2Pharm III Flashcards
Adaptive immunity, Cell mediated:
Humoral:
T-lymphocytes
B lymphocytes
Where does the body learn to recognize “self” antigens?
Thymus gland
*central tolerance
What are the 3 specialized forms of T lymphocytes?
*which do we believe is involved in autoimmunes?
Helper
Cytotoxic
*Suppressor
T/F
Suppressor T cells regulate/dampen helper and cytotoxic T cells, preventing immune rxns from damaging the self
*this is Self Tolerance
True
When the immune system properly recognizes self/non-self antigens:
When this fails:
Immunologic tolerance
Autoimmunity
T/F
Autoimmunity is in 2% of the pop and the majority are women (and elderly, genetically susceptible)
True
Hypothesis of Autoimmunity is that T and B lymphocytes escape central tolerance mechanisms in the ______ gland
Thymus
What 2 major factors are necessary to develop autoimmmune disease?
Inherited susceptibility genes
Environmental triggers
What genes predispose to autoimmune disease?
MHC - major histocompatibility complex
What is the function of MHC genes?
2
encode cytokines
are recognized by T-lymphocytes for antigen processing
What are 3 common environmental triggers for autoimmune disease?
infection
high fever
trauma
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
RA
MS
Type I diabetes
Foreign antigens release cytokines that can activate T-lymphocytes and _______ T-lymphocytes
self-reactive
*infection as a trigger
What self-antigens can deposit in various places of the body, causing vasculitis, joint damage, and kidney damage?
Autoantibodies
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)
What autoimmune disease is initiated by autoantibodies that stimulate receptors that would normally only be stimulated by a hormone?
Hyperthyroidism
Organ specific autoimmune disease is mediated by what?
What is the Tx?
T-lymphocytes
reduce inflammation with coriticosteroids, anticytokines
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
Immunosuppressive drugs target what cells?
T cell responses
The goals for Pharmacologic interventions in autoimmune disease are generally what?
Palliative
*address inflammation with Aspirin/NSAIDS
What is a sign of toxicity to aspirin?
Tinnitus
T/F
GI, kidney, resp system, tinnitus are all adverse effects of Aspirin use
True
What are 2 oral complications of Aspirin/NSAID use?
Bleeding
Aphthous stomatitis
What is used to Tx RA when Aspirin/NSAIDS aren’t working?
Mechanism?
sulfasalazine (Azulfidine)
prostaglandin inhibitor
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?
4x
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
