unit 1 adrs/ddi Flashcards
Adverse Drug Reaction Versus Allergy
Type A [Side Effect] - common?
* Predictable?
* Overdose
* Side Effect -
Type B [Allergy] - common?
* predictable?
* mechanisms
Type A [Side Effect] - common
* Predictable (pharmacologic action), Dose Related, Can Affect Anyone
* Overdose - Hepatic failure (acetaminophen)
* Side Effect - Nephrotoxicity (with aminoglycosides); diarrhea (amoxicillin)
Type B [Allergy] - uncommon
* Unpredictable (hypersensitivity reaction), Not dose related, Cannot affect anyone
* Anaphylaxis; photoallergy
* Antibody or T-cell Stimulatio
Low-Risk factors of Penicillin Allergy Assessment
utacaria may be a reuslt of viral infection and misinterpreted aas an allergy.
Low-risk allergy symptoms – most commonly rash and itching – likely do not represent true IgE allergy
high risk factors of penicillin allergy
Questions to ask when assessing an allergy
Describe reaction
route?
How long ago?
Timing of reaction?
tx?
Use of what before reaction?
Use of what since reaction?
Describe reaction
Administered PO or IV?
How long ago did the reaction occur?
Timing of reaction?
Immediate (< 4hrs)
Delayed (>24 hrs)
Any treatment required?
Use of penicillins or cephalosporins before reaction?
Use of penicillins or cephalosporins since reaction?
ADRs of non-Beta lactams compared to beta lactams, significance of this?
‘Non-beta-lactam antibiotics were associated with more adverse drug
reactions than penicillins or cephalosporins, independently of the penicillin skin test result.
Cephalosporins can be used as safely or more safely than non-beta-lactam antibiotics in penicillin skin test positive and negative individuals.
Penicillin Allergy Summary
* True allergy?
* Review?
* Family history of penicillin allergy, GI symptoms, headache, yeast infection?
* Hive and non-hive rash reports [not SJS-like]?
* Severe/high-risk reactions [e.g. SJS, Anaphylaxis-like, DRESS, Serum sickness?
ñ True allergy (IgE) is rare; Penicillin-Cephalosporin cross-reactivity NOT 10%
ñ Review the documented allergy or Interview the patient
- Family history of penicillin allergy, GI symptoms, headache, yeast infection
►Not Allergy - Comfortable giving any penicillin or cephalosporin
- Hive and non-hive rash reports [not SJS-like]
►Likely not Type-1 Allergy - May give amoxicillin, especially with distant history and penicillin benign skin reaction
- Can use a cephalosporin without concern
- Severe/high-risk reactions [e.g. SJS, Anaphylaxis-like, DRESS, Serum sickness]
►Type-1 or CTC Allergy - Use an alternative antibiotic [reasonable to consider later generation cephalosporin]
2021 AHA Statement for those with cillin allergies
More cautious approach- not to use cepph in those with hx to pencillin allergies (anaphylaxis, utacaria, angioedema)
Amoxicillin/Clavulanate
Pediatric Antibiotic Associated Diarrhea
- 35 articles reporting on 42 studies were included for analysis
- 33 trials reported on amoxicillin/clavulanate
- 6 trials on amoxicillin
- 3 trials on penicillin V
- In total, the 42 trials included 7729 children treated with an oral penicillin
about 19.8% incidence
Amoxicillin/Clavulanate
Antibiotic Associated Diarrhea
seen in 25% with 250: Amoxicillin 250 mg /clavulanate 62.5mg per 5mL
reducing augmentin shits
Goal 14:1 ratio of amoxicillin to clavulanate to lessen this side effect
ideal: 600: Amoxicillin 600 mg /clavulanate 42.9mg per 5mL *
what can be used for prohylaxis with G+ suspected
penicillin
when would ceph not be used in those with a hx of rxns to cillins? what is used instead
use macrolides or doxy
Why risk using amoxicillin rather than clindamycin?
Risk of using amoxicillin:
* No risk if the reaction is?
* Any non-SJS rash history to amoxicillin? re-exposed?
* Risk of a severe reaction is ?
* Risk for sever reaction if initial ‘allergy’ was immediate onset, ?
Why risk using amoxicillin rather than clindamycin?
Risk of using amoxicillin:
* No risk if the reaction is GI, headache, yeast infection, family history
* Any non-SJS rash history to amoxicillin, re-exposed to amoxicillin 93-94% tolerate with no subsequent reactions
* Risk of a severe reaction is 0.001%
* Risk for sever reaction if initial ‘allergy’ was immediate onset, 0.29%
Risk of Clindamycin
Among oral antibiotics commonly prescribed by dentists, clindamycin has
the highest fatal (2.9/million prescriptions), serious (233.2/million
prescriptions), and overall (337.3/million prescriptions) ADR rates.
* Double any other dental antibiotic
* >15 times higher than amoxicillin
* Amoxicillin has the lowest fatal
(0.1/million prescriptions), serious
(11.9/million prescriptions), and overall
(21.5/million prescriptions) ADR rates
Risk of C. difficile Infection By Antibiotic
* Clindamycin
* Augmentin
* Cephalexin
* Amoxicillin
* Penicillin
- Clindamycin 25-fold increased risk (greatest risk)
- Augmentin 8.5-fold
- Cephalexin (Keflex) 3-fold
- Amoxicillin 2-fold
- Penicillin 1.8-fold
Recurrence and Mortality of c dif
Antibiotic Duration Impacts CDI Risk
use under 3 days to decrease risk
PPI and Abx
lower ph of stomach reduicing sporicidal emzyme ability
probiotic use with Abx?who can benefit?
May consider for higher risk individuals:
* 65yo+
* recent hospitalization or nursing home
* weak immune system (HIV/AIDS, cancer, or
taking immunosuppressive drugs)
* previous C. diff infection
* taking proton pump inhibitors
metro ADRs
- Metallic taste, dry mouth
- Dark urine
- Skin rashes
- Disulfiram reaction? (headache, flushing, N/V) avoidance of alcohol no longer required
metro interactions
warfarin interactions
majority activtity from s isomer which is increased due to CYP2C9 inhib= INR increased
Empiric Warfarin Dose Reduction with metro
clindamyacin Disadvantages
* infection?
* oral suspension?
* High doses of oral clindamycin (>450 mg Q6H) may cause?
- C. difficile infection
- Clindamycin oral suspension unpleasant taste
- High doses of oral clindamycin (>450 mg Q6H) may cause esophagitis
tetracycline and c dif as respiratory agent
- Tetracyclines demonstrated no increased risk (OR, 0.92) vs no antibiotic
exposure
safe agent for those with hx of CDI
which tetracycline does not discolor peds teeth
doxy
Doxycycline Considerations
* Tooth Discoloration? recomendations?
* Avoid during?
* GI? More common with? which form is better tolerated?
* esophogus?
* Peak plasma concentration may be reduced ~20% by?
* skin?
* Renal/hepatic disease?
Doxycycline Considerations
* Tooth Discoloration: Updated recommendations from the American
Academy of Pediatrics permit doxycycline for ≤21 days in children of all ages
* Avoid during pregnancy, teratogenic
* GI upset: More common with hyclate salt but Monohydrate less acidic, better tolerated
* Erosive esophagitis – avoid taking at bedtime, drink full glass of water
* Peak plasma concentration may be reduced ~20% by high-fat meal or milk
* Phototoxicity (skin rashes) may occur
* Renal/hepatic disease patients can use doxycycline
do we fw ERTHYROMYCIN?
●spectrum?
■ Adverse effects:
■ Strong inhibitor of?
■ Highest risk of?
NOT USED
●Narrow spectrum: LOTS of resistance
■ Adverse effects: Prokinetic, GI disturbances, diarrhea (can be used with gastroparesis, cramping
■ Strong inhibitor of CYP3A –many drug interactions.
■ Highest QTc prolongation risk among antimicrobials
Clarithromycin (Biaxin) –used?
Liver metabolism?
metabolim?
Less drug-drug interactions than?
AVOID USE
Liver metabolism: Moderate CYP3A inhibitor.
Prodrug: metabolized to active compounds
Less drug-drug interactions than Erythromycin but more than azithromycin
clarithromyacin adr
metallic taste
Both Erythromycin and Clarithromycin slow what? implications of this?
Both Erythromycin and Clarithromycin slow CYP3A4
Accumulation of other drugs that are metabolized through 3A4
* Benzodiazepines
* Transplant Drugs (cyclosporine, tacrolimus)
* HIV Drugs
* CCBs (amlodipine, diltiazem)
does azithromyacin influence CY3A4
limited effect
azithrhomyacin Side Effects:
- Possible reversible tinnitus with large doses
- Liver reports – jaundice, necrosis, failure
why are macrolides not top choice for odontogenic infections?
■ No activity against?
■ Alternative?
■ Less effective than?
■ Overall limit use due to?
■ % of viridans group Streptococci resistant? implications?
■ No activity against Bacteroides, common in dental abscesses
■ Alternative antibiotic in odontogenic infections.
■ Less effective than b- Lactams (2nd choice)
■ Overall limit use due to already high resistance rates.
■ 50% of viridans group Streptococci resistant, not good for prophylaxis
Pregnancy and Lactation
* Good Safety abx
- Cephalosporins, penicillins, clindamycin, azithromycin
Pregnancy and Lactation bad abx
- Doxycycline – Ca++ chelation
- Fluoroquinolones – kidneys/cartilage
- Sulfamethoxazole/trimethoprim – various/kernicterus
- Metronidazole in 1st Trimester – limited data
other antimicrobials increasing warfarin con./ INR
TMP-SMX and fluconazole
acyclovir interactions
tizanidine
acyclovir adrs
GI upset, malaise; Local pain (topical)
valcyclovir interaction
tizanidine
valcyclovir Adverse Effects
GI upset, headache
maternal use of valcyclovir
Following maternal administration of valacyclovir, acyclovir is detectable in cord
blood and amniotic fluid; Pregnancy Category B
Higher than serum concentrations present in breast milk (caution)
DDIs: Acyclovir and Valacyclovir
penciclovir ddi
minimal
penciclovir adr
Erythema, headache
maternal penciclovir
not used
famciclovir ddis
minimal
famiciclovir adrs
Nausea, headache
famciclovir in pregnancy
docosanol ddi
none
docosanol adrs
well tolerated
Oseltamivir ddi
minimal
Oseltamivir adr
gi, headache
Oseltamivir maternal
Oseltamivir phosphate and its active metabolite oseltamivir carboxylate cross the
placenta. Use during pregnancy and breastfeeding is acceptable.
Limited excretion into breast milk
Baloxavir marboxil ddi
Baloxavir marboxil adrs
gi upset
Baloxavir marboxil pregnancy
Pregnancy: No adverse events in animal reproduction studies; minimal data; not
recommended
Unknown if excreted in breast milk
NRTI adrs
common and serious adrs
- Common: N/V/D, upset stomach, headache
- Serious: bone marrow suppression (and associated increased risk of bleeding or oral ulcers), peripheral neuropathy, pancreatitis, lipoatrophy, hepatic steatosis, lactic acidosis
NRTI contraindications
- Abacavir and moderate or severe hepatic insufficiency
NRTI ddi
- Tenofovir products and high-dose or multiple NSAIDs May enhance nephrotoxic effects of tenofovir
- Category D: Consider Therapy Modification
nnrtis adr
common ones, sedation? serious adr?
Rilpivirine must be administered with?
Rilpivirine must be administered with a full meal to increase absorption
(better absorbed with acids)
Rilpivirine*
PLUS ddi
Efavirenz or Etravirine ddi
Protease Inhibitors and P450
- CYP3A4 substrates
- Often “boosted” by pharmacokinetic enhancers
protease inhibitors adrs
oral adverse effects of these PIs
* Fosamprenavir -
* Atazanavir -
* Ritonavir -
- Fosamprenavir - Perioral numbness (lips), taste changes
- Atazanavir - Dental (tooth) pain, taste changes
- Ritonavir - Taste changes
Darunavir ddi with:
Atazanavir ddi with:
Fosamprenavir ddi with:
INSTIs general adrs
- Generally well tolerated
- Increased weight gain, insomnia, dizziness
INSTIs: DDIs
* Raltegravir PLUS:
- Proton pump inhibitors= may increase concentrations of raltegravir
- Category B: No Action Needed
Pharmacokinetic Enhancers general adrs
gi upset
Pharmacokinetic Enhancers dentistry related adrs
- Ritonavir: Metallic or bitter taste, oral ulcers or inflammation, perioral numbness/tingling, increased bleeding risk (if DDI with anticoagulants)
- Dry mouth
Ritonavir ddis with:
Cobicistat ddis with:
allylamines adrs/ddi
- Little drug interaction potential
- Few side-effects
Clotrimazole (Mycelex) dosage
* Metabolized in? contraindicated in?
* Avoid in combination with?
* Oral Troche?
10mg (1 troche) dissolved slowly 5 times daily for 7-14 days
* Metabolized in liver – 3A4. Contraindicated in liver disease.
* Avoid in combination with benzodiazapines; HIV
* Oral Troche for management of oral candidiasis
triazoles ddi
Fewer drug-drug interactions and expanded spectrum
* Still metabolized via the cytochrome P450 enzyme system
* All azole agents are both metabolized by and slow down hepatic cytochrome P450 activity
triazole side effect profiles
Safer side-effect profiles than ketoconazole for systemic use
Fluconazole (Diflucan)
* absorb
* t1/2
* excretion where
* ddi
* preg category
*
second gen azole
Drugs that Stimulate Metabolism of Azoles
Viscous Lidocaine
* Relieves?
* IMPORTANT
* Use how much?
* action
- Topical anesthetic
- Relieves pain associated with irritated oral/pharyngeal mucous membranes
- IMPORTANT: ingesting too much can lead to arrhythmias
- Use minimal amounts
- Swish and SPIT
Dental Concerns: Bisphosphonates
associated with? mechanism? precipitated by?
BP duration and MRONJ
increased incicdence when used over longer times
Denosumab Risk of MRONJ
high and low doses
High Dose Denosumab : High prevalence (2-5% Osteonecrosis)
Mechanism of MRONJ
Profound and prolonged inhibition of bone resorption with over-suppression of bone remodeling (ie, low bone turnover), and infection are the main mechanisms
Postulated that MRONJ is a form of avascular necrosis, possibly caused by inhibition of angiogenesis.
what limits chemotherapeutics use?
Adverse reactions limit use
GI disturbances (N/V/D)
Hair loss
Bone marrow suppression
(anemia, increased infection risk)
alkylating agents ADRs/toxicity
oppurtunistic infections possible=thrush
platinum compounds nn adr
Neurotoxicity
Drugs enter into the dorsal root ganglion and binds to DNA, causing apoptosis.
Platinum compounds form intrastrand adducts and interstrand crosslinks altering tertiary structure of DNA. This promotes alterations in cell-cycle kinetics, leading to an attempt of
differentiated postmitotic dorsal root
ganglion neurons to re-enter cell cycle,
which leads to the induction of apoptosis
Regardless of the mechanism, apoptosis results in secondary damage to peripheral nerves
Oxaliplatin association with:
Cold-induced?
breathing?
Mm?
Jaw?
swallowing?
mm appearence?
Voice?
Ocular?
pain triggered by exposure to cold liquids
Cold-induced perioral paresthesias – 95%
Cold-induced pharyngolaryngeal dysesthesia – 92%
Dyspnea – 40%
Muscle cramps – 34%
Jaw stiffness – 34%
Dysphagia – 30%
Visible fasciculations – 30%
Voice changes – 6%
Ocular changes – 0.7%
methotrexate dental note
Dental Note: oral mucositis
Oral pain; Erythema; Difficulty opening the mouth
DNA cycle specific agents are most stomatotoxic
Methotrexate, etoposide known to be secreted into the saliva
further increasing stomato toxicity potential
DNA cycle specific agents associated with oral mucositits
Methotrexate
5FU
Cytarabine
Doxorubicin
Etoposide
Bleomycin
what can be seen orally with cytotoxic abx?
mucositis
vinkaalkloids/ vincristine toxicity
Peripheral neuropathy-numbness, tingling
Neurotoxicity may also be persistent, deep aching and burning pain that mimics a toothache
Side Effects: Cell Replication Inhibition
Primarily GI tract, Bone marrow, Oral cavity
Mucositis painful inflammation along GI
Develops within 1-week of chemotherapy initiation
Stomatotoxic (toxic effects on the oral tissues)
Impairment of bone marrow (myelosuppression)
suppressing white blood cells, red blood cells, and platelets
GET LABS THE DAY BEFORE ANY PROCEDURE
WBC >2000
ANC >2000
Platelets >75,000
Oral Complications Common to Chemotherapy & Radiation
Oral mucositis (20-40%)
Infection
Xerostomia/salivary gland dysfunction
Functional disabilities
Taste alterations
Nutritional compromise
Abnormal dental development
Oral mucositis with Chemotherapy & Radiation
inflammation and ulceration of the mucous membranes
can increase the risk for pain, oral and systemic infection, and nutritional compromise
Infection with Chemotherapy & Radiation
viral, bacterial, and fungal
from myelosuppression, xerostomia, and/or damage to mucosa from chemotherapy or radiotherapy
Xerostomia/salivary gland dysfunction with Chemotherapy & Radiation
dry mouth d/t thickened, reduced, or absent salivary flow
increases the risk of infection and compromises speaking, chewing, and swallowing
persistent dry mouth increases the risk for dental caries
Functional disabilities with Chemotherapy & Radiation
impaired ability to eat, taste, swallow, and speak
due to mucositis, dry mouth, trismus, and infection
Taste alterations with Chemotherapy & Radiation
changes in taste perception of foods, ranging from unpleasant to tasteless
Nutritional compromise with Chemotherapy & Radiation
eating difficulties due to mucositis, dry mouth, dysphagia, and loss of taste
Abnormal dental development with Chemotherapy & Radiation
altered tooth development, craniofacial growth, or skeletal
development in children secondary to radiotherapy and/or high doses of chemotherapy before age 9
Taste Alterations - Chemotherapy
Common occurrence following
chemotherapy administration
Lasts 3-4 weeks post-treatment
common meds of taste of alterations
Cisplatin
Cyclophosphamide
Doxorubicin
5-Fluorouracil
Methotrexate
Paclitaxel
Vincristine
Neurotoxicity of chemo
side effects of what rx’s
Persistent, deep aching and burning pain that mimics a toothache, but no dental or mucosal source can be found.
side effect of certain classes of drugs (vinca alkaloids; platinum compounds)
Bleeding with chemo
oral bleeding from the decreased platelets and clotting factors
Radiation caries:
Radiation caries: lifelong risk of rampant dental decay that may begin within
3 months of completing radiation treatment if changes in quality or quantity of saliva persist
Osteonecrosis with radiation
blood vessel compromise and necrosis of bone exposed to high-dose radiation therapy; results in decreased ability to heal if traumatized
Cyclosporine – Side Effects
Cyclosporine AND Tacrolimus DDIs
Cimetidine (Tagamet)
Clarithromycin (Biaxin)
Erythromycin
Corticosteroids
Fluconazole (Diflucan)
Itraconazole (Sporanox)
Ketoconazole (Nizoral)
Cyclosporine AND Tacrolimus Cimetidine DDI
Reports implicate cimetidine and
famotidine as increasing
cyclosporine concentrations and/or
decreasing cyclosporine clearance
Clarithromycin and tarcolimus
One report describes 2 female
patients (aged 37 and 69
years), who each experienced
acute renal failure and more
than a 2.3-fold increase in
tacrolimus serum
concentrations after 9 doses of
clarithromycin therapy (250
mg daily)
Corticosteroids and cyclosporine
Toxic effects of prednisone and/or
cyclosporine, if agents combined
Azoles and cyclosporine concentrations
Serum cyclosporine concentrations have been reported to
increase as much as tenfold in transplant patients
following the initiation of azole antifungal agents
what bp has the highest risk for MRONJ
zolendronate
