Pharm Flashcards
Respiratory pharmacology focuses on….
Asthma
COPD
Allergic rhnitis
Cough
Classification of asthma based on severity?
Intermittent: <2 weeks , <2 times/ month (nighttime awakening)
Mild persistent: >2 weeks but not daily, 3-4 times / month
Moderate persistent: Daily , >1 time / week but not nightly
Severe persistent: Throughout the day, 4-7 times week
Pharm for Asthma
Bronchodilators: B2 adrenergic agonist, Anticholinergic, methylxanthines
Anti-inflammatory drugs: Corticosteriod, release inhibitors, immunomodulators, leukotriene-modifying agents
B2 adrenergic agonist:
Inhaled short acting B2 adrenergi agonist (SABA)
Inhaled long acting B2 adrenergic agonist (LABA)
SABA
- Albuterol,
- Terbutaline
- Pirbuterol
LABA
- Salmeterol
- formoterol
Mechanism of B2 adrenergic agonist
Binds to and activate B2 adrenergic receptors on airway smooth muscle cells.
Activation of B2 receptors stimulate adenylyl cyclase and increase CAMP, which activate protein kinase A, which phosphorylates and inactivates myosin light chain kinase. result in relaxation of the airway smooth muscle cells and bronchodilation
USe of SABA
DOC for acute asthma symptoms and prevention of exercise - induced bronchospasm.
Use of LABA
- LABA are combined with inhaled corticosteriod for long term
- NO USE OF LABA ALone
- NOT for acute
SAMA : INhaled short acting muscarinic antagonist
Ipratropium
LAMA:inhaled long acting muscarinic antagonist
Tiotropium
MOA of SAMA AND LAMA
Inhaled ipratropium and tiotropium block muscarnic receptor on the airways causing bronchodilation and reduction of respiratory secretion. M3
Effect of SAMA and SABA
Ipratropiun is less effective than SABA
Adverse effect of anticholinergic
Low access to the systemic circulation and systemic adverse effects
Minor anticholinergic effets xerostomia might occur = dry mouth
Safer than SABA in patients with cardiovascular disease
Bronchodilators: Methylxanthines
Theophylline :
Inhibit phosphodiesterase
Increase in CAMP evokes bronchodilation
Use of Theophylline
Given IV or orally.
Alternative use
has narrow therapeutic window , adverse effect
ADverse effect of theophylline
At high concentration, cardiac arrhythmias and seizures can occur
Inhaled corticosteroids(ICS)
- Beclomethasone
- Budesonide
-Flunisolide
Fluticasone
Systemic corticosteriods
- Predinisone
- prednisolone
- methylprednisolone
- dexamethasone
MOA of corticosterioids
Inhibit phospholipase A2 and inhibit transcription of COX-2 resulting in reduced formation of leukotrienes and prostaglandin
- prolonged use of SABAs results in B2 recpetor desensitization
- corticosteroids prevent or reverse this desensitization.
Uses of corticosteroids
ICS = most effective long term control medication in the management of persistent asthma.
- Oral corticosteroids can be added to ICS for longterm control of severe persistent
Dependent edema is a term that doctors use to describe gravity-related swelling in the lower body
T/F A short course of systemic corticosteroids is used for moderate and severe acute exacerbations of asthma to speed recovery and to prevent recurrence of exacerbation
True
Adverse effects of ICS ?
ICS has lower bioavailability than systemic corticosterioids so risk of potential AE is reduced.
- Local AE include oropharyngeal candidiasis,dysphonia, reflex cough and bronchospasm.
- Long-term may result in osteoporosis and cataracts. Cause deceleration of vertical growth in children.
Adverse effects of systemic corticosteroids?
Hypercortisolisms and Cushing’s syndrome.
What are the release inhibitor?
- Cromolyn
- nedocromil
What do they inhibit?
- Mast cell degranuation and prevent both antigen induced and exercise induced bronchospasm in asthmatic patients.
Uses of release inhibitor?
Not useful in managing an acute asthma attack
- alternative medication for mild persistent asthma
- used to prevent exercised induced bronchospasm
- largely replaced by other therapy
AE of cromolyn and nedocromil?
Throat irritation, cough, mouth dryness.
Rare: Chest tightness and wheezing, include dermatitis, myositis, orgastroeneteritis,
What is anti-inflammatory drugs that is immunomodulators?
Omalizumab
USe of omalizumab?
Monoclonal antibody
-prevents binding of IgE to basophils and mast cells.
Used in the managment of patients with severe persistent asthma with evidence of allergy.
AE of omalizumab?
Anaphylaxis
Anti-inflammatory drugs : Leukotriene modifying agents
Leukotriene receptor antagonists:
- Montelukast,
- Zafirlukast
5- Lipoxygenase inhibitor:
Zileuton
Orally(everything)
AE of montelukast?
Insominia, anxiety, depression , suicidal thinking
so psychic patients NONO
AE of Zileuton?
Hepatotoxicity
Long term management of asthma:
Intermittent : No dailty long-term control medication Mild persistent: Low dose ICS Moderate persistent: Low dose ICS +LABA - Medium dose ICS Severe persistent: Medium dose ICS+LABA - or high dose ICS +LABA
Management of acute exacerbation of asthma
- SABA
- SAMA
- systemic corticosteroids (moderate and severe)
Use of Oxygen for COPD?
for severe hypoxemia long-term oxygen therapy increase survival.
Can LABA be used alone for copd?
YES,
- combining a LAMA witha LABA can improve lung function and reduce symptoms and exacerbation rates.
- REgular use of inhaled LABa or LAMA is recommended for patients with moderate to severe dyspnea.
SABA &SAMA for copd?
Acute exacerbation
ICS can be used alone for COPD?
NOOO
- Use of ICS plus a LABA improves lung function and reduces exacerbation
- ICS are less effective than inhaled LABA for treatment of COPD
What is mucolytic agents?
N-Acetylcysteine
- breaks disulfide linkage in mucus and lowers viscosity
Antibiotics for COPD?
Exacerbation of COPD frequently involve bacterial infection (complication of Chronic bronchitis)
Management of stable COPD?
A: Mild or infrequent symptoms (low risk of exacerbation)= SABA, Sama, LABA or LAMA
BL Moderate to severe symptoms(low risk) = LABA or LAMA
C: Mild or infrequent symptoms but high risk of exacerbation : LAMA
D: Moderate to severe symptoms &high risk : LAMA
if highly symptomatic: LAMA+LABA
If asthma/ COPD overlaps: ICS+LABA
If dual treatment doesn’t work = ICS+LABA+LAMA
Management of COPD Exacerbation?
A SABA+_ SAMA is the inital treatment
Systemic corticosteroids should be given
Antibiotic should be given if signs of bacterial infection are present
- Oxygen therapy should be given if the exacerbation is severe.
What is allergic rhinitis?
- inflammation of nasal mucosa induced by different allergen.
- nasal congestion
Treatment : allergen avoidance and pharmacotherapy
What is the first line treatment for allergic rhinitis?
GLucocorticoid nasal sprays
AE of glucocorticoid nasal sprays?
Local irritation of the nasal mucosa,
Noselbleed
Nasal septal perforation
Nasopharyngeal candidiasis
Classification of oral antiistamines?
First generation : Diphenhydramine,Chlorphniramine
has liphophillic meaning sedationn
Second - generation: Loratadine, Fexofenadine, Cetirizine.
Hydrophillic meaning no sedation.
What are the nasal decongestants?
Phenylephrine, pseudoephedrine.
= should Be used no longter than 3 days due to risk of rebound nasal congestion.
Medication for cough
-Codeine
- Dextromethorphan.
:
Support cough reflex via direct action on the cough center in the medulla of the brain
AE: Constipation and drowsiness(OPIOD)
DExtrometrophan is safer and has lower abuse potential than codeine.
General characteristic for mycobacteria:
- located intracellularly
- intrinsically resistant to most antibiotics
- quick to develop resistance
- therapy can be months or even years
- combination therapy required for active infection
Tuberculosis:
mycobacterium tuberculosis
- can lead to serious infections of the lungs, GI tract, skeleton and meningies
Classification of resistance:
1.monoresistant TB: resistance to only one first line drug
2. Polydrug - resistance: more than one first tine drug
(other than both rifampin and isoniazid)
3. multidrug -resistant TB: resistance to at least both rifampin and isoniazid
4. Extensively drug resistant TB: resisant to any fluroquinolone and to at least one of other 2nd line drug
Latent TB and Active TB:
Latent TB: no signs and symptoms
no radiologic evidence, no laboratory evidence
but positive for TST/PPD test, treatment recommended for some group of people
Active TB: signs and symptoms, radiologic evidence, laboratory evidence, TST/PPD test , treatment is warranted
!
Principles of therapy for tuberculosis:
- most sites of disease require 6 months treatment
- CNS and bone disease require 12 months treatment
- standard is a quadruple therapy(RIPE regimen)
- Dose is dictated by patient weight
What are the first line drugs and second line drugs for tuberculosis?
- First line drugs (RIPE)
1. Rifamycin
2. Isoniazid
3. Pyrazinamide
4. Ethambutol - second line drugs:(SEAL)
1. Streptomycin
2. Ethionamide
3. Amikacin
4. Levofloxacin
- Rifamycins:
- Rifampin
- rifabutin (mainly used in HIV patients)
- part of combination therapy for active infections
- If used alone, reistance rapidly emerge
- used in the treatment of latent infection
MOA and MOR for rifampin:
MOA: binds to Beta subunit of bacteria DNA -dependent - RNA polymerase— leading to inhibiton of RNA synthesis
MOR: point mutation in rpoB(gene for the beta subunit of TNA polymerase)
Rifampin is a strong CYP P 450 inducer, while rifabutin
is not.
Antimicrobial spectrum for rifampin:
- bactericidal against both intracellular and extracellular mycobacteria
- bactericidal against both dividing and non-dividing mycobacteria
- Active against Gram positive and negative organisms
- Activity against MRSA
Rifampin:
- Serious staphylococcal infection
- MRSA
- Active TB, Latent TB(isoniazid intoleratnat)
- Leprosy (delays resistance to dapsone)
- prophylaxis for meningitis and H. influenzae type B in exposed individuals
AE of rifampin:
- Red organge body fluids
- harmless
- safe in pregnancy
Rifabutin:
- preferred drug for use in HIV patients due to less induction of CYP enzymes
- can be a substitute to those patients who are intolerat to rifampin.
(not sure for pregnancy)
So Rifampin:
Rna polymerase inhibitor rapid resistance if used alone ramps up CYP 450 Red-orange body fluid Rifampicin
Isoniazid?
- synthetic analog of pyridoxine
- Abbreviated INH
- most potent anti-TB drug
- if used alone, resistance rapidly emerge
Antimicrobial spectrum of isoniazid?
- Bacterial against both intracellular and extracellular mycobacteria
- Bacterial against actively diving mycobacteria
- Bacterial against slowly diving mycobacteria
MOA and MOR of isoniazid?
MOA: inhibits synthesis of mycolic acid leading to disruption of cell wall
MOR: High level of resistance due to deletion of KatG
(catalase-peroxidase)
Low level of resistance due to overexpression of inhA and mutation of KasA
Pharmacokinetics of isoniazid:
- CYP P450 inhibitor
- metabolized by the liver N-acetyltransferase via acetylation.
AE of isoniazid:
- Neurotoxicity like peripheral neuropathy (alleviated by giving pyridoxine- vitamin B6)
- Hemolysis in G6PD
- hepatotoxicity
- Lupus like syndrome
- safe in pregnancy
INH:
Isoniazid
Immune(lupus like syndrome)
Neurotoxicity
Hemolysis and hepatotoxicity
*isoniazid injuries neurons and hepatotocytes.
What is pyrazinamide?
- if used alone, resistance rapidly emerge
- relative of nicotinamide
MOA and MOR of pyrazinamide?
- MOA: must be enzymatically hydrolysed by mycobacterial pyrazinamidase (encoded by pncA) to active pyrazinoic acid.
- MOR: impaired uptake of pyrazinamide or mutation in pncA.
Pharmacokinetics of pyrazinamide?
- oral
- ## works best in acidic ph<6 (within phagolysosomes and granulomas)
AE of pyrazinamide?
- non-gouty polarthralgia
- hyperuricemia
- hepatotoxicity
- only given in pregancny if benefits outweigh the risk, otherwise avoided.
PYRAZINAMIDE:
Polyarthraligia (non-gouty)
Pains (joints, abdomen, muscles
Photosensitivity
Porphyria
RIP Hepatotoxicity
Rifampin, Isoniazid, pyrazinamide
Ethambutol
if used alone , resistance rapidly emerge
- Least potent against MTB
MOA and MOR of Ethambutol?
MOA: inhibits arabinosyltransferase (encoded by the emb gene) leading to decreased carbohydrate polymerization of cell wall.
MOR: mutation usually overexpression of emb gene
AE of ethanmbutol?
- visual disturbances
- decreased visual acuity
- red,green color blindness
- safe in pregancy
Ethambutol?
Eye problems
Ethambutol
when do we use second line drugs of TB?
In case of resistance of 1st line drug
- Failure of clinical response to conventional therapy
- serious treatment limiting adverse drug reaction
Streptomycin
- MOA: inhibit protein synthesis by binding at 3-s mycobacterial ribosome
-given parenterally.
AE: ototoxicity, nephrotoxicity, - toxicity associated are dose related and can be reduced by limiting therapy to no more than 6 months whenever possible
- Teratogenic
Ethionamide?
chemically related to isoniazid MOA: blocks mycolic acid synthesis AE; Neurtoxicity, hepatotoxicity, resistance can develop rapidl if used alone - No cross resistance with isoniazid
Amikacin
like streptomycin
- MOA: inhibits protein synthesis
- AE: same as streptomycin(TERATOGENIC)
- prevalence of amikacin resistant strains are low
- most multidrug resistant strains still remain susceptible to this drug.
LEvofloxacin
-FLuoroquinolone
MOA: interferes with DNA replication by inhibitng DNA gyrase(topoisomerase II)
AE: tendinopathy
- Teratogenic
Latent tuberculosis regimen
- Isoniazid : 6-9 months
- Rifampin : 4 months
- Isoniazid + Rifampin = 3 months
Active pulmonary tuberculosis: including miliary tuberculosis not involving CNS, bone or joints.
Initial phase: Rifampin, Isoniazid, Pyrazinamide, Ethambutol = 2 months.
Continuation phase: rifampin, isoniazid= 4 months
Initial phase: rifampin, Isoniazid, Ethambutol = 2 months
continuation: rifampin, isoniazid= 8months.
Extrapulmonary tuberculosis regimen involving CNs and bone, joints
Initial: RIPE= 2 months
, continuation: rifampin, isoniazid = 10 months
What is leprosy?
- caused by Mycobacterium leprae and mycobacterium lepromatis
- primarily granulomatous disease of perioheral neres and mucosa of upper respiratorytract’
drugs for leprosy:
- Dopasone
- Rifampin
- Clofazimine
= DR. Clof.
What is dapsone?
- structurally related to sulfonamides
MOA: inhibits folate synthesis via dihydropteroate synthase inhibition - Also used in the treatment of pneumonia caused by pneumocystis jirovecill in HIV-AIDS patients
AE of dapsone?
hemolysis in G6PD deficient patients
- Methemoglobinemia- common but usually clinically insignificant.
- Erythema nodosum leprosum often develops during the treatment of lepromatous leprosy which can be treated with Thalidomide
Clofazimine?
- used in treatment of multi bacillary leprosy
- MOA: inhibits replication by binding to DNA.
AE of clofanzimine?
- Discoloration of the skin and conjunctivae- most prominent
- GI irritation
- Does not cause erythema nodosum leprosum
Treatment of leprosy?
Type of leprosy: Pauci-bacillary(1-5 skin lesion) = Dapsone+rifampine
multi-bacillary(more than 5 skin lesion) = Dapsone+rifampin+clofazimine
So, Pauci-bacillary = DR
Multi-bacillary= DR. Clof
Principles of cancer chemotherapy?
- cancer chemotherapy strives to causea lethal cytotoxic lesion that can arrest a tumor’s progression.
- the attack is generally directed aginst DNA or metabolic sites essential to cell replication.
*for example, the avilability of purine and pyrimidine precursors for DNA or RNA synthesis.
Indication for chemotherapy:
- Primary chemotherapy: Chemotherapy indicated when neoplasm are disseminated and not amenable to surgery.
- Adjunvant chemotherapy: Chemotherapy used to attack micrometastases following surgery and radiation.
- Neoadjuvant chemotherapy: chemotherapy given prior to surgery to shrink the cancer.
Treatment regimens:
- A given dose of drug destroys a constant fraction of cells.
- The term log kill is used to describe this phenomenon.
1. 1- log kill reduces the number of cancer cells by 90%.
A 2 - log kill by 99%
A 3- log kill by 99.9%
Treatment regimen:
- In bacterial infections, a 3 log reduction in microorganisms may be curative bc the immune system can eradicate residual bacteria
- Tumor cells are not as readily eliminated and additional treatment is required.
Tumor susceptibility and the cell cycle:
- Rapidly dividing cells are more sensitive to anticancer drugs, whereas non prolifeating cells usually survive their effects.
- Human neoplasms that are most susceptible to chemotherapeutic agents are those with a large growth fraction
- Slow- growing tumors with a small growth fraction are often unresponsive to cytotoxic drugs.
Cell cycle specificity of drugs:
- Cell cycle specific drugs: exert their action on cells traversing the cell cycle.
- Cell cycle- nonspecific drugs: ccan kill tumor cells whether they are cycling or resting in the G0 compartment
Cell cycling : S phase and M phase
Cell cycle- specific drugs are ……
more effective in hematologic malignancies and other tumors in which a large proportion of the cells are in the growth fraction.
*Cell cycle nonspecific drugs are useful in low growth fraction solid tumors as well as in high growth fraction tumors
Resistance to cytotoxic drugs:
- Primary resistance: no response to the drug on the first exposure
- Acquired resistance:
1. single drug resistance: due to increased expression of one or more genes
2. multidrug resistance: resistance emerges to several different drugs after exposure to a single agent.
Regarding multidrug resistance:
- mainly due to overexpression of membrane efflux pumps.
- P-glycoprotein is the most important efflux pump responsible for multidrug resistance.
The therapeutic window for chemotherapeutic agent is …..
narrow.
The dose of drug needed to achieve adequate tumor cell kill often causes toxicity to normal tissues.
Chemotherapeutic agents cause a wide variety of toxicities.
Thereby aimed at killing rapidly prolifering cells affects normal cells undergoing rapid proliferation:
Exmaples:4???
- Buccal mucosa: The buccal mucosa is the lining of the cheeks and the back of the lips, inside the mouth where they touch the teeth.
- bone marrow
- GI mucosa
- hair cells
Common AE of chemo (toxicity)
- Severe vomiting
- stomatitis: a general term for an inflamed and sore mouth,
- bone marrow suppression: when fewer blood cells are made in the marrow.
- Alopecia(hair loss)
What is tumor lysis syndrome?
- Due to rapid cell death that follows chemotherapy. Mainly in patients with leukemia or lymphoma.
- manifestation: hyperuricemia
- hyperkalemia
- hyperphosphatemia
- hypocalcemia (due to precipitation of calcium phosphate)
- uric acid and calcium phosphate crystals may precipitate in the kidney and lead to renal failure.
common adverse effects: myelosuppression
Cytarabine Alkylating agents doxorubicin Daunorubicin Vinblastine
- high myelosuppresion
Common AE : emetogeneic potential like vomiting, retching.
Cisplatin mechloretamine cyclophosphamide carmustine dacarbazine
Doxorubicin &daunorubicin
cardiotoxicity
Cyclophosphamide &ifosfamide
hemorrhagic cystitis
Cisplatin
nephrotoxicity, ototxicity, peripheral neuropathy
bleomycin &busulfan
pulmonary fibrosis
Vincristine &paclitaxel
peripheral neuropathy
Asparaginase
hypersensitivity
Reduces the chemotherapy -induced nausea and vomiting
5-HT, Nk-1 antagonist, and desamethasone
Rescues bone marrow from methotrexate
Leucovorin
Reduces hemorrhagic cystitis caused by cyclophospamide and ifofasmide
Mesna
Reduces anthracycline induced cardiotoxicity
Dexrazoxane
Reverse neutropenia
Filgrastin &Sargramostin
Reverse anemia
Erythropoietin
Reverse throbocytopenia
IL-11
Reduces renal toxicity caused by cisplatin.
Amifostine
prevent hyperuriceia of tumor lysis syndrome
Allopurinol or rasburicase
5-Ht3 antagonist:
Ondansetron
NK-1 antagonist:
Aprepitant
Coricosteroid
dexamethasone
Adjunt therapy:
Benozodiazepines.
Most antineoplastic agents are ….
mutagen (anything cause mutation)
- neoplasm may arise 10 or more years after the originial cancer was cured
- Treatment- induced neoplasms are especially a problem after therapy with alkylaing agents.
- Antimetabolites:
targets pathways related to nucleotide and nucleic acid synthesis.
- They are cycle -specific
- Maximal cytotoxic effects are in the S-phase.
S phase dna replication
folate analogs of antimetabolites:
methotrexate
- structurally related to folate
Methotrexate : inhbits…
dihydrofolate reductase
- the cell is deprived of folate
Methotrexate makes DTMP and purine nucleotides
decrease and consequently , synthesis of DNA and RNA and protein decreases- cell death.
Methotrexate undergoes conversion to a series of
polyglutamates
-the process is catlyzed by the enzyme folylpolyglutamate synthase
AE of methotrexate:
- common: stomatitis, mucositis, myelosuppression,
- renal damage
- hepatic fibrosis and cirrhosis
- pneumonitis
- neurologic toxicities.
Leucovorin :
N-formyl THF.
Antidote to drugs that decreases levels of folic acid, such as methotrexate, to rescue the bone marrow.
Leucovorin provides the normal tissue with the reduced folate, thus circumventing the inhibiton of DHFR.
The reason why leucovorin selectively resuces normal but not malignant cells is incompletely understood.
Antimetabolites: Purine analogs:
- 6- mercaptopurine
- 6-thioguanine
Info of 6- mercaptopurine:
converted to thio-imp by the salvage pathway enzy, HGPRT
- thio IMP inhibits the first step of the de novo pruine ring biosynthesis.
- Thio IMP also blocks formation of AMP and GMP from IMP.
- dysfunctional RNa and DNA result form incorporation of guanylate analogs.
6- mercaptopurine:
- metabolized to thiouric acid by xanthine oxidase
- If allopurinol is given to reduce hyperuricemia, dose of 6- mercaptopurine must be decreased to avoid accumulation of drug
AE of 6-mercaptopurine:
- nasuea, vomitng ,diarrhea
- bone marrow suppression
- hepatotoxicity
6- thioguanine:
- converted to the nucleotide, which then inhibits purine synthesis and phosphorylation of GMP to GDP.
- it can be incorporated into RNA and DNA.
6-thioguanine
used for acute nonlymphocytic leukemias
Toxicities: hepatocitity, bone marrow suppression, nausea vomitting ,diarrhea
Thiopurines:
6- mercaptopurine and 6-thioguanine are also metabolized by the enzyme thiopurine METHYLTRANSFERASE.
-patient who have weak activigy of TPMT are at increased risk for severe toxicities such as myelosuppression.
Pyrimidine analogs: 5-fluorouracil, cytarabine.
5- Fluorouracil : converted to the deoxyribonucleotide 5- FDUMP.
- inhibits thymidylate synthase: DNa synthesis is inhibited
Thymineless death results
5-fluorouracil:
- thymidylate synthase blocked
- metabolized by dihydropyrimidine dehydrogenase
5- fluorouracil , and leucovorin
- combination is used as chemotherapy for colorectal cancer.
- Therefore, leucovorin potentiates the activity of 5- fluorouracil.
AE of 5- fluorouracil
hand and foot syndrome :: desquamation of the palms and soles (peeling skin)
Cyrarabine:
The incorporated residue inhibits DNA polymerase.
Antitumor antibiotics:
-BInd to DNA through interclation between bases and block synthesis of new rna and dna cause dna strand breakage and interfere with replication.
Anthyracycline:
Doxorubicin and daunorubicin.
Four major mechanisms of anthracylcine:
- inhibits Topoisomerase II
- intercalation in dna with consequent blockage of dna and rna synthesis and strand breakage
- binding to cell membranes to alter fluidity and ion transport
- generation of free radicals
AE of anthyraclcine:
- cardiotoxicity,
myelosuppresssion
cardiotoxicity relieved by dexrazoxane
Bleomycin:
Cell cycle specific, arrest cells in G2 phase
AE of belomycin:
pulmonary fibrosis
pulmonary toxicity
Alkylating agents:
alkylating of DNA is what leads to cell death.
Alkylating agents:
- toxicities occur particularly in rapidly growing tissues like the bone marrow, GI tract, and gonands
- nausea and vomiting are common
- alkylating agents are mutagenic and carcinogenic
- cyclophosphamide is the most widely used
Alkylating agents: nitrogen mustards:
- mechlorethamine
- cyclophosphamide
- ifosfamide
- melphalan
Mechlorethamine:
powerful vesicant : skin irritation. blisters. only given IV>
AE of mechlorethamine:
- severe nausea and vomiting
- severe bone marrow depression
- alopecia
- immunosuppression
Cyclohphosphamide:
- activated by CYP2B
- Can be given orally or IV.
- broad clinical spectrum
- alkylating agent
AE of cyclophosphamide:
- hemorrhagic cystitis
relieved the symptoms by mesna, - Acrolein , a metabolite of cyclophosphamide is responsible for the hemorrhagic cystitis
Ifosfamide:
- similar toxicity profile to cyclophosphamide
- high dose regimen: severe neuroligical toxicity, including hallucination, coma and death
Melphalan:
- AE: bone marrow suppression
Nitrosoureas: carmustine and lomustine:
- very lipophilic
- cross the blood brain barrier
useful in treatment of brain tumours
Other alkylating agents:
- busulfan
- dacarbazine
- procarbazine
Bulsulfan :
myelosuppression is the main toxicity
- may cause pulmonary fibrosis
dacarbazine:
- Given IV.
- acts as methlyating agent after activation in the liver
procarbazine:
Convereted by liver p 450 enzymes to alkylating metabolities.
- AE: bone marrow depression
- weak MAO inhibitor: hypertensive reactions may result if given with sympathomimetic agents, or tyramine containing foods.
- disulfiram like reactions.
Platinum coordination complexes: cisplatin and carboplatin
Inhibit DNA synthesis and bind DNA through formation of cross links.
GIVen IV.
AE of cisplatin:
- nausea and vomiting
- ototoxicity
- peripheral neuropathy
- nephorotoxicity
- Amifostine is releif for ae of cisplatin
AE of carboplatin:
Dose limiting toxicity is myelosuppression
microtubule inhibitors:
microtubules have a critical role in mitosis which makes them important targets for cancer therapy.
Vinca alkaloids: vincristine and vinblastine,
- Vinca alkaloids bind to beta tubulin and inhibit its abillity to polymerize into microtubules.
- this results in mitotitc arrest in metaphase
- cell division stops and cells die by apoptosis
AE of vincristine and vinblastine?
1. Vincristine: peripheral neuropathy. Bone marrow depression is mild. -alopecia 2. Vinblastine: Myelosuppression is the doselimiting adverse effect. Peripheral neuropathy. Alopecia
Paclitaxel?
- paclitaxel is an alkaloid derived from the bark of the PAcific yew
Taxane MOA:
Stabilizing agent
- Taxanes bind to the beta-tubulin subunit of microtubules and promote microtubule polymerization.
- stabilization of the microtubules in a polymerized sate arrest cells in mitosis and leads to apoptosis
AE of taxane: paclitaxel:
Hypersensitivity, myelosuppression, peripheral neuropathy, alopecia
-Hypersensitivity is reduced by premedication with dexamethasone, diphenhydramine and an H2 blockers.
EPipophyllotoxins:etoposide
- inhibits Topoisomerase II
resulting in dna damage through strand breakage.
-blocks cell in late S- g2 phase.
AE of etoposide: nausea, vomiting, alopecia, myelosuppression
Camptothecins: topotecan, irinotecan
Inhibits topoisomerase I , inhibition results in DNA damage
- Myelosuppression and diarrhea are the two main common advese Effect.
hormonal agents: glucocoricoids, estrogen inhibitors, and androgen inhibitors.
- Glucocoricoid: prednisone: - glucocorticoids are lympholytic and suppress mitosis in lymphocytes. They are used for acute leukemia and malignant lymphomas.
Estrogen inhibitors: Selective estrogen receoptor modulators:
Tamoxifen and raloxifene.
- SERM s binds to estrogen receptor and act as agonists or antagonis depending on the itssue,
Tamoxifen:
- an antagonist on breast tissue
an agonist in nonbreast tissue - metabolized by CYP2D6 to a more potent SERM.
- Strong inhibitors of CYP2D6 should be avoided.
- Metastatic breast cancer in women and men
- preventive agent in women at risk for breast cancer.
AE of tamoxifen:
- hot falshes, nausea, vomitng fluid retention
- vaginal bleeding.
- venous thromboembolism
- increase incidnce of endometrical cancer.
Strong inhibitors of CYP2D6
Bupropion, fluoxetine, paroxetine.
Raloxifene:
- raloxifene is an antiestwrogen in uterus and breast, while promoting estrogenic effects in the bone to inhibt resorption.
- treamtent and prevention of osteoporosis in postmenonpausal women
- Prophlyaxis of breast cancer in high risk polymenopasual women.
AE of raloxifene:
- hot flashes, leg cramps, venous thromembolism.
Estrogen antagonist:
- fulvestrant is devoid of estrogen agonist activity
- fluvestrant binds to the estrogen receptor inhibits its dimerization and increases its degradation.
- treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with diease progression following antiestrogen therapy.
- second line!!
Aromatase inhibitors:
aromatase converts androstenedione to estrone
- in postmenopausal women, this conversion is the primary source of circulating estrogen
- Aromatase inhibitors are the standard of care for adjuvant treatment of postmenopausal women with hormone receptor positive breast cancer.
Aromatase inhbitors: - anastrozole, letrozole
Exemestane:
- nonsteroridal
- reversible competitive inhibitors of aromatase
- irreversible inhibitor of aromatase
Gonadotropin releasing hormone agonists:
- Goserelin,
leuprolide, - gonadotropin-releasing hormone.
- when given continuously or as a depot preparation , they cause an initial surge in LH and FSH levels, resulting in a transient increase in circulating gonadal steroids followed by inhibition of gonadotrpin release
- Result in reversible suppression of ovarian and testicular steroidogenesis
- the flare phenomenon can be counteracted with flutamide.
Gonadotropin releasing hormone agonist: goserelin , leuprolide.
Testeosterone levels fall to 1-% of their inital values after a month with GnRH analogs
-The flare phenomenon can be counteracted with flutamide
Use of GRHA:
- adavanced carcinoma of the prostate, alone or in combination with flutamide
- advanced breast cancer in premenopausal women
- management of endometriosis.
What is flutamide:
,metabolized to an active metabolite that acts as a competitive antagonist at the androgen receptor, preventing its translocation to the nucleus.
What is receptor tyrosine kinases:
mutation that constitutively activae protein tyrosine kinases are implicated in malignant transformation
- therefore, protein tyrosine kinases are targets for cancer therapy.
What is trastuzumab:
Breast cancer with HER2 overexpresssion
- monoclonal antibody against Her2
Tyrosine kinase inhibitors; monoclonal antibodies:
- getfitinib
- erlotinib
- lapatinib
- imatinib
- trastuzumab
- bevacizumab
clinical use of tyrosine kinase inhibitors:
- Getfitinib: nonsmall cell lung cancer
- Erlotinb: nonsmall cell lung cancer pancreatic cancer
- Lapatinib: breast cancer with HER2 overexpression (2nd line
- Imatinib: ph chrnonic myleoid leukemia
Ph +acute lymohoblastic leukemia
myelodysplatic/myeloprliferative diseases - trastuzumab: breast cancer with HER2 overexpression
- Bevacizumab: metastic colorectal cancer nonsmapp cell
What is asparaginase:
asparaginase hydrolyzes serum asparagine, depriving these cells of the asparagine necessary for protein synthesis, leading to cell death
- AE of asparaginase: hypersensitivity
decrease in clotting factors
liver abnormalities,
pancreatitis,seizures, coma due to ammonia toxcity.
What is hydroxyurea>
- inhibits ribonucleotide reductase
- this leads to depletion of deoxynucleotide triphosphate pools.
Killed cells in S phase. - given orally
Interferons alpha
- approved for hair cell leukemia, chronic myelogenous leukmeia, malignant melanoma and kaposi sarcoma
Key drugs of choice for cancer:
- brain = lomustine, carmustine
- Breast: hormone receptor postive= aromatase inhibitor, tamoxifen, fluvesrant, GnRh agonist,,
- Breast: overexpression HER2: trastuzumab
- prostate: GnRh agonist flutamide
- OVarian: cisplatin
- Testicular: cisplatin
- Lung: cisplatin
- colorectal: fluoruracil leucovorin
