxic

False *salts are toxic

Antidotes to gold toxicity:

dimercaprol penicillamine

Exposure to mercury leads to what 3 things?

tremors impaired cognition sleep disturbance

Chest pain, dyspnea, cough, hemoptysis, impairment of pulmonary function, interstitial pneumonia:

Acute mercury exposure

Continuous exposure to what leads to fine tremor, initally in the hands but moving to the eyelids, lips, and tongue

mercury

elemental mercury - neurotoxic inorganic mercury - corrosive to what? Antidotes:

oral cavity/gut dimercaprol, penicillamine

Enzyme inhibitor in the production of heme (inhibits protoporphyrin IX and accumulates aminolevulonic acid)

Lead (Pb)

Antidotes to Lead:

calcium EDTA dimercaprol

What inhibits the same process as Lead and was historically used to treat enlarged joints/glands?

Cadmium

2 Antidotes to Cadmium:

dimercaprol calcium EDTA

The treatment to Cadmium poisoning mobilized the metal to the ______

kidneys *possible renal toxicity

What is the antidote to Iron poisoning?

deferoxamine

What is the antidote to Aluminum?

deferoxamine

Antidote to Nickel:

diethylthiocarbamate

4 requirements to heavy metal antogonists (antidotes)

water solubility small size chelate is stable/less toxic at physiological pH can't bind Ca++

The antidote for Arsenic, Antimony, Gold, and Mercury:

Dimercaprol

The antidote for Lead, Cadmium:

Calcium disodium edetate (EDTA)

Antidote for Gold, mercury:

Penicillamine

Antidote for Iron, Aluminum:

Deferoxamine