pharm e2
HEME
**know mechanisms of antiplatelets, how they defer, and interactions w/ other drugs, all antidotes
Thrombomodulin
On surface cells
Binds thrombin
complex activates protein C
inactivates factors V and VIII
(basically antagonize clotting factors)
Antithrombin III
Binds thrombin and inactivates
Heparin works w/ antithrombin III
Heparin secreted from mast cells
Heparin binds antithrombin III
Inactivates factors XII, XI, X and IX
Prostacyclin (PG12)
Inhibits plt activation
Thromboxane A2 (TXA2)
Stimulates plt activation
Plasmin
Digests fibrin
Inactivates factors V, VIII, and XII
(dissolves clot)
Fibrin
Cement that holds everything together
Platelet activation
Collagen exposed
Glycoprotein Ib (GPIb) binds to vWF, collagen binds glycoprotein Ia/IIa (GPIa/IIa) and releases TXA2 and ADP
ADP, TXA2 cause conformational change (change in shape) exposing GPIIb/IIIa
3 main classes / biggest targets for antiplatelet medications
Fibrinogen binds GPIIb/IIa cross linking plt plug
Thrombin (factor II) interacts w/ PAR1 and PAR4 receptors to stimulate plt activation
ADP activates P2Y1 / P2Y12 receptors which activate plts
ANTIPLATELETS
Aspirin (ASA)
Irreversibly acetylates COX enzymes
Inhibits TXA2 for life of plt (7-10 days) (COX1)
Prevent production of TXA2 and get rid of one of inputs that stimulates plt activation
Inhibits PG12 partially in epithelium (COX-1)
Not the main effect we are looking for
COX maximally inhibited at 160 mg/day (higher doses inhibit PG12 - limit activity)
ASA acetylates both COX1 and COX2 (nonselective for COX 1 and 2)
COX2 expressed in endothelial cells and w/ inflammation
PG12 in humans due to COX2 in endothelial cells
COX2 produced PGI2
COX 2 inhibitors block PGI2 and not TXA2
SE
Stomach ulcers
Bleeding
NSAIDS
COX inhibition
ASA: 7-10 days
Ibuprofen- 24 hours
Naproxen, etc - 48 hours
Piroxicam - 72 hrs
Reversible inhibitors - very little plt inhibitory activity
SE
GI
Dyspesia, gerd, PUD
Bleeding - GI
*know what can be synergistic together
ADP receptor blockers
Inhibits ADP binding to plt receptors
P2Y1 receptor: pathway induces shape change and aggregation
P2Y12 receptor: inhibits cAMP induced inhibition of plt activation
Basically taking away signals that tell plts to activate
Activation of both receptors is needed for complete activation, blocking just one only limits plt activation
Direct inhibition of fibrinogen binding to GPIIb/IIa
Interferes w/ binding of vWF
3 main drugs
Clopidogral (plavix)
Ticagrelor (brilinta)
Prasugrel (effient)
(ticagrelor and prasugrel typically stronger)
Concentration dependent inhibition of plt activation
Delayed 2-3 days for clinical effect
maximal effect 8-11 days
Synergistic w/ ASA
Indications
Prevent stroke
MI
Peripheral artery disease
Angioplasty
Clopidogrel (Plavix) Prodrug
Binds sulfur on P2Y12 receptor
Synergistic w/ ASA
Hepatic activation- loading dose (get to steady state right away)
Adverse effects
Hemorrhage
Neutropenia
Thrombotic thrombocytopenic purpura (TTP)
N/V/D
Rash
Prasugrel (Effient) Prodrug
Binds P2Y12 receptor
Synergistic w/ ASA
Hepatic activation - loading dose (get to steady state right away)
Recommended over clopidogrel due to more plt inhibition
Adverse effects
HTN
HA
Hyperlipidemia
Bleeding risk
Ticagrelor (Brilinta)
Not a prodrug but has active metabolite (which extends duration of action)
Binds P2Y12 receptor
Synergistic w/ ASA
Hepatic activation - loading dose (get to steady state right away)
Recommended over clopidogrel due to more plt inhibition
Adverse effects
Increased uric acid
Uric acid comes from degradation of proteins
(can cause gout which commonly affects big to and kidneys, make sure to stay hydrated)
Major bleeding
Dyspnea
(**note- if drug ends in mab = monoclonal antibody)
Glycoprotein IIb/IIa blockers (IV only)
Abciximab (ReoPro) infusions T1/2: 30 min)
Humanized monoclonal antibody
Its a protein -> have to give IV or subq bc metabolism
Specifically targets IIb/IIIa receptors and Prevent fibrinogen from forming link b/t plts, basically occupying site w/ antibody
Immediate onset, stays bound 18-24 hours after infusion stopped
Expensive
Angioplasty w/ ASA and heparin, prevent restenosis
Adverse effects
Bleeding
Thrombocytopenia (TCP)
Immunogenic 3-5% develop antibodies (abs)
Repeat dose can develop neutral abs making drug less effective
Eptifibatide (integrilin) infusions
Peptide inhibitor of fibrinogen binding to PGIIb/IIa
Infusions up to 96 hrs
Infusion w/ ASA and heparin
Acute coronary events and angioplasty
Adverse effects
Bleeding (main risk)
Thrombocytopenia
Less immunogenicity
Not a full ab = smaller protein than abciximab = less immunogenic bc smaller target for immune system to find
Can use as alternative for abciximab
Tirofiban (Aggrastat) infusions
Non peptide inhibitor
Not prpetide protein related -> lowest risk w/ immunogenicity
Renal elimination
Infusion used w/ heparin
Adverse effects
Bleeding (main risk)
Bradycardia
Dizziness
Most important clotting factors are X and II
When driving, hands are on 10 and 2
Are in common pathway
Clotting cascade
Intrinsic system
aPTT
Extrinsic system
PT (prothrombin time)
Common pathway
X -> Xa
(prothrombin) II -> IIa (thrombin)
(fibrinogen) I -> I a (fibrin)
Anticoagulants
Heparin
Glycosaminoglycan found in mast cells
10-15 glycosaminoglycan chains containing 200-300 monosaccharide units
(basically a really long sugar chain)
Chains attached to a core protein
Molecular weight varies
Give for @ risk of clot - prophylactic dose
(when people say heparin, they mean unfractionated heparin)
Unfractionated heparin (UFH)
Mechanism
Antithrombin III suicide substrate of activated factors IIa>Xa>IXa>XIa>Xiia (2, 10, 9, 11, 10)
Works w/ antithrombin III to inactivate other clotting factors
Affects intrinsic pathway - monitor aPTT
Heparin provides platform for binding of thrombin to antithrombin
Inc inhibitory activity 1000 fold
Specific saccharide sequences bind antithrombin and thrombin together (18 units), Xa and antithrombin (5 units)
Once antithrombin III and thrombin bound -> heparin released
UFH extracted from porcine intestinal mucosa or bovine lung
Might be a concern for religious patients
Not absorbed in GI tract - has to be given IV or subQ
Immediate onset w/ IV
1-2 hour delay w/ subQ
Doesn’t cross placenta or BBB, not in breast mik, plasma protein bound
Bc big molecule, can't cross barrier
Good for pregnancy
Dose dependent t1/2, may inc in cirrhosis and renal failure
Monitoring parameters
aPTT (activated partial thromboplastin time)
Therapeutic ratio 1.5 - 2.5
Indications
Venous thrombosis, pulmonary embolism (PE) MI, coronary angioplasty
Toxicity
Bleeding (major 1-5% IV)
Antidote for heparin bleeding is protamine sulfate (binds heparin)
******* test question ********
Heparin induced thrombocytopenia (HIT)
5-10 days after initiation of therapy
Abs to heparin and plt factor 4 -> activates plts
Discontinue heparin immediately and give lepirudin, argatroban, danaparoid
Avoid LMW heparin and warfarin until thrombosis resolves
Low molecular weight heparin (LMWH)
Glycosaminoglycans of lower molecular weight
Not big sugar chain like UFH- smaller
Preparations (not equivalent)
Enoxaparin (lovenox) (test Q*** focus on this one)
Dalteparin (fragmin)
Tinzaparin (innohep)
Mechanism
Minimal effect on thrombin (IIa), lacks sequence to bind antithrombin III
Inhibits factor Xa to same extent of UFH
Basically more specific for factor X and less activity for factor II
No monitoring bc doesn’t affect aPTT
Given subQ as fixed or weight adjusted dose once or twice daily
t1/2 = 3.6 hrs
Dec dose in renal failure and elderly (renal adjustment super important)
Monitoring not done routinely bc does not affect aPTT, but can monitor anti-factor Xa assay in renal failure and extremes of weight for renal adjustment
But most don't need monitoring
Fondaparinux (Arixtra)
Synthetic penta-saccharide based on antithrombin binding region of heparin (even shorter sugar chain)
Selective Xa inhibitor, no monitoring
Only factor x activity, no II at all
subQ once daily, t1/2: 17-21 hrs
Not used in renal failure, have to renal adjust
Low incidence of HIT
Indication: knee/hip replacement, PE, venous thrombosis
Direct thrombin inhibitors:
Based on Hirudin- natural product from salivary glands of medicinal leech -> inhibit thrombin directly
Primarily factor II activity
Lepirudin (Refludan)
Used in HIT, aPTT 1.5-2.5 x normal, renal excretion
Bivalirudin (Angiomax)
Coronary angioplasty, IV, renal excretion
Argatroban (acova)
Used in HIT, aPTT 1.5-3 x normal, hepatic excretion
Monitor w/ aPTT
Warfarin
Mechanism
Vit k antagonist
Vit k needed for producing clotting factors
Prevents recycling of vit k -> prevent formation of new clotting factors
Factors II, VII, IX, X, protein C and S are synthesized in liver and require reduced vit K
(Affects extrinsic pathway)
Warfarin inhibits vit K epoxide reductase
2 step process
Vit KO -> vit K -> vit KH2
Warfarin inhibits first enzyme at much lower does than second
Doesn't do anything to current circulating factors, only affects new factors
Therapeutic levels dec vit K dependent synthesis of cofactors by 30-50% and dec activity of those synthesized by 10-40%
No effect on existing carboxylated factors
Delay in onset; loading dose does not help
Some coagulation factors have a shorter half life- why you need a bridge
Anticoagulant effect begins in first 24 hrs
Antithrombotic effect 5-7 days
Initial hyper-coaguable state for first 24-48 hrs due to depletion of protein C, cover w/ heparin in high risk pts (warfarin bridge)
Given orally, 100% absorption
t1/2- 36 hrs, steady state in 3-5 days
Highly protein bound (99%) to albumin
Protein binding interactions can be a problem bc physiologically active portion of warfarin is not bound to albumin
Metabolized in liver
S- warfarin CYP2C9
R-warfarin CYP1A2 and 3A4
(2C9 inhibitor would inc warfarin levels bc not metabolizing, therefore inc bleeding risk)
Crosses placenta - Cl in pregnancy; Not present in breast milk
Not good for pregnancy
Drug interactions
Dec actions: agents altering
Uptake and metabolism of oral drugs or vit K (green leafy vegetables)
Synthesis, function, or clearance of clotting factors
Inc vit k- dec effectiveness of warfarin- risk for thrombosis / clotting
Too little vit k- warfarin works better - inc risk for bleeding
Inc actions: agents altering
CYP2C9 inhibition
Protein binding interactions
Vit K, dec due to abx
(gut bacteria is important source of vit K)
Liver function - low levels of factors
Elderly
Monitoring parameters
PT (prothrombin time) and INR (international normalized ratio)
PT measured value (II, VII, X)
INR calculated value that normalizes PT for international sensitivity index for each
Target INR = 2-3.5
Need higher levels in high risk pts
Mechanical herat valves
Warfarin resistance
Warfarin sensitivity- need less levels
CYP2C9 alleles (much less efficient metabolism)
Toxicity
Bleeding
INR > 4: inc cranial hemorrhage
INR > 5: give vit K1 (phytonadione) PO, IV, or SubQ (aquamephyton, mephyton, konakion)
Serious bleeding at any INR= fresh frozen plasma (FFP) + vit k
FFP has lots of vit K
Birth defects (avoid in pregnancy)
Skin necrosis in protein C or S deficiency
Alternatives to warfarin
Warfarin therapy is
Highly diet dependent
Requires frequent monitoring
Has multiple drug interactions
But is easily reversible (vit k)
Alternatives
Dabigatran Etexilate (Pradaxa)
Rivaroxaban (Xarelto)
Apixaban (Eliquis)
Dabigatran Etexilate (Pradaxa)
Oral direct thrombin inhibitor (alternative to warfarin)
Just affects factor II
Prevents fibrinogen -> fibrin, activation of factors V, VIII, XI, and XIII
Uses: DVT, PE, afib
No routine monitoring
Adverse reactions
Bleeding
Reversal agent is Idarucizumab (Praxbind)
Gastritis, dyspepsia
Renally excreted
Dialyzable, requires dose adjustment for CrCl
Idarucizumab (Praxbind)
Monoclonal antibody targeted against dabigatran
Indicated for rapid reversal of anticoagulation in dabigatran treated pts
Emergency surgery
Uncontrolled bleeding
Coagulation risks inc once given
Consider alternative anticoagulation like heparin
Adverse rxns
Anaphylaxis
Hypokalemia
Delirium
constipation
Rivaroxaban (Xarelto)
Oral factor Xa inhibitor (alternative to warfarin)
Just factor X activity
Uses: DVT, afib, PE
No routine monitoring needed
Adverse effects
Bleeding
Can be reversed w/ prothrombin complex concentrate (PCC)
GI upset
Renally excreted, but no specific dosage adjustment
Apixaban (Eliquis)
Oral factor Xa inhibitor (alternative to warfarin)
Uses: DVT, afib, PE
No routine monitoring needed
Adverse effects
Bleeding
Can be reversed w/ prothrombin complex concentrate (PCC)
GI upset
P-glycoprotein substrate
Metabolized by CYP3A4 (major)
Edoxaban (Savaysa)
Oral factor Xa inhibitor
Uses: DVT, afib, PE
No routine monitoring
Adverse effects
Bleeding
Can be reversed w/ prothrombin complex concentrate (PCC)
GI upset
Shouldn’t be used in afib patients w/ CrCl > 95 mL/min
Inc risk of stroke
Reduce dose by 50% if CrCl is 15-50 mL/min
Cleared through kidneys but if the kidney function is too good, it clears too quickly
Andexanet Alfa (Andexxa)
Modified version of factor Xa
Designed to reverse bleeding due to apixaban (Eliquis) and Rivaroxaban (xarelto)
Theoretically would work for edoxaban too)
Risk for secondary thrombosis
MI, ischemic stroke, VTE, death
Black box warning
DERM
Variables in response to topical drugs
Regional variation in drug penetration
Scrotum, face, axilla, scalp are more permeable
Thinner skin = more permeable
Concentration gradient
Inc concentration -> inc drug transfer
Ex: overcome corticosteroid resistance by inc concentration
(Basically where you apply and the amount of dose matters)
Dose schedule
Skin acts as reservoir for drugs (depot effect)
May permit once daily dosing of short acting drugs
Vehicles and occlusion
Vehicle can dramatically alter drug permeability
moistening/drying effects
Vehicle may be therapeutic itself
Occlusion increases efficacy (possible toxicity)
How much sits on skin
Vehicles
Consider
Drug solubility in vehicle
Ability of vehicle to hydrate stratum corneum (enhancing penetration)
Stability of drug in vehicle
Tincture (most drying) - use for oozing, vesiculation, crusting
Wet dressings
Lotions
Gels
Aerosols
Powders
Pastes
Creams
Foams
Ointments (least drying)- use for scaling, lichenification, xerosis
If its dry = you wanna wet it; if its wet = you wanna dry it
Cream Ointment Gel/Foam Lotion/Soln/Foam |
|
Acne Vulgaris
Four major factors affect
Inc sebum production
Alteration in keratinization process and hyperproliferation of ductal epidermis
Bacterial colonization (Propionibacterium acnes)
Release of inflammatory mediators in acne sites
Stress -> inc glucocorticoid secretion -> suppresses immune sx and cant fight bacteria as well
Patho
Pooling of sebum creates anaerobic conditions -> proliferation of P. acnes
T cell response -> inflammation
Lipase from bacteria hydrolyze TG into FFA -> inc keratinization and microcomedone formation
Cytokine production and chemokines generate pus
Noninflammatory: open and closed comedones
Inflammatory: papulopustular / nodular lesions (more severe)
Drug induced acne
Systemic corticosteroids
2-6 wks after initiation of therapy
Pustular inflammation on the trunk
Not w/ hydrocortisone
Removal leads to initial worsening (due to inc inflammation) - immune system coming back
Antiepileptics
Tuberculostatics
Lithium
Tx:
Goals
This is a chronic dz
Requires early, aggressive tx
Maintenance therapy
Waxes and wanes, inc tx to tx flares, scale back when wanes
Reduce number and severity of lesions
Slowing progression of signs and sx
Limiting duration and recurrence
Preventions of long term disfigurement
Avoid psychological suffering
Critical target: microcomedone
Eliminating follicular occlusion arrests cascade
Use pharm/nonpharm tx
Multiple mechanisms of action, target multiple pathogenic steps
Mild to moderate: topical
Moderate to severe: systemic
Non pharm
Cleansing
Surfactant systems to disperse and remove fat/oils from skin surface
Must balance b/t cleanliness and drying/irritation
Soaps not always the best products
Once rinsed off, no further active products remain
High pH may degrade some activity of other agents
Also less tolerable on skin
Don't wash too frequently (twice a day)
Topical therapy
Only works where its applied- requires application to whole affected area
Most cause irritation
Can lead to pt discontinuation
Start w/ lower strength and gradually inc
May consider using non-alcoholic solns
Benzoyl Peroxide
Mechanism
Penetrates stratum corneum unchanged and is them converted to benzoic acid
Benzoic acid has activity against P. acnes
Peeling and comedolytic effects
Start at low conc. (2.5%) once daily then inc as tolerated
Available OTC
Often found in combo w/ abx
Erythromycin, clindamycin, etc
Adverse rxns
Cab bleach hair or clothes
skin/mucous membrane irritation
Azelaic acid (Azelex)
Straight chain dicarboxylic acid
Mechanism
Not fully understood
Likely due to antimicrobial activity and inhibiting conversion of testosterone to dihydrotestosterone
Reduces hormonal component
Start once daily then inc twice daily
Adverse rxns
Mild skin irritation / dryness
Improves over 6-8 wks w/ continuous therapy
Hypopigmentation
Topical Retinoids
Retinoic acid (AKA tretinoin, Retin A)- acid form of vit A
Mechanism
Not completely understood
Corrects abnormal follicular keratinization
Reduces P. acnes counts
Reduces inflammation
First line tx for noninflammatory (comedonal) acne
Often combined w/ other agents for inflammatory
Useful for wrinkles and dyspigmentation
Adverse effects
Erythema, desquamation, burning/stinging
Dec w/ time and use of emollients like aquaphor
Photosensitivity and severe sunburn
Avoid in pregnancy
Tretinoin
Photolabile (apply nightly)
Benzoyl peroxide inactivates tretinoin (use BP at morning and tret at night)
Adapalene (Differin)
Stable in sunlight, stable w/ benzoyl peroxide
Tends to be less irritating
Tazarotene (Tazorac)
3rd gen retinoid used for acne and psoriasis
Sometimes combined w/ topical steroids to reduce skin irritation
Alitretinoin (panretin)
Used in kaposi sarcoma
Bexarotene (Targretin)
Used in t cell lymphoma
Topical abx for acne
Clindamycin (Cleocin-t)- preferred agent
Topical- not worried ab c. diff
Erythromycin (Eryderm)
Losing efficacy over time due to P. acnes resistance
Lack of systemic SE
When topicals aren't enough
Systemic retinoids
Isotretinoin (Accutane) - effective in 1-3 months
CONTRAINDICATED in pregnancy/breastfeeding
Men should avoid as well
Severe teratogenicity- iPledge/RIMS program
Adverse rxns
Retinoid dermatitis- erythema, pruritus, scaling
Photophobia
Arthralgia, HA, alopecia, brittle nails
Inc serum lipids
Monitor for depression
Systemic abx
Used for more extensive/difficult to tx disease
Tetracyclines
Tetracycline, doxycycline (vibramycin), minocycline (Minocin)
Most commonly used, safe/effective, inexpensive
Chelate calcium ions that prevent neutrophil and monocyte chemotaxis- don't take w/ milk
Contraindicated in children under 8 and pregnancy women
Trimethoprim / sulfacetamide (Bactrim)
Azithromycin (zithromax)
Ciprofloxacin (Cipro)
Other tx
Salicylic acid
Used for many years but few studies to support use
Keratinolytic
Mild anti-inflammatory / anti-microbial activity
Antiandrogens
Spironolactone (aldactone)
Dec testosterone activity
Gel available
Oral contraceptives
Useful in some women
Ethinyl estradiol and norethindrone / ethinyl estradiol
Regulates hormone levels
Can make it better or worse
Intralesional steroids
Effective for individual inflammatory nodules
Inject into individual lesions
Systemic absorption can occur -> adrenal suppression
Local tissue atrophy
Oral corticosteroids
Low dose can reduce sx in adrenal hyperactivity
Short course may be beneficial in highly inflammatory dz
Prednisone (deltasone), dexamethasone (decadron)
Acne type Description Suggested tx Followup if responds Follup if does not respond in 3 mos Adjustment if pt does not respond to previous action |
Type I Mainly comedones Occasional small inflamed papule or pustule No scarring -Topical retinoid drug of choice -benzoyl peroxide -salicylic acid Continue until completely cleared then stop or taper Tx as type II |
Type II Comedones More papules and pustules (mainly facial) Mild scarring -topical retinoid plus benzoyl peroxide, topical or abx Continue until clear then stop or taper Tx as type III |
Type III Numerous comedones, papules, pustules Spread to back chest and shoulders Occasional cyst or nodule Moderate scarring -systemic abx plus topical retinoid or benzoyl peroxide 4-6 mo w/ subsequent tapering and discontinuation as acne improves Other agents can also be stopped Add oral contraceptive or antiandrogen (women) Oral isotretinoin |
Type IV Numerous large cysts on face, neck, upper trunk Severe scarring -systemic abx plus topical retinoid, and benzoyl peroxide - +/- OC or antiandrogen (female) Taper and discontinue w/ improvement Oral isotretinoin |
Atopic Dermatitis- eczema
Common skin dz
Chronic disorder involving inflammation w/ pruritus
Part of atopic triad- asthma and allergic rhino-conjunctivits
Skin barrier dysfunction plays major role
Clinical presentation
Major indicators
Pruritus
Rash
chronic/repeated sx
Fmhx
Minor indicators
Dry, patchy scales
Inc serum IgE
Positive allergy skin tests
Susceptibility to skin infx
Goals of tx
Provide sx relief
Identify and eliminate triggers
Prevent future exacerbations
Minimize / prevent adverse rxns to tx
Tx any secondary skin infections
Nonpharm tx
Children
Lukewarm bath
Apply lubricant after bathing
Keep fingernails short
Sedating antihistamines to reduce night time itching
Avoid overheating
Distract child
Identify and remove irritants and allergens
Maintain good hydration
Pharm tx
Topical corticosteroids are gold standard
Choice of agent depends on severity and site
Low potency steroids
Suitable for face, intertriginous areas, infants
Better for thin skin and long term therapy
Medium potency
Used for the body
Exacerbations
Medium-high potency warranted
Use for 1-2 wks then switch to lower potency
Topical steroids
Adverse rxns
Systemic in nature
Related to potency, duration, area of body covered, occlusiveness of preparation (ointment > cream > lotion)
Local
Skin atrophy
Acne
Rosacea
Allergic dermatitis (related to vehicle)
Systemic
Adrenal suppression
Operates off neg feedback loop, shuts down, stopping cold turkey -> takes time to turn back on
Infx
Hyperglycemia
Glaucoma
Cataracts
Growth retardation (in children
Steroid Potency
Know 4 things that can affect potency
Drug itself
Strength / concentration
Salt form of drug
Dosage form (ie. less occlusive vs more)
Know hydrocortisone is the lowest potency
Class 1- superpotent
Class 2- potent
Class 3- upper mid strength
Class 4- mid strength
Class 5- lower mid strength
Class 6- Mild
Class 7- least potent (hydrocortisone)
Topical Immunomodulators
Tacrolimus Ointment (Protopic) and Pimecrolimus cream (Elidel)
Reduce extent, severity, and sx
Mechanism
Inhibit activation of T cells, mast cells, and keratinocytes
Suppresses immune system to a degree
Second line agents after topical steroids
Possible cancer risk
Avoid w/ weakened immune system
Adverse rxn
Burning sensation
Use high SPF sunscreen
Other tx
Oral corticosteroids
Sometimes used for short courses during exacerbations
Provides rapid relief
Need tapering dose to prevent flare up
Ex: prednisone (deltasone), dexamethasone (decadron), methylprednisolone (medrol dose pack)
Other topical abx
Bacitracin
Peptide abx -> prevents cell wall synthesis
Broad antimicrobial coverage
Strep, staph, anaerobic cocci, tetanus bacilli
Use alone or in combo w/ neomycin, polymyxin B
Adverse effect
Allergic dermatitis rarely
No systemic toxicity bc does not penetrate
Mupirocin (Bactroban)
Binds to bacterial t-RNA preventing protein synthesis
Coverage- most gram pos aerobes (MRSA)
Used to eliminate nasal carriage of s. Aureus
Not absorbed but may cause mucous membrane irritation
Polyethylene glycol vehicle
Polymyxin B
Peptide abx -> interrupts cytoplasmic membrane
Effective against gram neg organisms
Pseudomonas, e. Coli, klebsiella
Allergic rxn uncommon
Avoid using on open wounds / denuded skin in high doses -> risk for neuro/nephrotoxicity
Aminoglycosides
Neomycin and gentamicin
Inhibit bacterial protein synthesis
Good activity against gram neg organisms
Can have systemic accumulation
Neomycin frequently causes sensitization
Topical antifungals
Azole antifungals
Clotrimazole, Ketoconazole, Miconazole, Sertaconazole
Mechanism
Inhibit fungal P450 preventing cell wall formation
Used for topical and vaginal uses (Vulvovaginal candidiasis)
Sometimes combined w/ corticosteroids (more rapid sx relief)
Tx generally prolonged (2-3 wks)
Adverse rxns
Local irritation
Ciclopirox (Penlac)
Mechanism
Inhibits uptake molecular precursors at fungal cell wall
Used topically for dermatomycosis, candidiasis, and tinea versicolor
Also marketed as nail lacquer for onychomycosis of fingernails and toenails (< 12% effective- ppl often not compliant)
Allylamines
Nafitine and Terbinafine (Lamisil)
Mechanism
Inhibit production of ergosterol and prevent cell wall synthesis
Adverse rxn
Local irritation
Tolnaftate (Tinactin)
Well tolerated but must be used for long term tx to prevent recurrence
No candida activity
Nystatin
Used for candidal infx (cutaneous and mucosal)
No oral obsorption
Topical antivirals
Acyclovir (Zovirax) and Penciclovir (Denavir)
Synthetic guanine analogs
Active against HSV 1 and 2
Used for recurrent orolabial HSV infx
Adverse rxns
Local irritation
Imiquimod (Aldara)
Mechanism
Immunomodulator- simulates peripheral mononuclear cells for release interferon a and stimulates macrophages to produce TNF a and interleukins
Indications
External and perianal warts
AKs
BCC
Applied 2-5 x per wk
Adverse rxn
skin irritation in virtually all pts
Edema, vesicles, erosion, ulcers, -> degree of inflammation parallels efficacy
ONCOLOGY
Cancer
Dz of altered cell growth, cell division and differentiation
A mass of tissue, the proliferation of which is not controlled by normal physiological processes
Inc growth factors
Inc cyclin-dependent kinases
Altered gene expression (dec p53 gene -> tiggers apoptosis)
Dec contact inhibition
Tumor cells
Hyperplasia
Inc in size or number of cells (inc growth)
Function unchanged
Reversible
Metaplasia
Adaptive substitution of one differentiated cell type for another
Chronic irritation
Protective response
Some loss of function
Ex: callus
Dysplasia
Loss of uniformity
Loss of architectural orientation
Reversible
Neoplasia
Uncoordinated growth
Dec response to suppressor genes
P53, cyclin-dependant kinases
Immortalization
Telomerase
Irreversible
Benign
Localized
Enclosed in fibrous capsule
Surgical removal
Survival of pt
Malignant
Spreads to and destroys adjacent tissue
No capsule
Metastasize
Death of pt
Tumor grading system degree of differentiation
Grade 1
Closely resembles tissue of origin
Retains specialized function
Grade 2
Moderately differentiated
Less like tissue of origin
Inc mitosis
Grade 3
Poorly differentiated
Does not resemble tissue of origin
Inc variation and inc mitosis
Grade 4
Very poorly differentiated
No resemblance to tissue of origin
High variable
Enhanced mitosis
Metastatic
Principles of therapy
Single “clone-ogenic” tumor stem cell has potential for unlimited replication
Must kill every tumor cell
Different tumors have different growth patterns which can change based on stage
Well differentiated vs non differentiated
Slow vs fast tumor growth
Localized vs disseminated growth
Heterogeneity of tumor (multiple cells w/ diff characteristics)
Gompertzian cell growth
Each tumor takes constant time to double its size
Growth fraction (% of cells undergoing replication) dec as tumor size inc
Growth initially rapid -> flattens out as tumor outgrows nutrient supply
Chemo tx typically work better on rapidly dividing cells
High fraction = more aggressive
Tx should involve removal of tumor as first step (if you can)
Surgery- well localized and well differentiated tumors
Radiation- localized tumors, not easily removed
Chemotherapy- systemic effects inc chances against metastatic cells; targets all rapidly dividing cells
Drug conc., exposure time, and frequency of administration critical for effectiveness
Significant toxicities - myelosuppression, biggest risk, inc infx
Eraly detection and tx key to successful therapy; educate pt
Toxicity: kill rapidly dividing cells
Cells w/ highest growth rates:
Neoplastic cells- desired effect
Bone marrow- myelo and immune suppression -> inc risk for infx
GI tract- oral/intestinal ulceration -> stomatitis
Hair- alopecia
Reproductive cells- sperm, menstrual irregularities
Dosing regimen
High dose- intermittent schedule
Allows for recovery of RBCs
Time for maximum susceptibility
Where drug acts in cell cycle
Where tumor is in growth curve
Lower in growth curve = more likely to have more cells rapidly dividing = more susceptible to chemo
Cell cycle
Mitosis: cell division, 30-60 min
G0: resting phase, no division
G1: post-mitotic phase, enzyme synthesis prior to DNA synthesis, 18-30 hrs
S: DNA synthesis, 10-20 hours
G2: pre mitotic phase, protein and RNA synthesis, 2-10 hrs
Most non-malignant cells are in G0
Tumor cells don't necessarily proliferate faster than normal cells
Anticancer agents are not selective for tumor cells- damage all rapidly dividing cells
Cell kinetic parameters
Growth fraction: proportion of cells that are actively dividing in early stages of growth
S fraction: refers to percentage of cells in S phase, implies aggressiveness of tumor
Doubling time: time necessary for tumor to double in volume
Short doubling time indicates aggressive tumor
Dosage regimen
Combo therapy
Minimizes resistance and toxic effects
Adjuvant therapy- tx/minimize toxic effects (treats the pt not the cancer
Antiemetic drugs
Stimulate bone marrow growth
Chemotherapy
Timing
Cell cycle specific
Only targets cells as they are in a particular phase
Given as continuous infusions or as multiple doses in close timeframe (targets all cells hitting that phase)
Non cell cycle specific
Not schedule dependent (dose dependent) and can be given anytime
Chemo is given in cycles
Defined, repeating schedule
Allows for recovery from toxicity
Determined by clinical trials
Other types of therapy
Targeted
Small molecules that target specific extracellular receptors
Biologics
Growth factors, vaccines, monoclonal abs, cytokines, etc
Boost host immune system to fight cancerous cells
Resistance
Dec uptake of drug
Dec metabolism of prodrug
Inc metabolism of drug
Ind DNA repair enzymes
Inc gene transcription of target enzymes
Inc free radical scavengers
Mutation of target enzymes
****focus on mechanism, where in cell cycle, unique SE, and toxicities
ANTINEOPLASTIC AGENTS
Antimetabolites
Similar to nucleotides that make up DNA and RNA
Look like normal nucleotides -> get incorporated into DNA -> lack sugar backbone necessary for structure -> cant add anything else on -> disrupt DNA/RNA production to a degree (chain terminators) -> trigger apoptosis w/ enough damage
Body cant tell difference b/t these and naturally occurring nucleotides
Disrupt replication and cell division by preventing production of nucleic acids
Not selective for cancerous cells (rapidly dividing cells affected as well)
Targets S phase
3 categories
Pyrimidine analogs
Purine analogs
Folate antagonists
Pyrimidine analogs
Cytarabine (AraC, Cytosar)
Mechanism
Cytidine analog
Becomes phosphorylated and inhibits DNA polymerase -> disrupts strand elongation
Becomes incorporated into DNA and acts as chain terminators
Given IV or intrathecally
Used to tx many types of leukemia
Toxicity
Dose limiting leukopenia and thrombocytopenia
N, V, mucositis
Cerebellar syndrome (large doses) -> dysarthria, nystagmus, ataxia
Seen w/ renal dysfunction
Conjunctivitis / keratitis
Steroid eye drops or saline eye drops
Gemcitabine (Gemzar)
Structurally related to Cytarabine (Cytosar)
Mechanism
Fluorine substituted deoxycytidine analog
Inhibits DNA polymerase upon incorporation into DNA
Inhibits ribonucleotide reductase -> prevents deoxyribonucleotide production
Toxicity
Similar to other agents (myelosuppression, GI, etc)
Flu like sx- can be pretreated w/ acetaminophen
Fluorouracil (5-FU)
Capecitabine (Xeloda) -> converted to 5-FU
Mechanism
False pyrimidine - inhibits thymidylate synthase and inhibits thymidine formation
Thymidylate synthase produces new nucleotides
Incorporated into RNA to inhibit function
Used to tx many types of leukemia
Toxicity
Dose limiting leukopenia, diarrhea, mucositis
Cerebellar syndrome (large doses) - dysarthria, nystagmus, ataxia
Seen w/ renal dysfunction
Hand-foot syndrome- paresthesias, “stocking glove”
Conjunctivitis / keratitis
steroid/saline eye drops
Purine analogs
6-mercaptopurine (6-MP, purinethol)
Thioguanine (Tabloid)
Used frequently to tx ALL
Mechanism
Prevent purine synthesis (adenine, guanine)
Incorporated into DNA and inhibit DNA polymerase
Toxicity
Hepatotoxicity and myelosuppression due to toxic metabolites
Sometimes need genetic testing before to see if they can tolerate)
Pharmacogenetic changes in enzyme expression can lead to worsened toxicity
Folate antagonists
Methotrexate (MTX, Rheumatrex)
Used in ALL and some lymphomas
Used in rheumatologic conditions
Dose is higher in cancer than in autoimmune tx
Mechanism
Inhibit dihydrofolate reductase (DHFR)
Reduces tetrahydrofolate stores
Dec thymidylate and purine synthesis
Dec RNA/DNA production
Inhibits recycling of folic acid
Can be given orally, IV, or intrathecally
Toxicity
Myelosuppression
GI toxicity
Hepatotoxicity (dont drink alcohol)
Renal toxicity
Due to precipitation of MTX in renal tubules
MTX is highly protein bound to albumin and drugs displacing it may inc toxicity
Antidotes
Folinic acid (Leucovorin) -”leucovorin rescue”
Reduced folate and bypasses DHFR block
Dosing and duration determined by MTX levels
Sodium bicarbonate
Alkalinizes urine to prevent precipitation and enhance elimination
Glucarpidase (Voraxaze)
Directly metabolizes MTX
Expensive
Good for pts w/ renal failure or very high levels
Microtubule targeting drugs
Microtubules
Integral part of cytoskeleton and provide cell structure
Helps separate chromosomes
Form mitotic spindle during cell replication
Drugs affecting microtubule function
Taxanes
Vinca alkaloids
Taxanes (Plant alkaloids)
Paclitaxel (Taxol) and Docetaxel (Tacotere)
Mechanism
Promotes microtubule formation, prevents breakdown
Forms stable nonfunctional microtubules that prevent functions like mitosis
(mitosis cant continue)
Toxicities
Myelosuppression for both
Docetaxel- fluid retention
Paclitacel- neurotoxicity (peripheral neuropathies) and hypersensitivity
Both require pretreatment w/ corticosteroids to limit side effects
Vinca Alkaloids
Vincristine (VCR, Vincasar), Vinblastine (VBL), Vinorelbine (Navelbine)
Mechanism
Bind to tubulin and disrupt formation of microtubules (prevent formation of microtubules)
Cells cannot complete mitosis
**know these target microtubules and prevent mitosis
Toxicities
Fatal if given intrathecally
VBL and vinorelbine -> dose limiting myelosuppression
VCR- dose limiting neurotoxicity including hand-foot syndrome and paralytic ileus / constipation
Vesicants
Topoisomerase inhibitors
Topoisomerase I and II
Break and reseal DNA strands allowing for winding / unwinding of DNA structure
I causes single strand breaks, II causes double strand breaks (said hes not testing us on this specific detail)
Prevent DNA from reattaching -> eventually trigger apoptosis
Includes
Epipodophyllotoxins
Anthracyclines
Camptothecins
Epipodophyllotoxins
Etoposide (Toposar) and Teniposide (Vumon)
Mechanism
Bind to tubulin and inhibit microtubule formation
Cause DNA strand breakage by inhibiting topoisomerase II
Toxicity (nothing too unique here)
Dose limiting myelosuppression
N, V
Alopecia
Anthracyclines
Doxorubicin (Adriamycin), Daunorubicin, Mitoxantrone
Mechanism
Inhibit topoisomerase II
Intercalate into DNA
Jam b/t strands -> conformational change, shape affected -> damages DNA
Free radical production
Oxygen w/ 1 free electron = very reactive
Can denature proteins and cause lots of oxidative damage
Toxicity
Myelosuppression
Cardiomyopathy and CHF
Lifetime max dose a pt can receive, once you hit that limit, can never give again
Should have baseline echo performed
Due to limited ability of myocardium to detoxify free radicals
Alopecia
Red discoloration of urine, sweat, etc (make sure to educate pt)
Strong vesicants
Antidote
Dexrazoxane (Zinecard)
Chelates iron to prevent free radical generation -> cardioprotective
**** test Q
“Which is used ot prevent cardiomyopathy caused by anthracyclines? - Dexrazoxane (Zinecard)
Camptothecans
Topotecan (Hycamtin), Irinotecan (Captosar; well known for causing diarrhea)
Mechanism
Inhibit topoisomerase I
Toxicity
Dose limiting myelosuppression in both
Diarrhea (Irinotecan >>> Topotecan)
N/V
Alopecia
Dec cholinesterase activity (Irinotecan)
Alkylating agents
Oldest and most useful classes of chemotherapy
Developed after myelosuppression and lymph node shrinkage after exposure to mustard gas in WWI -> clinical trials proves usefullness in mid 1940s
Mechanism
Covalently bind to alkyl groups in proteins and DNA (triggers apoptosis)
May cross link b/t strands or b/t bases in same strand
Non cell cycle specific
Toxicity
Cytotoxic
Mutagenic
Teratogenic
Carcinogenic
Myelosuppressive
Pulmonary fibrosis
Most emetogenic
Nitrogen mustards
Cyclophosphamide (CPM), Ifosfamide (Ifex)
Used to tx many solid tumors and hematologic cancers (wide range bc non cell cycle specific)
Toxicity
Forms toxic metabolites- acrolein
Acrolein causes a hemorrhagic cystitis
CNS toxicity - encephalopathy (more w/ Ifosfamide)
Renal toxicity
Myelosuppression
Alopecia
N/V
Antidote
Mesna
Binds to and inactivates acrolein
Should be administered w/ vigorous hydration
Prevents hemorrhagic cystitis
Nitrosoureas
Carmustine (BCNU, Gliadel), Lomustine (CCNU, GLeostine)
Used to tx brain cancers due to lipophilicity
Can be used to prep for bone marrow transplant
Toxicity
Most myelosuppressive - can be fatal
Nadir (lowest point) may be delayed 4-6 wks
Can last up to 2 wks
Can be delayed and last a long time
Platinum Analogs
Cisplatin, Carboplatin, Oxaliplatin (Eloxatin)
Mechanism
Bind to and distort DNA structure preventing bases from lining up appropriately
Toxicity
Nephrotoxicity - managed w/ vigorous hydration
Ototoxicity
Peripheral neuropathy
Hypersensitivity / anaphylaxis risk
Severe N/V
Other alkylators
Dacarbazine, Temozolomide (Temodar)
Mechanism
Metabolized to MTIC that methylates guanine
Inhibit DNA, RNA, and protein synthesis
Toxicity
Vomiting, alopecia, myelosuppression
Nothing too unique here
Other alkylators
Busulfan (Myelran)
Acts similar to nitrogen mustards
Toxicity
Myelosuppression
GI
Pulmonary Fibrosis
Seizures
Hepatotoxicity
Misc. agents
Hormonal therapies
Effective for hormone sensitive cancers
Prostate, breast, endometrial
Therapies aim to antagonize receptors or prevent production of sex hormones
Block receptor or prevent production
Steroid hormones bind steroid responsive element on DNA (works at nucleus)
Binding activates or promotes gene expression, usually growth factors
Hormone response elements remains so that in presence of hormone, oncogenes can drive tumor growth
Diff tissues respond differently
Tumor growth of certain tissues regulated by steroid hormones
Glucocorticoids- suppress WBCs - used in acute lymphoblastic leukemias to dec leukemic cells
Anti-estrogens- brest, uterine, cervix, ovaries
antiandrogens - testicular and prostate (DHT stronger than testosterone)
Corticosteroids
Used for lymphotoxic effects (leukemias, etc)
Can also tx chemo induced N/V
Prednisone, dexamethasone, etc
Tamoxifen (Nolvadex)
Estrogen partial agonist (SERM), competes w estrogen for receptor binding
Tx estrogen dependent breast tumors
Has been used to reduce risk of developing breast tumors in women w/ strong FHx
Acts differently in diff tissues, activates some receptors, antagonizes others
Toxicity
Hot flashes, N, V, myelosuppression
DVT- estrogen in liver -> upregulates clotting factors
PE
Linked ot endometrial cancer
Positive estrogenic effects on bone and cholesterol
Raloxifene (Evista)
Selective estrogen receptor modulator (SERM)
Estrogen effects in bone, CV system
Antagonist in breast and uterine tissue
Used mainly in osteoporosis
Fulvestrant (Faslodex)
Selective estrogen receptor down regulator (SERD)
Less sensitive to effects of estrogen
Monthly IM injection
Pure anti-estrogen (SE are worse)
Indications: hormone sensitive metastatic breast cancer
Toxicity
N, HA
Pain
Vasodilation
Anastrozole (Arimidex) and Letrozole (Femara)
Competitive aromatase inhibitors; dec estrogen (purely anti estrogen)
Indications: oral administration in postmenopausal estrogen sensitive breast cancers
Replacing tamoxifen
Aromatase converts testosterone -> estradiol
Toxicities
N, hot flashes, hair thinning
Muscle pain
Exemestane (Aromasin)
Irreversible aromatase inhibitor
Dec estrogen levels 90%
Block production; stronger and worse SE
Used in women no longer sensitive to Tamoxifen
Toxities
N
Hot flashes
Edema
Fatigue
Less frequent gynecological sx
More common visual disturbances and bone fractures
FLutamide (Eulexin), Nilutamide (Nilandron), Bicalutamide (Casodex)
Synthetic anti-androgens -> prostate cancer
Binds androgen receptor to block testosterone stimulation of cancer cells
Antagonist of receptor
Dec testosterone levels = dec growth
Usually given w/ leuprolide or goserelin
SE: gynecomastia, DI distress
Leuprolide (Lupron), Goserelin (Zoladex)
Analogs of GnRH; occupy LHRH receptor in pituitary continuously, desensitize and inhibit release of FSH and LH
FSH and LH are responsible for testosterone release
Daily subQ or monthly depot
SE
Impotence
Hot flashes
Gynecomastia
N/V
Biological response modifiers
Protein kinases
Genome codes for 550 protein kinases and 130 protein phosphatases
Critical part of signal transduction pathways
More specific (cant tx as many cancers)
2 types
Receptor tyrosine kinases (humans 90)
Insulin receptor, epidermal growth factor, plt derived growth factor, fibroblast growth factor, vascular endothelial growth factor
Enzymatic tyrosine kinases (humans 32)
MAP, RAS, MEEK
Myeloid tyrosine Kinase inhibitors (TKI)
Most end in nib
Imatinib (gleevec) oral
CML, CMML
Dec myeloid TK’s responsible for cell proliferation
SE: N, V, edema
Epidermal growth factor TKI (ErbB1 or HER1)
Gefitinib (Iressa)
NSCLC
SE: diarrhea, rash, N, V, dry skin
HER1 (ErbB1) / EGFR TKIs
Erlotinib (Tarceva)
Metastatic NSCLC, pancreatic, head, neck
SE: diarrhea, rash, elevated liver enzymes
ErbB1 (HER1), ErbB2 (HER2) TKIs
Lapatinib (Tykerb) oral
Metastatic breast cancer no longer sensitive to Trastuzumab
In combo w/ Capecitabine (Xeloda); inc time for tumor growth from -4.4 to 8 mos
Enters CNS, effective in CNS metastasis
Toxicities: rash, N, fatigue, anorexia
Antibodies (ximab- chimeric, umab- humanized)
Rituximab (Rituxan)
Alemtuzumab (Campath)
Trastuzumab (Herceptin)
Cetuximab (Erbitux)
Bevacizumab (Avastin)
Rituximab (Rituxan)
Chimeric human murine ab to CD20 antigen on b lymphocytes
90% of NHL cells express CD20 antigen
CD20 regulates step in cell cycle activation
Blocking CD20 -> complement mediated lysis, apoptosis, ab mediated cytotoxicity
Given as 4 weekly infusions
Toxicity
Infusion related flu like syndrome- pretreat w/ tylenol, antihistamines, steroids
N, V
Urticaria
Bronchospasm
Mild myelosuppression
Alemtuzumab (Campath)
Binds CD52 antigen on T and B lymphomas, induces cellular cytotoxicity
Very specific, leaves healthy cells alone
Toxicities
Infusion rxn
Dec t cells
Opportunistic infx
Trastuzumab (Herceptin)
Recombinant human monoclonal ab to human epidermal growth factor 2 (HER2/neu, ErbB2)
Ab prevents binding of growth factor, can also down regulate growth factor receptor
Approved for use in metastatic breast tumors over expressing HER2 (ErbB2) oncogene
Used w/ doxorubicin and Taxol
Toxicity (weekly infusion)
Fever, chills (pretreat w/ acetaminophen, diphenhydramine, meperidine)
N, V, HA
Dizziness
Dyspnea
Cough
Cardiomyopathy- monitor echos
Cetuximab (Erbitux)
Ab to EGFR (HER1, ErbB1)
Toxicity: infusion rxn, skin rash, immune rxns
Bevacizumab (Avastin)
Ab to vascular endothelial growth factor (VEGF) - angiogenesis -> starve cancer cells
Toxicities
Severe HTN
Proteinuria
CHF
D, L - Asparaginase (Elspar)
Asparagine required for protein synthesis
Normal cells take up from plasma and can synthesize
Lymphoid tumors low levels of asparagine synthetase, must take up asparagine
Asparaginase depletes asparagine for protein synthesis in cancer cells
Used in combo for childhood acute lymphocytic leukemia (MTx must be given first bc ASPase stops protein synthesis and prevents MTX from working)
SE
Allergic rxns (protein)
Intracranial hemorrhage
Pancreatitis
Dec clotting factors
Ammonia toxicity - confusion, altered mental status
Immunotherapy
Tumor cells express proteins on cell surface
“Tumor assoc. Cell surface antigens
Cell surface antigens susceptible to attack by pt immune system
Tumor cells less antigenic than foreign cells
Basically turning up own immune system to kill cells
Interferon A
Alpha 2A- roferon A lysine 23
Alpha 2B- intron A arginine 23
Actions
Inc cytotoxicity of NK cells
Inc phagocytic ability of macrophages
Inc ability of macrophages to present “processed antigen” to t helper cells
subQ, mult times weekly up to 12 mos
Human recombinant form made in e. Coli
Adverse effects
Flu like sx (pretreatment ideal), fever, chills, myalgia, HA, hair loss, diminish w/ time w/ daily administration
Affects pt’s mood- dizziness, confusion, depression, aggression, dec mental status, visual problems, coma
Contraindicated in pregnancy, no breastfeeding, passes to fetus
Aldesleukin (IL-2) (Proleukin)
Interleukins- serve as molecular messenger b/t leukocytes
IL-2, t cell growth factor
Actions
Regulates proliferation, differentiation and recruitment of t cells, b cells, and thymocytes
Aldesleukin (IL-2) (Proleukin)
Stimulate proliferation and activation of lymphokine-activated killer cells (LAK) and tumor infiltrating lymphocytes (TIL)
Turns on NK cells
Induces interferon gamma
IV or infusion for 5 day cycles w/ 5-9 days b/t cycles
Recombinant human IL-2 made in e. Coli
Stimulates monocyte/macrophages to produce IL-1 and TNF
Adverse effects
Fever, chills, myalgia, N, V
Capillary leak syndrome; hypotension
Requires pressor therapy which causes vasoconstriction to inc BP
Arrhythmias, MI, HF
Pulmonary edema, failure
CNS- HA, dizziness, mental changes, seizures, coma
Hepatotoxicity
Myelosuppression
Use extreme caution in pts w/ cardiac, renal, or hepatic dz or seizure disorders
Pregnancy and breastfeeding should be avoided
Educate pts on serious SE w/ normal therapeutic doses
Dosing and administration
Many regimens are count dependent (have to have enough PLTs and WBCs (both rapidly dividing) to get next dose)
Heme system needs varying time to recover
Monitor plts and absolute neutrophil count (ANC)
Monitor organ function
Renal and hepatic function
Urinalysis
Watch how drugs are being dosed
Age dependent
BSA (height and weight)
Weight based
Safety and handling
Proper PPE when handling/administering chemotherapy
gloves/gowns/shoe covers / scrubs
Mask / eye protection if risk for aerosolization of hazardous materials
Pt excretions considered hazardous
Ftime depends on chemo being given
(diapers, blood, etc)
Supportive care
Hematologic
Repopulate cells or replace directly
Myelosuppression is MC dose limiting SE
Generally takes time to develop
WBC deplete faster than plts due to life span (6-12 hrs vs 5-10 days)
Inc risk for infx, anemia, bleeding
Avoid rectal administration in neutropenic pts
Avoid fresh flowers or fruits that don’t need to be peeled
Can be corrected w/ time, replacement, or colony stimulating factors
GI
N/V very common w/ chemo
Mucositis
Very painful
May prevent pt from eating and drinking
Infection
Need good oral hygiene
Salt rinses and chlorhexidine (Peridex)
Skin
Alopecia
Extravasation
Anthracyclines, vinca alkaloids, taxanes
Central access is better than venous
Severe tissue damage
Most can be managed w/ cold/hot compresses depending on rug
Hyaluronidase (Hyelenex) can break down subdermal tissue to aid absorption