Download Alkylating Agents

Alkylating Agents
Presented by :
Clinical Pharmacist: Heba Sabry,Reem Ahmed,Dina redda,Dalia El-Magraby and Heba
Othman.
Pharm-D 4 (2009)
Group 1.
Alkylating Agents


Contain an alkyl group (highly reactive
chemical group which allow them to form
irreversible covalent bond with other
molecules specially at the cross link of DNA).
In DNA, the N-7 position of guanine is
especially susceptible to alkylation, it
interferes with separation of the strands and
prevent mitosis.
COMMON STRUCTURE
CH2CH2Cl
CH2CH2Cl
or
R N
Ar
N
CH2CH2Cl
CH2CH2Cl
CH2CH2Cl
Ar N
+
CH2CH2
-
Ar
CH2CH2Cl
N
--
Nu
Enzyme, proteins
DNA, RNA
CH2CH2Cl
CH2CH2 Nu
Ar N
CH2CH2Cl
Alkylating Mechanism of
Mechlorethamine With Guanine Base
O
N
HN
NH2
O
HN
+
N
N
Alkylation bischloroethyl group
N
CH2CH2Cl
e.g.
NH2
N
R N
N
CH2CH2Cl
DNA Strand B
N
DNA Strand A
O
1
HN
2
NH2
N7-N7 Biguanyl DNA cross link
6
CH2CH2
5
3 4
N
Cl
N
7
N
DNA Strand A
CH2CH2
Cl N
O
NH
N
DNA Strand B
NH2
1. Attachment of the alkyl groups
to DNA bases.
2-Formation of cross bridges,
bonds between atoms in the DNA.
3-Induction of mispairing of the
nucleotides leading to
mutations.
Classification of alkylating agents
Nitrogen Mustard Nitrosourea
Ethylenamines
Melphalan
Carmustine
Chlorambucil Lomustine
Ifosfamide
Cyclophosphamide
Thiotepa
Alkylsulfonate Triazine
Busulfan
DTIC
Metal
salts
Cisplatin
Carboplatin
Oxatiplatin
Nitrogen Mustard
Cyclophosphamide
Trade
name
Ifosfamide
Endoxan® cytoxan®
Structure
CH2CH2Cl
O
N
P
Holoxane®
N
P
N
CH2CH2Cl
Well absorped orally.
Absorption
Distribution
Widely
BBB
Vd

Metabolism
PPB
O
O
distributed.
Cross.(brain tumour)
0.35-1.2 L/Kg.
10% - 56% minimal.
CH2CH2Cl
N H
CH2CH2Cl
No oral form
Widely
BBB
Vd
PPB
distributed.
Cross.
0.35-0.85 L /Kg.
Negligible.
Prodrugs metabolised by Cytochrome p450 to active metabolites in the
liver (acrolein and phosphoramide mustard which is a potent alkylator) .
(4-OH cyclophosphamide and aldophosphamide)

Elemination Unchanged 25% of oral and IV,
active metabolite 62% in the
urine for 48 hours.
Renally: 70-86%, 61%
unchanged after high dose
(5 gm/m2), 18% unchanged
Metabolism of Ifosfamide
Generation of CAA may explain differing antitumoral activities of IFO and
cyclophosphamide and Suppression of CAA metabolic pathway , although it may
be beneficial as a means of reducing neurotoxic responses, may also be associated
with a reduction in antitumor effect.
Ifosfamide has been shown to require metabolic activation by
microsomal liver enzymes to produce biologically active
metabolites. Activation occurs by hydroxylation at the ring
carbon atom 4 to form the unstable intermediate 4hydroxyifosfamide. This metabolite rapidly degrades to the
stable urinary metabolite 4-ketoifosfamide. Opening of the
ring results in formation of the stable urinary metabolite, 4carboxyifosfamide. These urinary metabolites have not been
found to be cytotoxic. N, N-bis (2-chloroethyl)-phosphoric
acid diamide (ifosphoramide) and acrolein are also found.
Enzymatic oxidation of the chloroethyl side chains and
subsequent dealkylation produces the major urinary
metabolites, dechloroethyl ifosfamide and dechloroethyl
cyclophosphamide. The alkylated metabolites of ifosfamide
have been shown to interact with DNA.

Cyclophosphamide
Dialysis
Dialyzable.
Administer the dose post
hemodialysis.
Ifosfamide
Not dialysable.
IV over 30-60 min, continuous IV
infusion
Administration
•PO. 1 hour before meal .
•IV Push over 3 to 5 min.
•Bolus infusion over 15-30 min, slow
infusion 1-24 hours.
Adverse effects
(Dose related)
•Heamorrhagic cyctitis, Hematuria. .
•Myelosuppression.
•Hyperurecemia.
•Gastrointestinal side effects.
•Pulmonary toxicity (interstitial pneumonitis).
•Nervous system toxicity , and nephrotoxicity with
ifosfamide.(Somnolence, confusion to sever encephalopathy).
Drug interaction
•Microsomal enzyme inducer (phenobarbital , phenytoin)
•Microsomal enzyme inhibitor ( chloramphenicol, chloroquin.)
•Inc. sedative effect of succynylcholine .
•Nephrotoxic drugs eg. Cisplatin
•Cyclophosphamide potentiate cardiac toxicity of anthracyclines.
Cyclophosphamide
Ifosfamide
Indication
Cancer of the bladder, bones, cervix,
endometrium, breast, lungs, prostate,
adrenal cortex, ovaries
Soft tissue sarcomas .
 Thymoma, brain tumour
 Wilms' tumour
Recurrent testicular cancer and
germ cell tumors
Sarcomas (soft-tissue, osteogenic
sarcoma, Ewing's sarcoma)
Non-Hodgkin's lymphoma
Hodgkin's disease
Non-small cell and small cell lung
cancer
Bladder cancer
Head and neck cancer
Cervix cancer
Doses
40-50mg/Kg in divided doses over 2-5 day.
CAF : 500mg/m2
FEC: 600mg/m2
1.2-2.5g/m2 for 3-5 days.
Drug
Reconstitutio Final
n
concentration
Dilution
Cyclophospha
mide 1000 mg
SWI
1000 mg: 50 mL
2000 mg: 100 mL
Signs of melting is
yellowish viscous
liquid.
< 1 g: 100 NS*
> 1 g: 250 NS*
high dose in BMT:
may need 500 NS*
NS,10 D5W, D5NS,
D5-Ringer’s,
Lactated Ringer’s,
Sodium Chloride
0.45%, Sodium
Lactate.
6d in ref, 24h at Rt.
2000 mg
(BMS)
(RT)53
no preservative
20 mg/mL
48 h F, 24 h RT
Ifosfamide
1000 m g
3000 mg
(Baxter)
(RT)
no preservative
1000 mg: 20 mL
SWI109
3000 mg: 60 mL
SWI
shake well
50 mg/mL
48 h F
0.6–20 mg/mL
500–1000 mL*NS,
D5W, D5-NS,
D5-1/2NS, Lactated
Ringer’s
72h. In ref.
24 h F, RT when
mixed with mesna10
D5W or Lactated
Ringer’s when mixed
Prophylaxis against hemorrhagic
cystitis




Against hemorrhagic cystitis, hyperhydration and mesna given. IV
dose of mesna is 20% given at 0, 4, 8 hours or (1mg/mg drug). May be
given orally at 4, 8 hours at 40% of the drug dose diluted in water or
juice.
Patients are encouraged to:
- drink plenty of water ( fluids) during therapy( most
adults
will require at least 2L/day ) .
-Void frequently .
- Avoid taking the drug at night .
Mesna react with acrolein and urotoxic metabolites to form nontoxic
metabolites .
Oral absorption of mesna is 50% bioavailability so oral dose should be
double that of IV dose.
Mesna
Upon entering the bloodstream mesna is immediately converted to an
inactive disulfide form, dimesna (dithiodiethanesulfate) which is
subsequently filtered and secreted by the kidneys, where the enzymes thiol
transferase and glutathione reductase reduce dimesna back to mesna.
The free sulfhydryl (thiol) groups of mesna combine directly with a
double bond of acrolein and with other urotoxic 4droxyoxazaphosphorine metabolites (4-hydroxycyclophosphamide and
4-hydroxyifosfamide) to form stable nontoxic compounds. The
metabolite acrolein has been implicated as the major
causative agent in oxazaphosphorine-induced urothelial toxicity
Chlorambucil
Trade name
Leukeran®
2 mg tab.
Uses
CLL , Hodgkin and non Hodgkin
lymphomas
,other uses as Behcet syndrome
,nephrotic syndrom and
autoimmune haemolytic anemia.
Doses
0.1-0.2 mg/kg /day.
Absorption
Rapid and complete .
Melphalan
Alkeran® either 2 mg tab . or 50
mg vial
Multiple myeloma,ovarian
cancer,
breast cancer,melanoma, certain
sarcomas,preperative BMT
regimens and other uses as
amyloidosis.
Oral: 0.1-0.5 mg/kg/day (duration
and interval according to the
indication).
IV: 10-140 mg /m2:
Oral: Incomplete and variable
food reduces the
absorption
(spacing).
Distribution
Widely distributed.
Vd
0.14-0.24L/Kg
PPB
99%
Widely distributed.
Vd
0.5-0.6L/Kg ,
PPB
60- 90%
Metabolism
Hepatic microsomal enzyme
oxidation.
Active metabolite : phenylacetic
acid mustard.
In plasma through hydrolysis to
mono,dihydroxy products
Chlorambucil
Melphalan
Renally excreted.
Elimination
Urinary excretion is low.
If BUN = 30 mg/dl or more :50 %reduction
Administration
One time with food.
On
an empty stomach .
Reconstitute
with 10 ml diluent and
dilute in NS ,IV infusion over 15 min.
May intraarterial,intraperitoneal or
by regional isolation perfusion
(melanoma)
Adverse reactions
Seizures.(high risk in children and with
high doses)


Haematologic: anemia,leukopenia
and thrombocytopenia may need
dose reduction.

Bronchopulmonary dysplasia.
May
Mutagenic,carcinogenic
infertility
Drug interaction
arterial or venous thrombus.
and teratogenic
.
NSAID,anticoagulant : risk of
bleeding ↑
Local:extravasation
and phlebitis.
Dermatologic: :rash,dermatitis and
allergy.
Mutagenic,carcinogenic and
teratogenic
infertility .
↑
:pulmonary toxicity
NSAID,anticoagulant : risk of
bleeding ↑
Cyclosporine:nephrotoxicity
Carmustine
ETHYLENAMINE DERIVATIVES
Thiotepa 15 and 30 mg vials
Uses
Bladder,breast and ovarian cancer
Carcinomatous meningitis, soft tissue sarcoma,
Hodgkin , NHL and in preperative BMT regimens.
Polyfunctional alkylating agent. (cytotoxic effect
of Thiotepa and its metabolite Tepa).
Absorption
Poorly absorbed, unstable in acidic medium ( no
oral form )
Distribution Rapid and extensive to tissues.
Vd
0.25-1.6L/Kg.
BBB
crossing and reaches CSF.
PPB
About 40% .
Thiotepa
Metabolism
In liver by oxidative desulfuration to
triethylenephophoramide(TEPA).
Elimination
60% of IV dose excreted in urine within 72 hours .
Administration
and doses
Reconstitute with sterile water to reach 10 mg/ml,
and further dilution with NS (1 mg/ml).
IV push (the doses range from 20 mg/m2 to 1000
mg/m2)
Intrathecal (carcinomatous meningitis)
Intravesical (bladder irrigation) 60 mg in 60 ml
NS and retained for 2 hrs.
Adverse
reactions
Haematologic.
Drug interaction
Intravesicular
injection may cause abdominal
pain and hematuria.
Decreases pseudocholinesterase activity,
prolonged apnea when administered with
succinylcholine.
- With mivacurium : risk of respiratory
deppression.
Metals salts
Trade Name
Structure
Cisplatin
Carboplatin
Oxaliplatin
Platinol®
Paraplatin®
Eloxatin®
O
NH3
Cl
Pt
NH3
Cl
NH3
NH3
Pt
O
•Cyclic rings increase chemical stability so they have less side
effects and less reactivity.
•Ring structure hydroxylated in water to form active moeity ,this
reaction is slower in carboplatin than in cisplatin so carboplatin
dose is 4-6 times that of cisplatin to produce the same cytotoxic
effect.
Cisplatin
Carboplatin
Oxaliplatin
•Seminoma cancer
•Ovarian cancer
•Testicular cancer
•Bladder cancer
•Head and neck cancer
•Cervical cancer
•NSCLC
•SCLC
•Brain cancer
•Neuroblastoma
•Wilm’s tumor
•retinoblastoma
•Colorectal cancer
CALVERT FORMULA =
Total dose(mg)=
Target AUC×(GFR+25)
85 mg/m2 in a combination
therapy
Indications
•Seminoma cancer
•Ovarian cancer
•Testicular cancer
•Bladder cancer
•Head and neck cancer
•Cervical cancer
•NSCLC
•SCLC
•Eesophageal cancer
•Brain cancer
•Melanoma
•Neuroblastoma
Doses
50-100 mg/m2 as a
single IV infusion every 34 weeks or 15-20 mg/m2
as a daili inf. For 5 days
every 3-4 weeks
Cisplatin
Carboplatin
Oxaliplatin
Side effect
•Nephrotoxicity
•Ototoxicity
•Neurotoxicity
•Ematogenesis
•Anaphylaxsis
•Hypomanesemia and
hypocalcemia
Stability
Further diluted in dextrose
5% or sodium chloride
and protected from light
•Hematological
toxicity(thrombocytopenia
,leukopenia)
•Anaphylaxsis
Further diluted in
dextrose 5% or sodium
chloride but dextrose is
preferable as after 24 hrs
in saline there is 4-5%
loss of carboplatin
•Anaphylaxsis
•neuropathy
Further diluted in dextrose
5% only
Cisplatin
Carboplatin
Oxaliplatin
I.V within 2-6 h (1
mg/min) or 24 h infusion
. It has been proposed
that a longer infusion
time of 6-8 hours may
decrease
gastrointestinal and
I.V within 15' (short infusion).
I.V within 2 h.
Administration
renal toxicities.
Hydration
•
Only required for cisplatin
Pretreatment hydration: Patients should be adequately hydrated before and for 24
hours after administration of cisplatin to ensure good urinary output and minimise
nephrotoxicity. Hydration may be achieved by IV infusion of 2 litres of either
sodium chloride IV infusion 0.9% or glucose-saline (eg glucose 4% in one-fifth
sodium chloride IV infusion 0.9%) over a 2 hour period. During the last 30 minutes
of the pretreatment hydration or after the hydration, 375 mL of 10% mannitol
injection may be administered via a side-arm drip.
Post-treatment hydration: Adequate hydration and urinary output must be maintained
during the 24 hours following infusion. It has been suggested that IV hydration
continue after treatment with the aim to administer 2 litres of sodium chloride IV
infusion 0.9% or glucose-saline over a period of 6-12 hours.
Radiation and Platinum Drug
Interaction
Platinum drugs have chemical as well as biochemical
and biological effects on cells, all of which may
interact with radiation effects.
The ideal platinum drug-radiation interaction would
achieve radiosensitization of hypoxic tumour cells
with the use of a dose of drug which is completely
non-toxic to normal tissues.
The amount of enhancement will vary with both the
platinum drug dose and the time interval between
drug administration and radiation. Clinical schedules
may produce an increase in tumour response and/or
Recommendations for minimizing
Nephrotoxicity include:






Prepare cisplatin in saline containing vehicles.
Infusion rate of cisplatin.
Vigorous hydration(2 L glucose and normal saline) +
KCl + MgSO4 before cisplatin administrarion.
Simultaneous administration of either mannitol or
furosemide.
Maintaining urine output 100-150 ml/hr for 24 hours
after cisplatin administration.
Avoid other nephrotoxic agents
(aminoglycosides,amphotericin…etc.).
Triazine
Structure
Dacarbazine(DTIC)
•Acts as an antimetabolite
inhibiting purine bases.
•Dimethyl triazinoimidazole
Carboxamide.
Distribution
Localized in liver.
BBB
minimal.
Vd
0.63L/Kg
PPB
minimal .
CONH2
N
N N
N
N
CH3
Metabolism
Through liver enzyme.
Elimination
•Renal 50% unchanged, 10 – 20% as its metabolite.
Administration
Infused within 30-120 mins. with light protection as this
compound unstable under light .
CH3
Dacarbazine(DTIC)
Adverse effects
•Extravasation(irritant not vesicant).
•Photosensitivity.
•Hepatotoxicity.
•Myelosuppression.
Drug interaction
•Microsomal enzyme inducer
Phenobarbitane
,carbamazepine.
•Microsomal enzyme inhibitor
amiodarone,
ciprofloxacin ,ketoconazole…etc.
•Inc. effect of allopurinol due to inhibition of xanthine
oxidase.
Triazine
Structure
Dacarbazine(DTIC)
Acts
as an antimetabolite
inhibiting purine bases.
Dimethyl triazinoimidazole
Carboxamide.
CONH2
N
N N
N
N
CH3
CH3
Distribution
Localized in liver.
BBB
minimal.
Vd
0.63L/Kg
PPB
minimal .
Metabolism
Through liver enzyme.
Elimination
Renal
Administration
Infused within 30-120 mins. with light protection as this
compound unstable under light .
50% unchanged, 10 – 20% as its metabolite.
Dacarbazine(DTIC)
Adverse effects
Extravasation(irritant
not vesicant).
Photosensitivity.
Hepatotoxicity.
Myelosuppression.
Drug interaction
Microsomal
enzyme inducer
Phenobarbitane
,carbamazepine.
Microsomal enzyme inhibitor
amiodarone,
ciprofloxacin ,ketoconazole…etc.
Inc. effect of allopurinol due to inhibition of
xanthine oxidase.
Procarbazine
Trade name
Matulane®, Natulane
Alkyl Sulphonate
Structure
Absorption
1-methyl-2-benzyl derivative
of hydrazine
completely absorbed from the GI tract.
Distribution
distributes
widely throughout the body tissues, concentrating
in the liver, intestinal wall, skin, and kidneys.
 Procarbazine crosses the blood-brain barrier .
Metabolism
extensive metabolism by the liver. Some metabolites have
cytotoxic activity.
Elimination
Both
Administration
orally
unchanged drug and its metabolites are excreted in the
urine. Seventy percent of a dose can be found in the urine in the
first 24 hours after a dose..
Procarbazine
Adverse
Effects
principal
toxic effect is bone marrow depression, resulting in
leukopenia, anemia, and thrombocytopenia. In patients with
preexisting renal, hepatic, or bone marrow impairment, severe
toxicity may occur.
Procarbazine therapy should be discontinued if the leukocyte
count is reduced to 4000/mm3 or less, or if the platelet count falls to
100,000/mm3 or less
Drug
interaction
CNS Depressants
Concomitant administration of CNS depressants such as
barbiturates, antihistamines, opiates, hypotensive agents, should
be undertaken with caution as these drugs may cause potentiation
of CNS depression caused by procarbazine.
•Other Drugs and Food
Patients receiving procarbazine should not drink alcohol since a
disulfiram-like reaction may result.
Since procarbazine hydrochloride possesses some monoamine
oxidase inhibitory activity, sympathomimetic drugs (including those
in nose drops and cough preparations), local anesthetics, tricyclic
antidepressants, and other drugs and foods with known high
tyramine content such as cheese, bananas, yogurt, tea, coffee, wine
and cola drinks, and cigarettes should be avoided.
Busulfan
Administartion
Orally
taken anytime during the day with large
amount of fluids before or shortly after meal.
IV infusion over 2 hours through central venous
catheter.
Adverse effects
Skin
Drug interaction
Phenytoin.(induction
hyperpigmentation.
Seizures.
Hepatic veno- occlusive disease.
of glutathione S-transferase).
Acetaminophen.(reduction of glutathione level)
Itraconazole.
NSAID and anticoagulant…..etc.
Succinylcholine.
NITROSOUREA
Carmustine
Trade name
BCNU – BiCNU
Structure
Distribution
O NO
C
NHCH2CH2Cl
N
CH2CH2Cl
not absorbed orally
Highly
Vd
BBB
PPB
Metabolism
CCNU -CeeNU
O
ON
Absorption
Lomustine
lipid soluble
2.6-3.3L/Kg
crossing
80%
NH C N CH2CH2Cl
Absorbed orally.
Highly
lipid soluble,
extensive tissue
distribution.
Vd
no information
found
BBB
crosing and
reaches CSF
PPB
moderate 50%
Hepatic microsomal enzyme oxidative system.
Alkyl Sulphonate
Trade name
Busulfan
Myleran®, Busulfex®
O
Structure
CH3
S
O
OCH2CH2CH2CH2O
O
1,4-Butanediol dimethanesulfonate
Absorption
Highly absorbed.
Distribution
Rapidly
Vd
BBB
PPB
S
CH3
O
distributed and eliminated from the plasma.
0.6-1L/Kg
crosses.
minimal.
Metabolism
Slowly , in the liver conjugated with glutathione.
Elimination
Renally ( 1% excreted unchanged ) .
Carmustine
Lomustine
Elimination
Renally: 60% to 70% of a
dose is excreted in urine
after 4 days as metabolites,
10% in respiration as CO2 .
Renally: slowly 60% of a
dose excreted after 48
hours with 50% excreted
in the 1st 12 h.
Administration
IV administration over a
period of 1-2 hours (to
prevent irritation at
injection site, burning with
rapid infusion),
reconstituted with alc.
Orally on empty
stomach with much
water as single dose .
Adverse
reactions
Vesicant.,Phelibitis
Delayed
Delayed
Toxicity
Pulmonary toxicity
Reversible
hepatotoxicity
Nephrotoxicity
GIT
toxicity,confusion…
hematological
toxicity.
Hepatotoxicity.
Pulmonary toxicity.
Drug interaction
Amphotericin
B.
Hematologic
Phenobarbital
increase
Carmustine
The
recommended
dose as single
agent
•150 to 200
mg/m²
intravenously
every 6 weeks.
Lomustine
•130 mg/m2 as a single oral
dose every 6 weeks
repeat course of should not be given until circulating blood elements
have returned to acceptable levels (platelets above 100,000/mm³,
leukocytes
above 4,000/mm³), and this is usually in 6 weeks
Doses subsequent to the initial dose should be adjusted according to
the
hematologic response of the patient to the preceding dose
Uses Brain tumour,Non-Hodgkin's
lymphomas,Hodgkin’sdisease,multiple myloma
Carmustine
Lomustine
Elimination
Renally: 60% to 70% of a
dose is excreted in urine
after 4 days as metabolites,
10% in respiration as CO2 .
Renally: slowly 60% of a
dose excreted after 48
hours with 50% excreted
in the 1st 12 h.
Administration
IV administration over a
period of 1-2 hours (to
prevent irritation at
injection site, burning with
rapid infusion),
reconstituted with alc.
Orally on empty
stomach with much
water as single dose .
Adverse
reactions
Vesicant.
Disorientaion,
Delayed
hematological
toxicity.
Hepatotoxicity.
Pulmonary toxicity.
Drug interaction
Amphotericin
B.
Microsomomal enzyme inducers.
ataxia.
Other alkylating agents :
Temozolomide
Trade
name
Uses
Temodar®
(cap.5,10,100 and 250 mg)
Refractory astrocytoma.
Absorption Completely absorped.
Is a prodrug and by hydrolysis
in the body turn into the active
molecule
Metabolism By liver ,cytochrome P450.
Elimination Renal elimination ,dose reduction may be
Administration
and doses
Side effects
Drug
interactions
necessary in renal impaairment (no
guidelines)
Orally, once daily.
Doses:150-200 mg/m2 for 5 days each 28
days cycle.
Haematologic
Severe nausea and vomiting
Teratogenic.
Valproic acid may reduce its clearance by 5 %.
Other alkylating agents :
Streptozocin
Trade
name
Zanosar®
(1 gm vial)
Uses
Pancreatic islet cell carcinoma
and carcinoid tumour.
Absorption Not absorped from GIT.
Metabolism By liver
Elimination
Renal elimination.
If crcl 10-50 ml/min:give 75 % of the dose.
If less than 10 ml/min : give 50% of the dose.
Administration
and doses
Direct IV injection or infusion..
Doses:500 mg/m2 IV /day for 5 days (every 6 weeks).
1-1.5 gm /m2 IV as a single dose (every week).
Reconstitute 1 gm with 9.5 ml NS or D5%, may further
dilution with NS or D5% and administered over 15 min ti 6
hrs.
Side effects
Nephrotoxicity in 25 -75 % of patients.
Haematologic
Severe nausea and vomiting.
May induce DM in animals.
Teratogenic.
Drug
interactions
-Avoid using with other nephrotoxic drugs.
Doxorubicin: it prolong doxorubicin half life so dose of doxorubicin should be reduced.
-Phenytoin may diminish the cytotoxic effect.of streptozocin.