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Classification of Chemo Classification of Chemo Therapeutics adverse reaction

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Classification of Chemo Classification of Chemo Therapeutics adverse reaction Powered By Docstoc
					            Classification of Chemo-Therapeutics
                                1- Anti-metabolites
Cell cycle phase specific
Resemble naturally occuring metabolite as pyrimidine bases (C,G, u); purine bases
(A,G) and folic acid
Either form non functional DNA, or inhibit enzymes involved in DNA Synthesis

   A- Flourinated pyrimidines or pyrmidines anti-metabolites (5- FU)

Class: pyrimidine anti-metabolite
Mechanism: 5-FU (pro-drug) is a flourinated analogue of naturally occuring pyrimidine




   B- CYTIDINE ANALOGUES (Ara-C or cytosine arabinosides or cytarabine)

Class: pyrimidine anti-metabolite
Mechanism: mainly affect DNA synthesis
USES : ANLL, lymphoma, intraperotenial for ovarian cancer
TOX. : Myelosuppression , alopecia,N, High dosese: CNS, ocular,hepatic, pulmonary,
       dermatologic

   C- PURINE ANTIMETABOLITE (6-MP & 6-TG)

Class: Purine anti-metabolite
Mechanism: real mech is unknown but




USES : 6-MP+ METHOTROXATE ARE USED FOR ALL
       6-TG USED FOR ANLL

TOX : ORAL DOSES PROVOKE MILD BM SUPRESSION
       CHRONIC USE PROVOKES HEPATIC INJURY

   D- CLADRIBINE (2- chlorodeoxyadenosine or 2CDA)

Class: Purine anti-metabolite recently discovered
Mechanism:
USES : HCL (Hairy Cell Lymphoma) and lymphoid malignancies
TOX. :The dose limiting toxicity is MYELOSUPRESSION

   E- FOLATE ANTAGONISTS (METHOTROXATE = MTX)

General principle:




NOTES: LEUCOVORIN RESCUE or thymidine rescue (but less pentration to cells)
LEUCOVORIN IS A FOLINIC ACID OR THF (reduced folate) used exogenously to
minimize MTX toxicity

uses : solid tumor and hematologic malagenecies with 6 MP IN ALL

Toxicity : Mucositis & myelosuppression
       Major organ toxicity: CNS, hepatic, pulmonary , renal and neurological damage
       Mild N, photosensitivity, hypersensitivity that can proceed to anaphylaxis
        Teratogenic

Body surface area (BSA) in calculating chemotherapy doses as it correlates with
C.O.P which determines renal & hepatic blood flow and thus affects drug elimination
Ex: a recommonded I.V loading dose of MXT for TTT OF ALL is 200 mg /m2 for a
ped patient, what would be the loading dose for an 8 y old whose BSA is 0.89 m2

N.B: generally Folic acid metabolism is affected by MXT? Trimethoprime,
     sulfonamides, pyrimethamine
                 2- PLANT ALKALOIDS (Cell cycle phase specific)

   A- VINCRISTINE & VINBLASTINE (VINCA ALKALOIDS)

PRINCIPle & MECHANISM:




In short ; vinca alkaloids disrupt the normal balance between (assembly &
          disassembly) so the net result is the inhibition of assembly

uses : Vincristine : Hematologic neoplasm (lymphoma) but has limited activity against
                    solid tumors
       Vinblastine: Lymphoma most particularly as a component of Hodgkin’s
                     disease regimen ABVD
             1ST LINE AGENT FOR BLADDER, TESTICULAR CANCERS

Toxicity : VINCRISTINE: Neurotoxicity (cross BBB) but not myelosuppressive
           (advantage)
           Vinblastine : myelosupression but not neurotoxic (the contrary)To
minimize the risk of neurotoxicity , vincristine should be given in a doses up to 2 mg
Added toxicity occurs for patients stabilised on INH or cis platin

   B- ETOPOSIDE (VP-16) & TENIPOSIDE (VM-26)

       TENIOPSIDE & ETOPOSIDE ARE SEMI-SYNTHETIC DERIVATIVES OF
                         PODOPHYLLIN TOXINs

PRINCIPLE & MECHANISM:
NOTES : ETOPOSIDE HAS LOW SOLUBILITY SO IT IS USED AS ETOPOSIDE
PHOSPHATE WHICH IS WATER SOLUBLE DERIVATIVE THAT RAPIDLY
CONVERTED INTO ETOPOSIDE
IT ALLOWS BOLUS DOSING AT HIGHER DRUG CONC AND PERMITS ALSO GOOD
ORAL BIOAVAILABILITY

uses : Hematologic neoplasm (leukemia),solid tumors, lung cancer, testicular
carcinoma, non hodgkin’s lymphoma
in high doses have a value as preperative therapy before bone marrow transplantation

Toxicity :Myelosuppression ,Mild N & V
          ALOPECIA AND MUCOSITIS ONLY AT HIGH DOSES

   C- TAXOLS OR TAXOIDS (PACLITAXEL &DOCETAXEL)

Paclitaxel was Isolatet from the bark of the pacific Yew tree ( rare) so
developement of semi or synthetic drug was hindered by inadequate natural source
supply that aids in understanding of biosynthetic pathway of this agents

PRINCIPLE & MECHANISM:




NOTES : VINCA ALKALOIDS INTERFER WITH ASSEMBLY OF MICROTUBULES
        TAXOLS INTERFER WITH DISASSEMBLY OF MICROTUBULES

USES : OVARIAN CANCERS AND BREAST CANCERS

Toxicity :Myelosuppression particularly neutropenia
            NO or Mild N & V
           TOTAL ALOPECIA AND MUCOSITIS
             3- ALKYLATING AGENTS (cell cycle phase non pecific)

THE MOST OLDEST AND THE MOST USEFUL ANTI6NEOPLASTIC AGENTS , they
                    are cell cycle phase non pecific



MECHANISM:




MEMBERS :1- NITROGEN MUSTARD DERIVATIVES
            MECHLORETHAMINE: only for Hodgkin’s lymphoma
            MELPHALAN: breast and ovarian cancers
            CHLORAMBUCIL: chronic lymphocytic leukemia
            CYCLOPHOSPHAMIDES: braod spectrum anti-neoplastic against
         leukemia, lymphoma, solid cancers specially breast, ovarian, sarcoma,

           2- NITROSOUREA ( act on G0 & G1)
             THEY PENTERATE CNS SO IT CAN BE USED FOR PRIMARY BRAIN
            TUMOR (CARMUSTIN, LOMUSTIN & STREPTAZOCIN)

          3- OTHERS ASTHIOTEPA, BUSULPHAN, PROCARBAZINE,
             DACARBAZINE (cell cycle non specific)

TOX.: carcinogens, mutagens, teratogens and myelosuppressive
   4- ANTHRACENES OR ANTHRACYCLINES (cell cycle phase non specific)

 THE MOSTWIDELY USED AND COMPLETELY UNDERSTOOD IS DOXORUBICIN
                         (ADRIAMYCIN)
      OTHER MEMBERS : DAUNORUBICIN, IDARUBICIN, EPIRUBICIN




MECHANISM:




USES : ONE OF THE MOST ACTIVE SINGLE AGENT USED FOR BREAST CANCER
       SARCOMA, GIT TUMORS ,BLADDER CANCERS,LUNG CANCERS
       H & non H lymphoma and CAN BE USED IN COMBINATION (ABVD)

TOX.:
*IN SHORT TERM : MYELOSUPRESSION, N, V ALOPECIA& MUCOSITIS§
*CARDIAC TOXICITY AT HIGH DOSES (TOTAL MAX DOSE IS 750 mg) TO
 AVOID CARDIO-TOXICITY
*EXTRAVASATION INJURY
                     5- ANTI-TUMOR ANTIBIOTICS

      SOURCE: BACTERIAL FERMENTATION SO CALLED ANTIBIOTICS




              6- HEAVY METALS (cell cycle phase non specific)




N.B: Added nephrtoxicity is common when FOSCARNET, ETHACRINIC ACID,
    AMPHOTIRICIN are used wih nephrotoxic chemotherapeutic agents
  7- MISCELLANOUS AGENTS (cell cycle phase specific)




8- BIOLOGIC RESPONSE MODIFIERS (2ND LINE THERAPY)
                             Regarding to angiogenesis

 CD146 Ab is discovered in 2004, as anti-angiogenic anticancer agent,
 it acts by blocking the action of CD146, a protein molecule originated from

  endothelial cells that plays a role in angiogenesis,
 on of the most important application of CD146 is the implication of human umblical

 cord endothelial cells in TTT of peripheral, cerebral and myocardial ischemia

                             9- ENDOCRINE THERAPY




ADVANTAGES : EFFECTIVE THERAPY
             THE LEAST TOXIC ANTICANCER DRUG
             MAJOR ORGAN TOX IS UNCOMMON
            Patient receiving tamoxifen should be instructed about hot flushing



                             10- CORTICOSTEROIDS

USEFUL AS ANTICANCER BECAUSE THEY HAVE LYMPHOCYTOTOXIC EFFECT
                (INHIBIT LYMPHOCYTES PROLIFERATION)
 SO USED IN TTT OF HEMATOLOGIC CANCERS INVOLVING LYMPHOCYTES AS
                           LYMPHOMA & ALL
   Summary on the implication of chemotherapeutcs

 ARA-C & 6-TG for ANLL
 6 –MP + MXT & L-ASPARGUNASE FOR ALL

 DACT & INTERFERON 2 & ‫ل‬CDA FOR HCL

 MECHLOROETHAMINE, MXT, ETOPOSOIDES, 2CDA, TENIPOSIDE &

  VINCRISTINE FOR LYMPHOMA OR NON HODGIKN’S LYMPHOMA
 MECHLORETHAMINE LONELY & VINBLASTINE AS A COMBINATION OF ABVD

 SYSTEM FOR HODGIKN’S LYMPHOMA BLEOMYCIN & DOXORUBICIN FOR H & N
 H LYMPHOMA
 CIS-PLATIN, INF & ‫ل‬ALDUSLEUKIN FOR MELANOMA

 NITROSOUREA & CIS PLATIN FOR BRAIN TUMOR

5FU (regional delivery), INTERLEUKIN & LEVAMISOLE (adjuvant therapy) FOR

 COLORECTAL CANCER
TAXOIDS, ARA-C (I.P), MELPHALAN, CIS-PLATIN,CYCLOPHOSPHAMIDE FOR

 OVARIAN CANCERS
TAXOIDS, MELEPHALAN, CYCLOPHOSPHAMIDE BREAST CANCER

CIS PLATIN & VINBLASTINE (FIRST LINE AGENT ), ETOPOSIDE,

 DOXORUBICIN, FOR TESTICULAR CANCERS
 CIS PLATIN & VINBLASTINE (FIRST LINE AGENT ), DOXORUBICI FOR

 BLADDER CANCER
 ACTINOMYCIN & MXT FOR PEDIATRIC TUMOR

 DOXORUBICIN FOR LUNG CANCER

BLEOMYCIN & INF ‫ل‬FOR KAPOSI’S SARCOMA

ALDUSLEUKIN FOR RENAL CANCER

5FU FOR HEPATIC CANCER



Remarks on adverse reaction of chemotherapeutics

Ocular toxicity 5FU ,ARA-C (high doses)
Hepatic tox: ARA-C (high doses), 6MP, 6TG (chronic use), levamisole (mild,
             reversibble)
Plmonary tox : ARA-C (high doses), Bleomycin
Teratogenicity: MXT, alkylating agents
Major organ tox: MXT, ARA-C
Neurotoxicity: VINCRISTINE (doses more than 2mg), cis- platin, carboplatin
Hematological toxicity: taxols (Neutropenia), carboplatin, IL2
(thrombocytopenia,anaemia), levamisole (grnulocytopenia but rare in 10% of cases)
Carcinogenesis and mutagens: cyclophosphamides, other alkylating agents
Cardiotoxicity: anthracyclines as doxirubici and other members (max dose 750mg)
Dermatological tox: bleomycin, L-asparginase (hypersensitivty reaction)
Nephrotoxicity : cis platin and carboplatin (but less than cis-platin), IL2
Ototoxicity: cis platin and carboplatin (but less than cis platin)
Extravasation ; see extravasation part
N & V ; See treatment of N & V
Mucositis : see mucositis

                                CANCER PREVENTION

* DIET :
Although, controversy exists over the role of dietary factors in carcinogenesis , some
generl associations have been observed;
1- Consumption of high fat diet appears to increase the risk of breast, colo-rectal
and prostate cancers
2- A decrease of fat intake to less than 30% of daily calories may decrease the risk
of cancer developement
3- A high alcohol intake has shown to incease the risk of many upper aerodigestive
tract malagnencies specially in smokers
* TOBACCO :
More than 90 % of all cases of lung cancer are diagnosed in smokers
Passive inhalation of ex-haled tobacco by-products and cigaratte smoke represents
signifcant risk factor for lung cancer in non smoking population (passive smokers)

                                   SUN EXPOSURE:
              Melanoma and skin cancer can be largely prevented by :
1- Minimizing exposure to the sun
2- Applying strong sun screen and sun-blocks containing SPF 15 or 30
SPF 30 gives maximal protection, any benfit from using SPF above 30 considered
negligible
 Protection duration = nomber of SPF X Time of exposure to sun
 The maximal protection for a person who needs to take a sun path for 10 min and
uses SPF 15 is 150 min, so this person can stay out in the sun15 times more longer
 An adequate amount should be applied repeatedly as it can wash off by sweating,
swimming, toweling off, washing, showering
 not indicated for children less than 6 monts? Immature metabolic and excretory
functions
3- Most sun blockers Block either UVA or UVB radiation only (not block both) except
those preprations that contain titanum oxide can block both radiations
Octylmethoxycinnamate blocks UVB
Homosalate blocks UVB
Padimate O blocks UVB
Avobenzone blocks UVA
4- Systemic sun screen ( Chloroquine phosphate; Dagrinol or Alexoquin)
 CHEMO-PREVENTION:
• It means the systemic use of natural or synthetic products to reverse, supress, or

  prevent carcinogenesis
• These products include :
1- Beta- carotenes or vitamin A ( 5000- IOOO0 IU)
2- Ascorbic acid (vit C 1 gm daily)
3- Tocopherol (vit E 400 – 800 IU)
4-Tamoxifen (tamofin, Nolvadex ) blocks the stimulatory effect of estrogen in
    breast cancer
it is mainly anti-estrogenic so can be used for chemo-prevention of breast cancer
(estrogen dependendant)
It is a hormonal therapy so, it has tolerable side effects Further investigation is
necessary to answer the 4 W QUESTIONS: (Who, when, what and what)
5- 5- alpha reductase inhibitor finasteride ( androcure) which inhibit the conversion
of testosterone to its active form dihydro-tesosterone so can be used for prostate
cancer prevention




                       GENERAL SUPPORTIVE CARE ISSUES

•Treament of cancer by anticancers is complicated by the incidence of serious
  toxicitis because anticancerous drugs are non differentiating
•Many of these toxicities involve rapidly differentiating cells? Such as BM
(myelosupression), intestinal mucosa (mucositis,N,V), hair follicules (alopecia),
•In addition, anticancers can provoke secondry cancer, infertility,
 So, We must be aware by these toxicities and must take also in consideration pain
 management and nutritional supprt although they are not specifically the result of
 drug induced toxicity (pain and loss of appetite together with the one of seven
 creteria help in preliminary diagnosis of cancer)



                               A- Myelosuppression

*BMS dose not occurs immediately after chemotherapy treatment ?

*WBCs (granulocytes, leucocytes) are most significantly affected? as they are
 rapidly proliferating and have short life span (6-12h) then platelet (life span 5-10
 days) and RBCs are the least affected (life span 3 months)
*Lowest blood cell count (usual nadirs) occurs two weeks after chemotherapy with
recovery by three to four weeks




TO AVOID MYELOSUPRESSION
•

courses of anti-neoplastic must be planned

Courses may be delayed for the granulocytes count to return to normal

For safely recieving another cycle of chemotherapy a WBC count of 3000/mm3 or

 granulocytes or neutrophil count of 1500 /mm3 and a platelet count of
 100,000/mm3 are usually required

IF UNDESIRABLE MYELOSUPRESSION HAS OCCURED
*The doses must be reduce and the magnitude of dose reduction depends on the
 degree of myelosupression but this may comprimize anti-tumor activity
* It is necessary to stop anti-neoplastics if WBCs count is less than 3000/mm3 and
  if platelet count is less than 100,000/mm3

                                 B- NEUTROPENIA

•It means a decrease of neutrophils count below to 500 cell/mm3
•Neutrophils are very important for immune system
•The duration of neutropenia is directly proportional to the risk of infection
•So neutropenia involves high risk of infection
•The diagnosis of infection in neutropenic patient is difficult and complicated
 because:
   usual signs & symptoms of infection (pus,abcess, infiltrates on chest x rays )
   depends on the presence of WBCs
   so the only reliable indication of infection in neutropenic patient is fever
  *Treatment of infection in febrile neutropenic patient involves broad spectrum
   antibiotic
     This antibiotic should be used on the basis of
1- Microbial covearge of most likely organisms,
2- Patient’s signs and symptoms if present ,
3- Side effects profile,
4- and cost


                         •TREATMENT      OF NEUTROPENIA

•Colony  Stimulating Factors (CSFs)
G-CSF : affects neutrophils
GM-CSF: affects neutrophils, monocytes & macrophages
MOA:
These hormones are naturally occuring cytokines glycoproteins which are essential

for the normal growth and maturation of of blood cell components (neutrophilis,
monocytes, macrophages, granulocytes)
 So they reduce the incidence, magnitude, and duration of neutropenia,    following
chemotherapy and subsequently prevent infection in cancerous patient .
 Cloning the gens for thr CSFs results in recombinant forms of these hormones :

1- Filgrastim is the synthetic form of G-CSF
2- Sargrmostim is the synthetic form of GM-CSF
ACTION:
When administered in patient with BMS an increase in WBCs occurs within 7-14 days
When administered in patient with normal BM an increase in WBCs occurs within 2-3
days
INDICATION:
1- patient with primary BMS( following chemotherapy & BM transplantation), these
agents can be used for short term
2- in patient with aplastic anaemia
ADMINSTRATION: I.V or S.C.
ADVERSE REACTION: Filgrastim : bone pain, splenomegaly, hyperurecimia
                            Sargramostim: pleural and pericardial effusion


                                  B- ANAEMIA

It is a common finding in cancerous patients , it may develops inciduously, can be
corrected by erythropiotein, it is not always due to chemotherapy? As there are
many other factors
Contributing factors:
1- anaemia of chronic disease
2- chronic GIT blodd loss
3- chemo & radio therapy
4- BM invasion by tumor
Manifistation:
 Generalized fatigue due to decrease Hb &RBCs with subsequent decrease in oxygen
 carrying capacity

Treatment: RBCs transfusion (remedy for short duration as it dosn’t treat BMS)
               Recominant erythropoietin that stimulates RBCs formation
ERYTHROPOIETIN: (Epoetin-α or Epogen)It is a glycoprotein hormone produced by
kidney and released in response to hypoxemia
It is a primary regulator of erythropoiesis
It stimulates proliferation of immature erythroid progenitor cells that give rise
marrow normoblasts, the precursor for mature red blood cells
It can be produced by recombinant DNA technology as 165 aa glycoprotein
Antibodies to biotch erythropoietin have not been detected
It is administered I.V. or S.C because it broken down in GIT
Its half life is 5-12 hours when administered I.V.
Its PK paramarters are not affected by dialysis
USES: is not recommonded for patients requiring immediate correction of severe
        anaemia
       aneamia associated with chronic renal failure for patients on & off dialysis
       anaemia after chemotherapy
       anaemia associated with AIDS for patients stabilised on zidovudine but only
       for those with low endogenous erythropoietin level


                           C- THROMBOCYTOPENIA

It is a decrease in platelet count so it is associated with high risk of bleeding
Treatment:
             Platelet transfusion (remedy for short duration as it dosn’t treat BMS)
              some CSFs for throbocytes are under investigation (thrombopoietin)

                                    E- ALOPECIA
Non life-threatening adverse reaction
It is temporary (reversible)
The degree of hair falls vary widely (depends on type of chemotherapy & dose)
Hair loss begins 1-2 weeks after chemotherapy
Hair regrowth may occur before the chemotherapy ‘courses are completed or after
stopping drugs


                    F- GONDAL TOXICITY OR INFERTILITY

Non life-threatening adverse reaction and dosn’t require much attention because it
may not occur
in addition it is a dose depenant ( high doses long tem combination therapy may
produce Infertility)
It considered risky at young age
In men anti-tumors provoke oligospermia and azospermia
Antitumors may hinder ovulation in women at young age recieving combination chemo-
therapy
For gonadl toxicity we must consider the following variables
1- Age
2- Duration of chemotherapy, type of drug , combination chemotherapy
    In general combined therapy has long lasting adverse reaction than single agent

                              G-     2RY MALIGNANCIES

Secondry cnacer may be induced by cheomtherapy and radio-therapy
Many types of solid tumors have been reported as chemotherpy induced malignancies
ANLL accounts for more than of 50% of 2ry cancers
The gruop of antineoplastic agents associated with 2ry cancers are alkylating agents
& etoposide



                                    H- MUCOSITIS

It is an inflammation of intestinal mucosa due to its susptibility to chemotherapy
induced toxicity (as it has high mitotic index and rapid turnover rate)
Agents most commonly associated with mucositis are 5FU & MTX
Symptoms
Painful ulceration
Local infection due to candida species, and herps simplex are common
Inability to eat & drink due to inflammation of buccal mucosa
Abdominal pain and Mild to life threatening diarrehea due to inflammation of lower
GIT
Treatment
Supportive treament by local or systemic analgesic
Oral hygiene
I.V fluid and electrolytes in case of severe cases associated with diarrhea

                               I-     EXTRAVASATION

*Certain antineoplastiics have the ability to cause severe tissue damage if they
 escape from vasculature
*The most famous drugs that cause extravasation are anthracycline, MMC, DACT,
vinca alkaloid and nitrogen mustard
*Tissue damage may provok pain, infection, and loss of mobility because anticancers
are higly reactive, irritant and usually taken either orally or I.V

*EXTRAVASATION PREVENTION
*Select the vien on the distal portion of the arm
*The drug should be administered slowely through the side arm of the running I.V
 solution half an hour after running of solution
*I.V. infusion but we must use a canulation technique
*Verification of needle stability
**EXTRAVASATION TREATMENT
*Needle is left in place and excess drugs is drawn off with a syring
*Injection with corticosteroids to reduce local inflammation
*Application of ice packs to the affected areas except for vinca alk apply hot pack
 (fibrosis)
*Use of antidotes
*Sod thjosulfate for nitrogen mustard extravasation
*Hyalourindase ( hyalogen) for vinca alkaloids extravasation
*Topical DMSO for anthracyclines and MMC extravasation
*Sodium bicarb for doxorubicin
*Local anaesthetics (ethyl chloride) is not recommonded as they are irritant & can
 cause tissue damage

                       ** TREARTMENT OF CANCER PAIN**

Cancer is accompanied with chronic intractable pain and also associated with
 neuropathic pain
It represents a major problem affecting 30% of racentely diagnosed cancers and

affects 75% of cancer cases in advanced stages that procceds to 100% in terminal
cases
Cancer pain can result from cancer itself, treatment (radiation, vinca alk, steroids)

and from other causes (post herpetic infection)
Cancer and neuropathic pains are characterized by

 Hyperexcitability

 Allodynia (sensation of pain in response to non noxious stimulus)

 Hyperalgesia ( increase pain sensation in response to normally painful stimulus)

Pharmaco-therapy
NSAIDs

Opioids (oral, parentera, topical and or I-Th in the sub-arachnoid space)

Anti-depressants

Anti- convulsant

Bio-therapy by implication of chromaffin cells
             ** TREARTMENT OF CANCER PAIN Anti-depressants**
1- TCAs
* Analgesia occurs with low doses within few days so outcome measurment should be
   initiated one week after treatment
*Effective in treatment of neuropathic and chronic cancers’ pain but some pains rest
  refractory
*Both 3ry amines ( amitriptyline, imipramin, doxepine and clomipramine) and 2ry
amines (nortriptyline and desimpiramine) are equi-potent but 2ry amines have less
sedative and anti-cholinergic effect so they are more perfered in elderly patients
MAO:
They inhibit NE or serotonin reuptake or both
TOX:
 Low thershold of toxicity
CNS: sedation & confusio
CV: hypotension, arrythemia, tachycardia
Anticholinergic adverse effects: (dry mouth, urine retention)
DOSE:
10 mg daily then increased gradually according to condition to 75 mg daily
 Contra-indication: CVD, benign prostate hypertrophy,hepatic disease

2- 2ND GENERATION NON TCAs BUPROPION (WELLBUTRIN)
MAO:
They inhibit NE and Dopamine reuptake
EFFICACY:
Relieving neuropathic pain of different etiology
But not effective in patient with non neuropathic low back pain

3- SNRIs
*VENLAFAXINE (EFFEXOR) & DULOXTINE (CYMBALTA)
*Effective in painful polyneuropathy both diabetic, non diabitic and cancer pain
MAO:
They inhibit NE and Serotonin reuptake
DOSE: 75-150 mg daily
SE: DOSE RELATED INCREASE OF BLOOD PRESSURE & HR
     GIT DISORDERS
     DOSE SHOULD BE REDUCED IN CASE OF RENAL IMPAIREMENT OR
     HEPATIC CIRRHOSISD
CI: concomitant use of SNRIs and MAOI
                                  Anti-convulsants

1- CARBAMZEPINE, PHENYTOIN & VALOPROATE
*Recommonded for neuropathic & cancer pain but not for acute somatic pain
MAO:
* Analgesia is due to blocking of sodium channel and increase of membrane stability
    REMARK: see kinetic, SE & DI

2- CLONAZEPAM
MAO:
* Analgesia is due to increase of γ- aminobutyric acid (GABA) levels and activation
of benzodiazipines receptors with subsequent increase of chloride ion which inhibits
neuronal activity DOSE: 0.5- 2 mg daily

4- GABAPENTIN (Gabtin & Neurontin, Conventin)
*It is the most commonly used as analgesic for neuropathic, diabetic
polyneyropathy,post herptic neurolagia and cancer related pain
*It has a good safety profile (total daily dose may reach to 3200 mg/day)
*It has no significant DI
*It dosn’t metabolised in liver , niether inducernor inhibitor to cytochrome system,
not bound to plasma protins, it is excreted unchanged in urine but some fraction
(20%) excreted in feaces
*Treatment usually starts with 100 mg daily to 4OO mg daily
*Gradual dose titration continues untill benfit occurs
*Most common side effects: dizziness, smonolence, confusion, edema
*Caution should be taken for elderly and patient with renal impairement

5- PREGABALIN ( Lyrica)
*It is a new anticonvulsant that has the same MOA, safety profile, kinetic as
gabapentin
* It is approved in JUNE 2007 as effective therapy for diabetic neuropathy,
postherpetic neuroalgia and for fibromyalgia

6- TIAGABINE
* It is a new GABA reuptake inhibitor,
* it has similar effectivenes as gabapentin but greater efficacy for sleep
  improovement
7- LAMOTRIGINE (Lamictal)
*It is the most commonly used drug for neuropathic, and cancer related neuropathic
pain in a dose dependant manner (50-200 mg day)
*It becomes more effective in high doses
*It provokes dose dependant skin rash

8- LEVETIRACETAM (Keppra), ZONISAMIDE (Zonegran) and OXCARBAZEPINE
(Trileptal)
* Most recently approved
*But they have some unique advese effects as hyponateremia, nephrolithiasis,
glucoma and wt loss
*It should be used only when other anticonvulsants cann’t be used

NOTES
* Trials approved that a 70% reduction in opoid intake withe the administration of
 anticonvulsants as analgesic therapy
*Caution should be taken in using anticonvulsants in women of childbearing age
 (teratogenic)
* antidepressants are considered as first line treatment for neuropathic and for
  cancer related pain before anticonvulsants
*Anticonvulsants has been recommonded as first and second line therapy



                       TREARTMENT OF NAUSEA & VOMITING
*N &V are common in cancer patients
*They are due to multiple factors as tumor itself, metabolic disorders
 (hypercalcemia), infections, drugs, radiotherapy & antineoplastic
*Certains chemotheraputics are emetogenic (CINV), they are classified into four
 four classes according to frequency of emesis (kris 2006)
1- High level 90% : cisplatin, mecloroethamine, streptazocine, cyclophosph > 1500
   mg/m2
2- Moderate level 30- 90% carbopatin, doxorubicin, cytarabine > 1000 mg/m2
3- Low level 10-30% : etoposide, MXT, MMC
4- Minimal level less than 10%: bleomycin, busulphan, vincristine
THEY INDUCE N AND VOMITING BY ACTIVATION OF BRAIN
CHEMOTRIGGER ZONE (CTZ)
* Acute emesis begins3- 6 h after TTT
* Delayed emesis begins 24 h after TTT and subside after 3-5 d
* Patient should be moniotered for at least 5 days to ensure relief of delayed emesis
*Severe N& V may reduce patient tolerance to chemotherapy
TREATMENT STRATEGY
 1- 5 HT3 ANTAGONISTS (dolasteron, granisteron, ondanosteron or zofran,
planosteron)
high level acute emesis a single dose of a 5HT3 antagonist before chemotherapy is
therapeutically equivalent to multi dose regimen and oral administration are often
effective as I.V. ones
It can be used with dexmethasone for high level emesis
SE/ conistpation,headach, diziness, flushing

2- Metoclopramide (Reglan) & prochlorperazine (inapsine)
   In moderate &lower level emesis the cost of 5HT3 is prohibitive and
metoclopramide and prochloroperazine can be used

3- Dexamethazon
    The most extensively used steroid in the treatment of CINV but not used alone
as it is not sufficiently potent, so used to enhance the effect of other agents as
5HT3 antagonist and metochlopramide
    With metochopramide it is useful for delayed emesis
Adjunct anti-emetic drugs is important for the sucessful chemo-therapy

4-Others (THC or Marinol) but not frequently used

Case study
A 45 Y OLD FEMALE PRESENTS WITH OVARIAN CARCINOMA, she is due to
receive a repeated course of carboplatin, and she is suffering from emesis
A- The woman must given anti-emetic just after chemotherapy
B- Ondanosterone and dexamethazone are the DOC
C- Metochopramide and dexamethasone represent the ideal therapy
D-Nausea & vomiting must be moinoitered 5 days after TTT

                       Neuropathic and cancer related pain

Associated with lesions in CNS
Coexist with other classic inflammatory conditions
Allodynia, hyperalgesia

** Pharmacological Treatment

 NSAIs, Opioids
 Anti-epeleptics & anti_depressant
 However these pains rest resistant to pharmacological therapeutic strategy
   so the intension of therapeutic reseach was directed to CELL THERAPY BY
IMPLICATION OF CHRMAFFIN CELLS which derived from medullary part of supra-
                            renal gland (adrenal gland)

                TREARTMENT OF CANCER PAIN (Chromaffin cells )

                          WHY CHROMAFFIN CELLS
1- DIVERSTY OF PRODUCTS SECRETED BY CHROMAFFIN CELLS
*CATECHOLAMINES
*PEPTIDES AS METENKEPHALIN AND LEU-ENKEPHALIN
*DOPAMINE
*Other neuroactive agents
2- NEUROCHEMICAL PLASTICITY
Adrenergic phenotype
Cholinergic phenotype
3- PHARMACOLOGICAL PLASTICITY
CAN BE IMPLICATED FOR
PAIN MANAGEMENT, PARKINOSINISM, ALZAHIEMER AND Depression

                  Source of Chromaffins Cells is adrenal gland




* the adernal gland composed of two parts
1- Cortex
2- Medulla contains chromaffin cells
 Chromaffin cells secret many neuroactive substances (catecholamines,
enkephalines,…….)
 CONCEPT OF CELL THERAPY FOR TTT OF PAIN . IMPLANTATION OF
     CHROMAFFIN CELLS INTO SUBARACHNOID SPACE (CNS)




                       Concept of immuno-isolalation

to avoid rejection and implication of highly toxic immunosuppressant drugs the
                  concept of immuno-isolation was developped

This concept involves microencasulation of chromaffin cells by natural polymer
 (alginate) and poly-L- lysine (PLL) to create an immune protective membrane
                          concept of immuno-isolation




This membrane allows
* Transportation in both directions of the substances having small M wt as neuro-
active substances, nutrients, oxygen
* Immuno-protection of encapsulated cells against immune system and complement
fractions

				
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Description: Classification of Chemo Classification of Chemo Therapeutics adverse reaction