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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_4518_Библиотеки_им_академика_М_И_Перельмана
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11 Therapeutics: Pharmacology, Chemotherapy, Radiation Oncology
https://t.me/medicina_free
Possible super-infection as highly
selective against gram (−)
Increase GI motility, inhibits
cytochrome p450, prolonged QT
Risk of Pseudomembranous colitis
Aerobic gram (−) including
pseudomonas
Gram (+) and (−)
(C. difcile)
Atypical organisms
No efcacy to MRSA
Anaerobes, +/− MRSA, some gram
(+), resistant to most gram (−) (i.e.
Haemophilus, Moraxella,
interfere absorption Ca, Mg, Fe,
and Al; predisposition to sunburn
Ototoxicity and nephrotoxicity
Pseudomonas)
Broad spectrum Gray-brown discoloration of teeth;
Pseudomonas, gram (−), no anaerobes
or MRSA coverage
Peripheral neuropathy, tendon
rupture in children, QT
prolongation, epidermal
necrolysis, rash
Nephrotoxic, ototoxic, “Red man”
syndrome
anaerobic coverage, pseudomonas
MRSA, C. difcile, not active against
gram (−)
increase Warfarin levels
Broad spectrum, MRSA Rash, bone marrow suppression,
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suppression, peripheral neuropathy
synthesis of cell wall
Binds to 50S ribosomal subunit
→ decrease protein synthesis
Clarithromycin
Monobactams Aztreonam Inhibition of mucopeptide
Macrolides Azithromycin
reduces toxin production
Erythromycin
Lincosamides Clindamycin Binds to 50S ribosomal subunit,
Impairs 30S ribosomal subunit
and tRNA binding
Tetracycline
Tetracyclines Doxycycline
Binds 30S ribosomal subunit,
bacteriocidal due to misreading
of mRNA
Inhibits of DNA gyrase Gram (−) aerobes, gram (+), broad
Gentamycin
Neomycin
Tobramycin
Levooxacin
Moxioxacin
Ooxacin
Aminoglycosides Amikacin
Quinolones Ciprooxacin
Glycopeptides Vancomycin Inhibition of N-acetylmuramic
acid and N-acetylglucosamine
into peptidoglycan
Competitive antagonist of
para-aminobenzoic acid (PABA)
for bacterial folic acid synthesis
sulfamethoxazole
Sulfonamides Trimethoprim-
Other antibacterials
Metronidazole Destabilizes anaerobic DNA Anaerobes only Metallic taste, bone marrow
Mupirocin Inhibits RNA synthesis S. aureus, MRSA (topical) Contact dermatitis
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Table 11.6 Antifungal drugs
Antifungals
Name MOA Efcacy Side effects
Amphotericin BBinds ergosterol Works well against Mucor;
increasing Candida albicans
resistance
AZOLES Inhibits lanosterol
conversion to
ergosterol
Clotrimazole
Fluconazole
Itraconazole
Ketoconazole
Posaconazole
Voriconazole
Capsofungin Inhibits of fungal
cell wall synthesis
Nystatin Binds ergosterol Broad fungal coverage Rash, itching
Table 11.7 Antiviral drugs
Antivirals
Name MOA Efcacy Side Effects
Acyclovir
Famiciclovir
Valcyclovir
Rimantidine Prevents uncoating of
Oseltamivir
Zanamivir
Inhibits of viral
polymerase
virus and release of
infectious viral nucleic
acids
Neuraminidase inhibitor Inuenza A and B—
Varied coverage Similar to those listed for
Not Mucor
Candida, Aspergillus
Fusarium, not Mucor
Skin infections
Candida, Aspergillus Hepatotoxicity
Herpes simplex and
Herpes zoster
Inuenza A- both active
treatment and prophylaxis
treatment must be initiated
within 36 h of symptom
onset
Infusion reactions,
nephrotoxic, cardiotoxic,
neurotoxic
amphotericin but less
severe
Bone marrow
suppression, StevensJohnson syndrome
Can interact with
acetaminophen or
aspirin
Nausea, vomiting
Diarrhea
Rare neuropsychiatric
issues
A. Wong et al.
Table 11.8 Medication for treatment of gastric acidity
Anti-reux
Class Name MOA Side effects
Histamine
blockers
Proton pump
inhibitors
Promotility
agents
Famotidine
Ranitidine
Cimetidine
Esopmeprazole
Lansoprazole
Omeprazole
pantoprazole
Metoclopramide Dopamine receptor antagonist which
Blocks histamine-2 receptors, prevents
histaminergic stimulation to acidsecreting parietal cells; take at least
30min prior to meal
Blocks H+/K+ ATPase pump on
parietal cells on luminal surface of
stomach; take at least 30–60min prior
to meal
increases tone of LES, increases
contraction of gastric antrum, relaxes
pylorus and duodenum; can be used as
adjunct to refractive GERD
Cytochrome p450
inhibition
Cytochrome p450
inhibition
Extrapyramidal
symptoms (i.e.,
movement disorders)
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Table 11.9 Interconversion of steroid compounds
Hydrocortisone 1
Prednisone 4
Methylprednisolone 5
Dexamethasone 25
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• Second-generation oral antihistamine
– Examples: loratadine, cetirizine, fexofenadine
– Side effects.: little to no anticholinergic activity, sedation/CNS effects (does
not cross the blood-brain barrier easily), or tachyphylaxis
Anticholinergics
• MOA: competitive antagonist of cholinergic receptors to decrease mucosal
secretions
– Example: ipratropium
– Side effects: nasal irritation, drying
Decongestants
• MOA: alpha-2 agonist to cause vasoconstriction
– Vasoconstriction → decrease edema, congestion, and hyperemia
– Minimal effect on rhinorrhea, itching, and sneezing
– Example: oxymetazoline, phenylephrine, pseudoephedrine
– Side effects: alpha-adrenergic: hypertension, tachycardia, arrhythmia, tachy-
phylaxis, rebound congestion with prolonged use (>3 days topical agents),
long-term use results in rhinitis medicamentosa (atrophy of glands and
chronic inammation of mucosal lining)
Corticosteroids
• MOA: inhibition of genetic transcription and protein synthesis to decrease
inammation
• Topical corticosteroids
– Example: beclomethasone, unisolide, uticasone, mometasone
– Side effects: mucosal dryness, epistaxis, tearing
• Oral corticosteroids
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– Example: prednisone, dexamethasone, methylprednisolone
– Side effects: uid imbalance, electrolyte disturbances, glycosuria, increase
susceptibility to infections, hypertension, hyperglycemia, osteoporosis, cataracts, central obesity, hypothalamic-pituitary axis suppression, avascular
necrosis of hip, peptic ulcer formation
Cromolyn Sodium
• MOA: mast cell membrane stabilizer to inhibit release of histamine
– Note: used for prophylaxis rather than active treatment
– No systemic absorption → no systemic adverse effects
Leukotriene Receptor Antagonist
• MOA: block leukotrienes from cellular activation
– Example: Montelukast
– Effective as treatment of allergic rhinitis
A. Wong et al.
Botulinum Toxin
• MOA: active component binds to presynaptic neuromuscular junction of motor
neurons inhibiting acetylcholine release → accid paralysis
– Example: Botulinum type A, botulinum type B
– Uses: spasmodic dysphonia, bruxism, facial dystonia, facial synkinesis,
hyperhidrosis, rhytids
– Side effects: nausea, pain at injection site, acne, unwanted paralysis and pto-
sis, bruising
Chemotherapy forHead andNeck Cancer
• See Table11.10 Chemotherapy agents.
• Five main types of chemotherapy agents:
– alkylating agents, antimetabolites, antitumor antibiotics, alkaloids, taxanes
• Most commonly used chemotherapeutic agents for head and neck cancer:
– 5-Fluoruracil (5-FU), carboplatin, cisplatin, docetaxel, paclitaxel
11 Therapeutics: Pharmacology, Chemotherapy, Radiation Oncology
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Table 11.10 Chemotherapy agents
Chemotherapy agents
Class Name MOA Toxicity
Alkylating
agents
Antimetabolites 5-Fluorouracil
Antitumor
antibiotics
Alkaloids Vincristine
Taxanes Paclitaxel
Cisplatin
Carboplatin
Methotrexate
Doxorubicin
Bleomycin
Mitomycin
Vinblastine
Docetaxel
Cross-linking and strandbreaking reactions with DNA
→ inaccurate DNA replication
→ cell death
Inhibit critical enzymes
involved in nucleic acid
synthesis or become
incorporated into nucleic acid
and produce incorrect codes →
inhibition of DNA synthesis
during S phase → cell death
Streptomycin derived and
cytotoxic
Affect structure and function of
nucleic acids via intercalation
of DNA base pairs, DNA
strand fragmentation, or
cross-linking DNA
Bind to free tubulin dimers and
disrupts balance between
microtubule polymerization.
Results in destruction of
mitotic spindles and arrest of
cells in metaphase
Stabilize tubulin polymers and
prevent cell division
Cisplatin: renal toxicity,
ototoxicity (obtain
pre-treatment audiogram),
myelosuppression,
neurotoxicity
Carboplatin:
thrombocytopenia
5-FU: stomatitis, alopecia
Methotrexate: megaloblastic
anemia, vasculitis,
pulmonary brosis,
stomatitis
Doxorubicin: cardiac
toxicity related to
cumulative dose
Bleomycin:
hyperpigmentation, rashes,
nail changes, pneumonitis
w/inltrates that can
progress to brosis
Vincristine: neutropenia,
peripheral neuropathy,
muscle weakness,
depression
Vinblastine:
reticulocytopenia, anemia,
paresthesias, muscle
weakness, depression
Paciltaxel: allergic-like
reaction with facial
erythema, tachycardia and
hypotension, cardiotoxicity
w/bradycardia, alopecia
Docetaxel: abnormal ECG,
neuropathy
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Chemotherapy Treatment Schemes
• Addition of chemotherapy:
– Improved clinical outcomes in those with advanced disease
– Demonstrates signicant benets in organ preservation
– Debulks larger tumors to allow for possible surgery
– Promotes longer time to disease progression
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A. Wong et al.
– Better locoregional control
– Fewer distant metastasis
– Longer survival times
• Neoadjuvant chemotherapy: use of therapy prior to denitive radiation or surgi-
cal therapy (i.e., induction)
– TAX 324 randomized phase III study showed better progression-free survival
and overall survival in patients with stage III or IV squamous cell carcinoma
of the head or neck treated with induction chemotherapy with docetaxel, cisplatin, and uorouracil (TPF) compared to cisplatin and uorouracil (PF).
• Concomitant chemotherapy: simultaneous use of chemotherapeutic and radiation treatments
– Consider concomitant chemotherapy (i.e., cisplatin) if presence of adverse
features—extracapsular nodal spread of tumor, positive resection margins,
multiple positive nodes, perineural or lymphovascular invasion
• Adjuvant chemotherapy: administered after denitive treatment with radiation,
surgery, or chemotherapy
Radiation Oncology
• Radiation absorbed dose: (rad)
– Energy deposited by ionizing radiation per gram of tissue
– 1 rad = 1 erg/cm
3
– 1 Gray (Gy) = 1 J/kg; 1 J=107 ergs
– 1Gy = 100 rads
• Electrons travel short distances in tissue → better for supercial lesions
• Mixed beams of electrons and photons → better to treat lesions requiring higher
surface doses
• Fractionation
– Standard fractionation
70Gy in 35 fractions over 7 weeks
– Hyperfractionation: Administration of multiple daily doses of radiation at the
size that would allow overall treatment time to be the same as that for conventionally fractionated course of once-a-day RT
Example: 1.1 to 1.2Gy/fraction for two fractions/day to total 74–80Gy
over 6–8 weeks.
Increased number of doses delivered.
Decreased intensity per dose delivered (1.15–1.2Gy per fraction).
Smaller dose fractions allow for higher total dose administered and higher
biological dose against tumor.
11 Therapeutics: Pharmacology, Chemotherapy, Radiation Oncology
https://t.me/medicina_free
Exploits differential sensitivity of tumor cells and normal tissue.
Delivered within the tolerance of late responding normal tissue.
Decreased risk of late complications because tissues that demonstrate
delayed toxicity are more dependent on size of individual doses than
tumors are
Increased acute side effects.
– Accelerated fractionation: Administration of multiple daily doses of radiation
at a larger size that would allow for shorter overall treatment time
Example: 67Gy in 42 fractions over 6 weeks
Allows shortening of total duration of XRT → reducing opportunity for
tumor proliferation
Higher intensity per dose delivered (1.5–2 Gy)
Decreased total dose
Increased acute side effects; decreased late side effects
• Postoperative radiation therapy
– Indications:
Close or positive surgical margins
Perineural spread
Lymphovascular invasion
Contiguous tumor extension into the bone or skin
Multiple nodal involvement
Extra capsular extension of nodal disease
Timing for delivery typically within 3–4 weeks
Radiotherapy completed within 11 weeks gave better outcome than
>11 weeks
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• Preoperative radiotherapy
– Indications:
Cancer with marginal resectability
Small radiocurable disease
Large adenopathy
Adverse Events (Sequelae fromChemotherapy/Radiotherapy)
oftheHead andNeck
• Mucositis
– Atrophy of squamous epithelial tissue, absence of vascular damage and
inammatory inltrate
– Loss of stem cells in basal layer interferes with replacement of cells in super-
cial mucosal layer which are lost through normal physiologic sloughing
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A. Wong et al.
– Transient effect, but usually exacerbated in patients with history of alcohol
and tobacco use
– Typically presents with hyperkeratinization → erythema
– Severity in decreasing order: soft palate, mucosa of hypopharynx, cheek, base
of tongue, lips, and dorsal tongue
– Radiation with concurrent chemotherapy can increase rate of mucositis
– Treatment: aggressive oral hygiene, topical anesthetic (magic mouthwash),
diet modication, ETOH, and tobacco cessation
• Salivary gland damage
– Secondary to progressive degeneration of acinar epithelium and onset of
interstitial brosis
– Substantial irreversible decrease in the production and output of saliva
– Salivary thickening and mucoid, reduced pH → allowing ora to ourish
– Increase in dental caries, sensitivity, and periodontal disease
– Sparing one salivary gland (i.e., one parotid gland or submandibular glands)
can decrease incidence of xerostomia
– Treatment: copious uids with meals, salivary substitutes, pilocarpine, uo-
ride treatments
Pilocarpine (muscarinic receptor agonist) may improve or prevent xerostomia when given after completion of RT.Requires weeks of treatment to see
improvement. Often prematurely stopped by patients due to cholinergic
side effects.
• Osteroradionecrosis (ORN)
– Changes include hyperemia, endarteritis, and thrombosis of vasculature.
– Fibrosis and fatty degeneration of marrow.
– Poor response to trauma and infection.
– Mandible is the most commonly affected bone.
– Maxillary ORN uncommon because it has bilateral blood supply, but can be
seen in RT for nasopharyngeal cancer.
– Staging:
Stage I: Supercial involvement only involving cortical bone with exposure
Stage II: Localized involvement of exposed cortical bone with underlying
medullary bone necrosis
Stage III: Diffuse involvement of bone with full thickness
– Treatment ranges from oral rinses, antibiotics, local debridement, and hyper-
baric oxygen therapy to radical resection.
– Dental consultation, pre-radiation dental extractions (of diseased teeth), and
improved oral hygiene are essential.
– Presence of ORN despite aggressive treatment → raise suspicion for cancer
recurrence.
11 Therapeutics: Pharmacology, Chemotherapy, Radiation Oncology
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• Alterations in taste
– Typically due to damage to taste buds and decreased salivary ow
• Trismus
– Secondary to muscle and ligament brosis and scarring
– Treatment: jaw exercises and stretching
• Cutaneous reactions
– Erythema, dryness, swelling, brosis
– Treatment: moisturizers, mild cleansers, corticosteroids
• Others: Alopecia, brosis, post radiation-induced cancer
Biologic Therapy
• Newest addition to treatment of head and neck cancers with ongoing research
• Cetuximab: humanized monoclonal antibody directed against epidermal growth
factor receptor (EGFR), which is overexpressed in HNCs
– Initially approved in the USA for use in combination with RT for locally or
regionally advanced HN SCC.Now also approved for use in combination
with platinum-based therapy plus 5-FU as rst-line therapy for recurrent
locoregional or metastatic HN SCC.
– Chemotherapy plus cetuximab showed prolonged overall survical compared
to chemotherapy alone.
Further Reading
1. Ang KK, etal. Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001;51(3):571–8.
2. Becker DE.Nitrous oxide and inhalation anesthetics. Anesth Prog. 2008;55(4):124–31.
3. Chu CS.Basic principles of chemotherapy. Clinical gynecologic oncology. 2nd ed. Amsterdam:
Elsevier; 2017. p.449–69.
4. Dershwitz MRC. Pharmacology of intravenous anesthetics. In: Longnecker DE, Brown
DL, Newman MF, Zapol WM, editors. Anesthesiology. 1st ed. New York: McGraw-Hill
Professional; 2007.
5. Fairbanks DNJ.Pocket guide to antimicrobial therapy in otolaryngology—head and neck surgery. 13th ed. Alexandria: American Academy of Otolaryngology—Head and Neck Surgery
Foundation Inc; 2007.
6. Forman SA, Mashour G. Pharmacology of inhalational anesthetics. In: Longnecker DE,
Brown DL, Newman MF, Zapol WM, editors. Anesthesiology. New York: McGraw-Hill
Professional; 2007.
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7. Hershcovici T, Fass R.Pharmacological management of GERD: where does it stand now?
Trends Pharmacol Sci. 2011;32(4):258–64.
8. Khurram Saleem Khan IH, Buggy DJ. Pharmacology of anaesthetic agents II: inhalation
anaesthetic agents. Contin Educ Anaesth Crit Care Pain. 2014;14(3):106–11.
9. Levine A, Govindaraj S, DeMaria S Jr. Anesthesiology and otolaryngology. New York:
Springer Science and Business Media; 2013.
10. Lobato EB, Nikolaus G, Kirby RR. Complications in anesthesiology. Philadelphia:
Lippincott; 2007.
11. Lorch JH, etal. Induction chemotherapy with cisplatin and uorouracil alone or in combincation with docetaxel inlocally advanced squams cell cancer of head and neck: long-term results
of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011;12(2):153–9.
12. Nguyen LN, Ang KK.Radiotherapy for cancer of the head and neck: altered fractionation
regimens. Lancet Oncol. 2002;3(11):693–701.
13. Nolan JP.Anaesthesia and neuromuscular block. In: Bennett PN, Sharma P, editors. Clinical
pharmacology. 11th ed. Churchill Livingstone; 2012. p.295–310.
14. Ogden S, Grifths TW.A review of minimally invasive cosmetic procedures. Br J Dermatol.
2008;159(5):1036–50.
15. Parry A. Management and treatment of local anaesthetic toxicity. J Perioper Pract.
2011;21(12):404–9.
16. Patil PM.Malignant hyperthermia in the oral and maxillofacial surgery patient: an update.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011;112(3):1–7.
17. Pignon JP, etal. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an
update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14.
18. Posner MR.Paradigm shift in the treatment of head and neck cancer: the role of neoadjuvant
chemotherapy. Oncologist. 2005;10(Suppl 3):11–9.
19. Schwartz HC, Kagan AR.Osteoradionecrosis of the mandible: scientic basis for clinical staging. Am J Clin Oncol. 2002;25(2):168–71.
20. Vermorken JB, Mesía R, Peyrade F, Beier F, de Blas B, Celik I, Licitra L.Impact of tumor
HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma
of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III extreme trial. Ann Oncol. 2014;25(4):801–7.
21. Vermorken JBMR, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D,
Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer
C, Schueler A, Amellal N, Hitt R.Platinum-based chemotherapy plus cetuximab in head and
neck cancer. N Engl J Med. 2008;359(11):1116–27.
22. Vissink A, et al. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med.
2003;14(3):199–212.
23. Wang SX, Simpson CB. Anesthesia for ofce procedures. Otolaryngol Clin N Am.
2013;46(1):13–9.
A. Wong et al.
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