Anticancer, Dermatologic and Ocular

ANTICANCER
Cell life cycle

• Knowledge of the cell life cycle and cell cycle kinetics is essential to
the understanding of the activity of chemotherapy agents in the
treatment of cancer
Phases of the cell cycle
1. M phase, or mitosis, is the phase in which the cell divides into two
daughter cells
2. G1 phase, or postmitotic gap, is when RNA and the proteins
required for the specialized functions of the cell are synthesized in
preparation for DNA synthesis
3. S phase is the phase in which DNA synthesis and replication occurs
4. G2 phase, or the premitotic or postsynthetic gap, is the phase in
which RNA and the enzymes topoisomerase I and II are produced
to prepare for duplication of the cell
Phases of the cell cycle
5. G0 phase, or resting phase, is the phase in which the cell is not
committed to division
• Cells in this phase are generally not sensitive to chemotherapy
• Some of these cells may reenter the actively dividing cell cycle
• In a process called recruitment, some chemotherapy regimens are
designed to enhance this reentry by killing a large number of actively
dividing cells
Cell growth kinetics
• Several terms describe cell growth kinetics
• Cell growth fraction is the proportion of cells in the tumor dividing or
preparing to divide
• As the tumor enlarges, the cell growth fraction decreases because a
larger proportion of cells may not be able to obtain adequate
nutrients and blood supply for replication
• Cell cycle time is the average time for a cell that has just completed
mitosis to grow and again divide and again pass through mitosis. Cell
cycle time is specific for each individual tumor
• Tumor doubling time is the time for the tumor to double in size
• As the tumor gets larger, its doubling time gets longer because it
contains a smaller proportion of actively dividing cells owing to
restrictions of space, nutrient availability, and blood supply.
• The gompertzian growth curve illustrates these cell growth concepts
• Tumor cell burden is the number of tumor cells in the body
• Because a large number of cells is required to produce symptoms and
be clinically detectable (approximately 109 cells), the tumor may be in
the plateau phase of the growth curve by the time it is discovered
• The cell kill hypothesis states that a certain percentage of tumor cells
will be killed with each course of cancer chemotherapy
• As tumor cells are killed, cells in G0 may be recruited into G1,
resulting in tumor regrowth
• Thus, repeated cycles of chemotherapy are required to achieve a
complete response or remission
• The percentage of cells killed depends on the chemotherapy dose
• In theory, the tumor burden would never reach absolute zero because
only a percentage of cells are killed with each cycle
• Less than 104 cells may depend on elimination by the host’s immune
system
Cycle specificity of chemotherapy
• Chemotherapeutic agents may be classified according to their
reliance on cell cycle kinetics for their cytotoxic effect
• Combinations of chemotherapy agents that are active in different
phases of the cell cycle may result in a greater cell kill
1. Phase-specific agents are most active against cells that are in a
specific phase of the cell cycle
• These agents are most effective against tumors with a high growth
fraction
Phase-specific agents
• Theoretically, administering phase-specific agents as continuous intravenous
infusions or by multiple repeated doses may increase the likelihood of
hitting the majority of cells in the specific phase at any one time
• Therefore, these agents are also considered schedule-dependent agents
• Examples are as follows:
a) M phase: mitotic inhibitors (e.g., vinca alkaloids, taxanes)
b) G1 phase: asparaginase, prednisone
c) S phase: antimetabolites
d) G2 phase: bleomycin, etoposide
Phase-nonspecific agents
2. Phase-nonspecific agents are effective while cells are in the active
cycle but do not require that the cell be in a particular phase
• These agents generally show more activity against slow-growing
tumors
• They may be administered as single bolus doses because their activity
is independent of the cell cycle
• These drugs are also considered dose-dependent agents
• Examples are alkylating agents and antitumor antibiotics
Cell cycle–nonspecific agents
3. Cell cycle–nonspecific agents are effective in all phases, including
G0
• Examples are carmustine and lomustine
• Radiation therapy is also considered cell cycle nonspecific
Drug resistance
• A fundamental issue in cancer chemotherapy is the development of cellular drug resistance.
Some tumor types, e.g. malignant melanoma, renal cell cancer, and brain cancer, exhibit
primary resistance, i.e. absence of response on the first exposure, to currently available
agents
• The presence of inherent drug resistance is thought to be tightly associated with the
genomic instability associated with the development of most cancers
• For example, mutations in the p53 tumor suppressor gene occur in at least 50% of all
human tumors
• Preclinical and clinical studies have shown that loss of p53 function leads to resistance to
radiation therapy as well as to resistance to a wide range of anticancer agents
• Defects in the mismatch repair enzyme family, which are tightly linked to the development
of familial and sporadic colorectal cancer, gives rise to resistance to unrelated anticancer
agents, including the fluoropyrimidines, the thiopurines, and cisplatin/carboplatin
Drug resistance
• In contrast to primary resistance, acquired resistance develops in response to
exposure to a given anticancer agent
• Experimentally, drug resistance can be highly specific to a single drug and is
usually based on a specific change in the genetic machinery of a given tumor cell
with amplification or increased expression of one or more genes
• In other instances, a multidrug-resistant phenotype occurs, associated with
increased expression of the MDR1 gene, which encodes a cell surface transporter
glycoprotein (P-glycoprotein)
• This form of drug resistance leads to enhanced drug efflux and reduced
intracellular accumulation of a broad range of structurally unrelated anticancer
agents, including the anthracyclines, vinca alkaloids, taxanes, camptothecins,
epipodophyllotoxins, and even small molecule inhibitors, such as imatinib
Alkylating agents
Alkylating agents
• Examples
• Containing bis(chloroethyl)amines functional group -
cyclophosphamide, mechlorethamine, melphalan, and chlorambucil
• Nitrosoureas - carmustine (BCNU), lomustine (CCNU), and semustine
(methyl-CCNU)
• Others – Ifosfamide, thiotepa and busulfan
Mechanism of action
• Alkylating agents exert their cytotoxic effects via transfer of their alkyl
groups to various cellular constituents particularly in the nucleus
• The general mechanism of action of these drugs involves
intramolecular cyclization to form an ethyleneimonium ion that may
directly or through formation of a carbonium ion transfer an alkyl
group to a cellular constituent
• In addition to alkylation, a secondary mechanism that occurs with
nitrosoureas involves carbamoylation of lysine residues of proteins
through formation of isocyanates
Mechanism of action
• The major site of alkylation within DNA is the N7 position of guanine
• These interactions can occur on a single strand or on both strands of DNA
through cross-linking, as most major alkylating agents are bifunctional, with
two reactive groups
• Alkylation of guanine can result in miscoding through abnormal base pairing
with thymine or in depurination by excision of guanine residues
• The latter effect leads to DNA strand breakage through scission of the sugar-
phosphate backbone of DNA
• Thus, although alkylating agents are not cell cycle specific, cells are most
susceptible to alkylation in late G1 and S phases of the cell cycle and express
blockage in G2
Resistance
• The mechanism of acquired resistance to alkylating agents may
involve:
1. Increased capability to repair DNA lesions
2. Decreased transport of the alkylating drug into the cell
3. Increased production of glutathione and glutathione-associated
proteins, which are needed to conjugate the alkylating agent
4. Increased glutathione S-transferase activity, which catalyzes the
conjugation
Adverse effects
• The adverse effects usually associated with alkylating agents are
generally dose-related and occur primarily in rapidly growing tissues such
as bone marrow, the gastrointestinal tract, and the reproductive system
• Nausea and vomiting can be a serious issue with a number of these
agents
• In addition, they have direct vesicant effects and can damage tissues at
the site of injection as well as produce systemic toxicity
• As a class, alkylating agents are carcinogenic in nature, and there is an
increased risk of secondary malignancies, especially acute myelogenous
leukemia
Cyclophosphamide
• Cyclophosphamide is a widely used alkylating agent,
• It has high oral bioavailability – it can be administered via the oral
and intravenous routes with equal clinical efficacy
• It is inactive in its parent form, and must be activated to cytotoxic
forms by liver cytochrome P450 mixed-function oxidase system –
converts cyclophosphamide to 4-hydroxycyclophosphamide, which is
in equilibrium with aldophosphamide
• These active metabolites are delivered to both tumor and normal
tissue, where nonenzymatic cleavage of aldophosphamide to the
cytotoxic forms—phosphoramide mustard and acrolein
Cyclophosphamide
• Hemorrhagic cystitis is a bladder toxicity that is seen most commonly
after administration of cyclophosphamide and Ifosfamide
• Acrolein, a metabolite of these agents, is thought to cause a chemical
irritation of the bladder mucosa, resulting in bleeding
• Prevention – aggressive hydration with subsequent frequent
urination, and the administration of the uroprotectant mesna
• Mesna acts by binding to acrolein and preventing it from contacting
the bladder mucosa
Nitrosoureas
• These drugs appear to be non-cross-resistant with other alkylating
agents; all require biotransformation, which occurs by nonenzymatic
decomposition, to metabolites with both alkylating and carbamoylating
activities
• The nitrosoureas are highly lipid-soluble and are able to cross the blood-
brain barrier, making them effective in the treatment of brain tumors
• Mechanism of action
• Although the majority of alkylations by the nitrosoureas are on the N7
position of guanine in DNA, the critical alkylation responsible for
cytotoxicity is on the O6 of guanine, which leads to G-C crosslinks in DNA
Nitrosoureas
• Pharmacokinetics
• After oral administration of lomustine, peak plasma levels of
metabolites appear within 1–4 hours; CNS concentrations reach 30–
40% of the activity present in the plasma
• Urinary excretion appears to be the major route of elimination from
the body
• One naturally occurring sugar-containing nitrosourea, streptozocin, is
interesting because it has minimal bone marrow toxicity
• This agent has activity in the treatment of insulin-secreting islet cell
carcinoma of the pancreas
Nonclassic alkylating agents
Procarbazine
• Mechanisms—Procarbazine is a reactive agent that forms hydrogen
peroxide, which generates free radicals that cause DNA strand scission
Pharmacokinetics
• Procarbazine is orally active and penetrates into most tissues,
including the cerebrospinal fluid
• It is eliminated via hepatic metabolism.
Clinical use—The primary use of the drug is as a component of
regimens for Hodgkin’s and non-Hodgkin’s lymphoma, and brain tumors
Procarbazine
Toxicity—Procarbazine is a myelosuppressant and causes
gastrointestinal irritation, CNS dysfunction, peripheral neuropathy, and
skin reactions
• Procarbazine inhibits many enzymes, including monoamine oxidase
and those involved in hepatic drug metabolism
• Adverse events can occur when procarbazine is given with other MAO
inhibitors as well as with sympathomimetic agents and tyramine
containing foods
• Disulfiram-like reactions have occurred with ethanol
• The drug is leukemogenic
Nonclassic alkylating agents
• Other nonclassic alkylating agents include:
1. Dacarbazine – administered parenterally
• Used for malignant melanoma, Hodgkin's lymphoma, soft tissue
sarcomas, and neuroblastoma
• Main dose-limiting toxicity is myelosuppression, but nausea and
vomiting can be severe and in some cases also a potent vesicant
2. Bendamustine
Platinum analogs
• They are thought to exert their cytotoxic effects in the same manner
as alkylating agents
• As such, they kill tumor cells in all stages of the cell cycle and bind
DNA through the formation of intrastrand and interstrand cross-links,
thereby leading to inhibition of DNA synthesis and function
• The primary binding site is the N7 position of guanine
Platinum analogs
• Cisplatin
• Indications – small cell and small cell lung cancer, esophageal and
gastric cancer, head and neck cancer, and genitourinary cancers,
particularly testicular, ovarian, and bladder cancer
• Extensively cleared by the kidneys and excreted in the urine – dose
modification is required in the setting of renal dysfunction
• Toxicity – severe nausea and vomiting; nephrotoxicity, peripheral
sensory neuropathy, ototoxicity, nerve dysfunction
Platinum analogs
• Carboplatin (2nd generation platinum analog)
• It exhibits significantly less renal toxicity and gastrointestinal toxicity
as compared to cicplatin
• Its main dose-limiting toxicity is myelosuppression
• It has therefore been widely used in transplant regimens to treat
refractory hematologicmalignancies
• Administration –vigorous intravenous hydration is not required for
carboplatin therapy, therefore carboplatin is viewed as an easier
agent to administer to patients
Platinum analogs
• Oxaliplatin (third-generation platinum analog)
• Identical to those of cisplatin and carboplatin
• However, tumors that are resistant to cisplatin or carboplatin on the basis of
mismatch repair defects are not cross-resistant to oxaliplatin, and this
finding may explain the activity of this platinum compound in colorectal
cancer
• Indications : colorectal cancer as part of the FOLFOX regimen (5-
fluorouracil/leucovorin/oxaliplatin), colon cancer, and other gastrointestinal
cancers, such as pancreatic, gastroesophageal, and hepatocellular cancers
Platinum analogs - oxaliplatin
• Toxicity
• Neurotoxicity is the main dose-limiting toxicity and is manifested by a
peripheral sensory neuropathy of two types:
• Acute form that is often triggered and worsened by exposure to cold,
and a chronic form that is dose-dependent
• Although this chronic form is cumulative in nature, it tends to be
reversible, in sharp contrast to cisplatin-induced neurotoxicity
Antimetabolites
Antimetabolites
• They include:
1. Antifolates
2. Purine antagonists
3. Fluoropyrimidines
4. Deoxycytidine analogs
Antifolates
• Examples – methotrexate (mtx); pemetrexed
• Methotrexate
• MTX is a folic acid analog that binds with high affinity to the active catalytic
site of dihydrofolate reductase (DHFR), interfering with the synthesis of
tetrahydrofolate (THF), which serves as the key one-carbon carrier for
enzymatic processes involved in de novo synthesis of thymidylate, purine
nucleotides, and the amino acids serine and methionine
• Inhibition of these various metabolic processes thereby interferes with the
formation of DNA, RNA, and key cellular proteins
Methotrexate
• MTX mechanism continued…
• Intracellular formation of polyglutamate metabolites, with the
addition of up to 5–7 glutamate residues, is critically important for the
therapeutic action of MTX, and this process is catalyzed by the
enzyme folylpolyglutamate synthase (FPGS)
• MTX polyglutamates are selectively retained within cancer cells, and
they display increased inhibitory effects on enzymes involved in de
novo purine nucleotide and thymidylate biosynthesis, making them
important determinants of MTX's cytotoxic action
Resistance to MTX
1. Decreased drug transport via the reduced folate carrier or folate
receptor protein
2. Decreased formation of cytotoxic MTX polyglutamates
3. Increased levels of the target enzyme DHFR through gene
amplification and other genetic mechanisms
4. Altered DHFR protein with reduced affinity for MTX
5. Recent studies have suggested that decreased accumulation of drug
through activation of the multidrug resistance transporter P170
glycoprotein may also result in drug resistance
Methotrexate
• Administration and pharmacokinetics
• MTX is administered by the intravenous, intrathecal, or oral route
• However, oral bioavailability is saturable and erratic at doses greater
than 25 mg/m2
• Renal excretion is the main route of elimination – dose modification
is required in the setting of renal dysfunction
• Care must also be taken when MTX is used in the presence of drugs
such as aspirin, penicillin, cephalosporins, and nonsteroidal anti-
inflammatory agents, as they inhibit the renal excretion of MTX
Methotrexate
• The biologic effects of MTX can be reversed by administration of the
reduced folate leucovorin (5-formyltetrahydrofolate) or by L-
leucovorin, which is the active enantiomer
• Leucovorin rescue is used in conjunction with high-dose MTX therapy
to rescue normal cells from undue toxicity, and it has also been used
in cases of accidental drug overdose
• Toxicity - Mucositis, diarrhea, myelosuppression with neutropenia
and thrombocytopenia
Fluoropyrimidines
• 5-Fluorouracil
• 5-Fluorouracil (5-FU) is inactive in its parent form and requires
activation via a complex series of enzymatic reactions to ribosyl and
deoxyribosyl nucleotide metabolites. One of these metabolites, 5-
fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), forms a
covalently ternary complex with the enzyme thymidylate synthase and
the reduced folate 5,10-methylenetetrahydrofolate, a reaction critical
for the de novo synthesis of thymidylate
• This results in inhibition of DNA synthesis through "thymineless death.“
5-Fluorouracil
• Mechanism continued
• 5-FU is converted to 5-fluorouridine-5'-triphosphate (FUTP), which is
then incorporated into RNA, where it interferes with RNA processing
and mRNA translation
• 5-FU is also converted to 5-fluorodeoxyuridine-5'-triphosphate
(FdUTP), which can be incorporated into cellular DNA, resulting in
inhibition of DNA synthesis and function
• Thus, the cytotoxicity of 5-FU is thought to be the result of combined
effects on both DNA- and RNA-mediated events
5-Fluorouracil
• Pharmacokinetics and administration
• 5-FU is normally administered intravenously with a half-life of 10–15 minutes
• The clinical activity of this drug is highly schedule-dependent and because of
its extremely short half-life, standard schedules of administration should be
followed
• Up to 80–85% of an administered dose of 5-FU is catabolized by the enzyme
dihydropyrimidine dehydrogenase
• A pharmacogenetic syndrome that involves partial or complete deficiency of
the DPD enzyme, and in this setting, which is seen in up to 5% of all cancer
patients, severe toxicity in the form of myelosuppression, diarrhea, nausea
and vomiting, and neurotoxicity, has been observed
5-Fluorouracil
• Indications
• Colorectal cancer
• Cancers of the breast, stomach, pancreas, esophagus, liver, head and
neck, and anus
• Toxicity
• Major toxicities include myelosuppression, gastrointestinal toxicity in
the form of mucositis and diarrhea, skin toxicity manifested by the
hand-foot syndrome, and neurotoxicity
Leucovorin
• Mechanism of leucovorin in FOLFOX regimen
• Enhances the effects of 5-fluorouracil’s metabolite (5-flurouridylic acid
acid) by stabilizing its bond with thymidilate synthase to inhibit DNA
and RNA synthesis
Capecitabine
• Capecitabine is a fluoropyrimidine carbamate prodrug with 70–80% oral
bioavailability
• It is metabolized first in the liver then at the tumour site to 5-FU
• Indications: metastatic breast cancer, colon cancer, colorectal cancer (XELOX
regimen)
• Toxicity
• The main toxicities of capecitabine include diarrhea and the hand-foot
syndrome
• While myelosuppression, nausea and vomiting, and mucositis are also observed
with this agent, the incidence is significantly less than that seen with intravenous
5-FU
Deoxycytidine analogs
• Examples – Cytarabine, gemcitabine
• Cytarabine
• Cytarabine (ara-C) is an S phase-specific antimetabolite that is converted
by deoxycytidine kinase to the 5'-mononucleotide (ara-CMP)
• Ara-CMP is further metabolized to the diphosphate and triphosphate
metabolites, and the ara-CTP triphosphate is felt to be the main
cytotoxic metabolite
• Ara-CTP competitively inhibits DNA polymerase alpha- and DNA
polymerase beta-, thereby resulting in blockade of DNA synthesis and
DNA repair, respectively
Cytarabine
• After intravenous administration, the drug is cleared rapidly, with
most of an administered dose being deaminated to inactive forms
• The clinical activity of this drug is highly schedule-dependent and
because of its rapid degradation, it must be given by continuous
infusion over a 5–7 day period
Cytarabine
• Indications
• Its activity is limited exclusively to hematologic malignancies, including
acute myelogenous leukemia and non-Hodgkin's lymphoma. This agent
has absolutely no activity in solid tumors
• Toxicities include myelosuppression, mucositis, nausea and vomiting,
and neurotoxicity when high-dose therapy is administered
• Cytarabine induced kerato-conjunctivitis has been known to occur in
patients receiving high dose (>1000 mg/m2) or multiday regimens; it can
be prevented by prophylactic administration of corticosteroid eye drops
(every 4-6 hours up to 48 hours after last cytarabine administration)
Purine antagonists
• 6-Thiopurines
• Examples - 6-Mercaptopurine (6-MP), 6-Thioguanine
• 6-Mercaptopurine (6-MP)
• Indications - This agent is used primarily in the treatment of
childhood acute leukemia, and a closely related analog, azathioprine,
is used as an immunosuppressive agent
6-Mercaptopurine (6-MP)
• 6-MP is inactive in its parent form and must be metabolized by
hypoxanthine-guanine phosphoribosyl transferase (HGPRT) to form
the monophosphate nucleotide 6-thioinosinic acid, which in turn
inhibits several enzymes of de novo purine nucleotide synthesis
• The monophosphate form is eventually metabolized to the
triphosphate form, which can then get incorporated into both RNA
and DNA
• Metabolism - 6-MP is converted to an inactive metabolite (6-thiouric acid) by an
oxidation reaction catalyzed by xanthine oxidase
• The purine analog allopurinol, a potent xanthine oxidase inhibitor, is frequently
used as a supportive care measure in the treatment of acute leukemias to prevent
the development of hyperuricemia that often occurs with tumor cell Lysis
• Because allopurinol inhibits xanthine oxidase, simultaneous therapy with
allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to
excessive toxicity
• In this setting, the dose of mercaptopurine must be reduced by 50–75%
• In contrast, such an interaction does not occur with 6-TG, which can be used in full
doses with allopurinol.
• The thiopurines are also metabolized by the enzyme thiopurine
methyltransferase (TPMT), in which a methyl group is attached to the
thiopurine ring
• There is a pharmacogenetic syndrome in which there is partial or
complete deficiency of this enzyme
• Patients with this genotype are at increased risk for developing severe
toxicities in the form of myelosuppression and gastrointestinal
toxicity with mucositis and diarrhea
Fludarabine
• Fludarabine phosphate is rapidly dephosphorylated to 2-fluoro-
arabinofuranosyladenosine and then phosphorylated intracellularly by
deoxycytidine kinase to the triphosphate form
• The triphosphate metabolite interferes with the processes of DNA synthesis
and DNA repair through inhibition of DNA polymerase alpha and DNA
polymerase beta
• The triphosphate form can also be directly incorporated into DNA, resulting in
inhibition of DNA synthesis and function
• The diphosphate metabolite of fludarabine inhibits ribonucleotide reductase,
leading to inhibition of essential deoxyribonucleotide triphosphates
Fludarabine
• Indications – Low-grade non-Hodgkin's lymphoma and chronic
lymphocytic leukemia (CLL), acute myeloid leukemia
• PK and administration - It is given parenterally and up to 25–30% of
parent drug is excreted in the urine
Fludarabine
• Toxicity
• The main dose-limiting toxicity is myelosuppression
• This agent is a potent immunosuppressant with inhibitory effects on CD4 and
CD8 T cells. Patients are at increased risk for opportunistic infections,
including fungi, herpes, and Pneumocystis jiroveci pneumonia (PCP)
• Patients should receive PCP prophylaxis with trimethoprim-sulfamethoxazole
(double strength) at least three times a week, and this should continue for up
to 1 year after stopping fludarabine therapy
• The agent cladribine has similar properties to fludarabine including prolonged
immunosuppression characterized by low levels of CD4 and CD8 T cells
Natural product cancer
chemotherapy drugs
Vinca alkaloids
• These include vinblastine, vincristine and vinorelbine
• Vinblastine
• Vinblastine is an alkaloid derived from the periwinkle plant Vinca rosea
• Indications - Hodgkin's and non-Hodgkin's lymphomas, breast cancer, and
germ cell cancer
• Mechanism of action - involves inhibition of tubulin polymerization,
which disrupts assembly of microtubules, an important part of the
cytoskeleton and the mitotic spindle
• This inhibitory effect results in mitotic arrest in metaphase, bringing cell
division to a halt, which then leads to cell death
Vinblastine
• Vinblastine and other vinca alkaloids are metabolized by the liver
P450 system, and the majority of the drug is excreted in feces via the
biliary system
• As such, dose modification is required in the setting of liver
dysfunction
Vinblastine
• Toxicity
• Adverse effects include nausea and vomiting, bone marrow
suppression, and alopecia
• This agent is also a potent vesicant, and care must be taken in its
administration
Vincristine
• Vincristine is an alkaloid derivative of Vinca rosea and has similar
pharmacologic properties as vinblastine but its toxicity profile is
different
• Indications – ALL, the lymphomas, pediatric tumors including
rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma, and Wilms'
tumor
Vincristine
• Toxicity
• The main dose-limiting toxicity is neurotoxicity, usually expressed as a
peripheral sensory neuropathy, although autonomic nervous system
dysfunction with orthostatic hypotension, urinary retention, paralytic
ileus, or constipation, cranial nerve palsies, ataxia, seizures, and coma
have been observed
• While myelosuppression occurs, it is generally milder and much less
significant than with vinblastine
• The other potential adverse effect that can develop is the syndrome
of inappropriate secretion of antidiuretic hormone (SIADH)
Taxanes & related drugs
• Paclitaxel is an alkaloid ester derived from the Pacific yew (Taxus brevifolia)
and the European yew (Taxus baccata)
• Indications - broad range of solid tumors, including ovarian, advanced breast,
non-small cell and small cell lung, head and neck, esophageal, prostate, and
bladder cancers and AIDS-related Kaposi's sarcoma
• The drug functions as a mitotic spindle poison through high-affinity binding to
microtubules with enhancement of tubulin polymerization
• This promotion of microtubule assembly by paclitaxel occurs in the absence of
microtubule-associated proteins and guanosine triphosphate and results in
inhibition of mitosis and cell division
Paclitaxel
• It is metabolized extensively by the liver P450 system, and nearly 80% of
the drug is excreted in feces via the hepatobiliary route
• Dose reduction is required in the setting of liver dysfunction
• Toxicity
• Hypersensitivity reactions may be observed in up to 5% of patients, but
the incidence is significantly reduced by premedication with
dexamethasone, diphenhydramine, and an H2 blocker
• Other adverse effects include myelosuppression, peripheral sensory
neuropathy, nausea, vomiting, hypotension, arrhythmias
Paclitaxel
• A novel albumin-bound paclitaxel formulation (Abraxane) is approved
for use in metastatic breast cancer
• In contrast to paclitaxel, this formulation is not associated with
hypersensitivity reactions, and premedication to prevent such
reactions is not required
• Moreover, this agent has significantly reduced myelosuppressive
effects compared with paclitaxel, and the neurotoxicity that results
appears to be more readily reversible than is typically observed with
paclitaxel
Docetaxel
• Docetaxel is a semisynthetic taxane derived from the European yew
tree
• Its mechanism of action, metabolism, and elimination are identical to
those of paclitaxel
• Indications - advanced breast cancer, non-small cell lung cancer, head
and neck cancer, small cell lung cancer, gastric cancer, advanced
platinum-refractory ovarian cancer, and bladder cancer
• Toxicity - hypersensitivity neurotoxicity, fluid retention,
myelosuppression with neutropenia
Ixabepilone
• Although not a taxane, ixabepilone is a novel microtubule inhibitor
indicated for metastatic breast cancer
• Of note, this agent continues to have activity in drug-resistant tumors
that overexpress P-glycoprotein or tubulin mutations
• The main adverse effects include myelosuppression, hypersensitivity
reactions, and neurotoxicity in the form of peripheral sensory
neuropathy
Epipodophyllotoxins
• Examples – etoposide and teniposide
• Etoposide is a semisynthetic derivative of podophyllotoxin, which is
extracted from the mayapple root (Podophyllum peltatum)
• Indications - Etoposide has clinical activity in germ cell cancer, small
cell and non-small cell lung cancer, Hodgkin's and non-Hodgkin's
lymphomas, and gastric cancer
• Mechanism of action - involves inhibition of topoisomerase II, which
results in DNA damage through strand breakage induced by the
formation of a ternary complex of drug, DNA, and enzyme
Etoposide
• The oral bioavailability is about 50%, requiring the oral dose to be
twice that of an intravenous dose
• Up to 30–50% of drug is excreted in the urine, and dose reduction is
required in the setting of renal dysfunction
Camptothecins
• The camptothecins are natural products derived from the Camptotheca
acuminata tree
• Mechanism of action - they inhibit the activity of topoisomerase I, the
key enzyme responsible for cutting and religating single DNA strands
• Inhibition of this enzyme results in DNA damage
• Topotecan
• Indications - advanced ovarian cancer, small cell lung cancer
• PK - The main route of elimination is renal excretion, and dosage must
be adjusted in patients with renal impairment
Irinotecan
• Irinotecan is a prodrug that is converted mainly in the liver by the
carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold
more potent as an inhibitor of topoisomerase I than the parent
compound
• Indications - metastatic colorectal cancer
• PK - In contrast to topotecan, irinotecan and SN-38 are mainly
eliminated in bile and feces, and dose reduction is required in the
setting of liver dysfunction
Irinotecan
• Toxicity
• Myelosuppression and diarrhea are the two most common adverse
events
• There are two forms of diarrhea: an early form that occurs within 24
hours after administration and is thought to be a cholinergic event
effectively treated with atropine, and a late form that usually occurs
2–10 days after treatment
• The late diarrhea can be severe, leading to significant electrolyte
imbalance and dehydration in some cases
Antitumor antibiotics
Anthracyclines
• The anthracycline antibiotics, isolated from Streptomyces
peucetius var caesius
• Examples – doxorubicin, Daunorubicin, idarubicin, epirubicin
• Mechanism of action – anthracyclines intercalate between DNA base
pairs, inhibit topoisomerase II, and generate free radicals; They block
the synthesis of RNA and DNA and cause DNA strand scission;
Membrane disruption also occurs to alter fluidity and ion transport
• The free radical mechanism is the cause of the cardiotoxicity
associated with the anthracyclines
Anthracyclines
• Administered via the intravenous route
• The anthracyclines are metabolized extensively in the liver; up to 50%
of drug is eliminated in the feces via biliary excretion, and dose
reduction is required in the setting of liver dysfunction
• Although anthracyclines are usually administered on an every-3-week
schedule, alternative schedules such as low-dose weekly or 72–96
hour continuous infusions have been shown to yield equivalent
clinical efficacy with reduced toxicity
Anthracyclines
• Clinical use
• Doxorubicin – is very widely used in combination with other
anticancers in many adult and pediatric solid tumors and lymphomas
• Daunorubicin and idarubicin are used in acute myeloid leukemia
Anthracyclines
• Toxicity
• The main dose-limiting toxicity of all anthracyclines is myelosuppression,
with neutropenia more commonly observed than thrombocytopenia
• In some cases, mucositis is dose-limiting
• Cardiotoxicity
• Two forms are observed:
1. The acute form occurs within the first 2–3 days and presents as
arrhythmias and conduction abnormalities, other electrocardiographic
changes, pericarditis, and myocarditis. This form is usually transient and
in most cases is asymptomatic
Anthracycline toxicity
2. The chronic form results in a dose-dependent, dilated
cardiomyopathy associated with heart failure
• The chronic cardiac toxicity appears to result from increased
production of free radicals within the myocardium
• This effect is rarely seen at total doxorubicin dosages below 500–550
mg/m2 (the cumulative maximum lifetime dose for epirubicin is 900
mg/m2)
• Use of lower weekly doses or continuous infusions of doxorubicin
appear to reduce the incidence of cardiac toxicity
Anthracycline toxicity
• Chronic cardiotoxicity cont…
• In addition, treatment with the iron-chelating agent dexrazoxane is
currently approved to prevent or reduce anthracycline-induced
cardiotoxicity in women with metastatic breast cancer who have
received a total cumulative dose of doxorubicin of 300 mg/m2
• The anthracyclines can also produce a "radiation recall reaction,"
with erythema and desquamation of the skin observed at sites of
prior radiation therapy
Mitoxantrone
• Mitoxantrone is an anthracene compound whose structure resembles
the anthracycline ring
• Mechanisms - It binds to DNA to produce strand breakage and
inhibits both DNA and RNA synthesis
• Clinical use - It is indicated for prostate cancer, non-Hodgkin
lymphoma, adult and pediatric acute myeloid leukemia
Mitoxantrone
• Toxicity
• Myelosuppression with leukopenia is the dose-limiting toxicity, and
mild nausea and vomiting, mucositis, and alopecia also occur
• Although the drug is thought to be less cardiotoxic than doxorubicin,
both acute and chronic cardiac toxicity are reported
• A blue discoloration of the fingernails, sclera, and urine is observed
1–2 days after drug administration
Mitomycin
• Mitomycin (mitomycin C) is an antibiotic isolated from Streptomyces
caespitosus
• Mechanism - It undergoes metabolic activation through liver enzyme-
mediated reduction to generate an alkylating agent that cross-links DNA
• Hypoxic tumor stem cells of solid tumors exist in an environment conducive
to reductive reactions and are more sensitive to the cytotoxic actions of
mitomycin than normal cells and oxygenated tumor cells
• It is active in all phases of the cell cycle, and is the best available drug for use
in combination with radiation therapy to attack hypoxic tumor cells.
• Clinical uses – squamous cell carcinomas of the anus, cervix and for breast,
gastric, and pancreatic cancer
Mitomycin
• Mitomycin is given intravenously and is rapidly cleared via hepatic
metabolism
• Intravesically administered mitomycin for superficial bladder cancer
is not absorbed systemically hence no systemic toxicity
• Toxicity - Myelosuppression, mucositis, anorexia and fatigue,
nausea/vomiting, hemolytic-uremic syndrome manifested as
microangiopathic hemolytic anemia, thrombocytopenia, and renal
failure
Bleomycin
• Bleomycin is a small peptide that contains a DNA-binding region and
an iron-binding domain at opposite ends of the molecule. It acts by
binding to DNA, which results in single-strand and double-strand
breaks following free radical formation, and inhibition of DNA
biosynthesis
• The fragmentation of DNA is due to oxidation of a DNA-bleomycin-
Fe(II) complex and leads to chromosomal aberrations
• Bleomycin is a cell cycle-specific drug that causes accumulation of
cells in the G2 phase of the cell cycle
Bleomycin
• Clinical uses
• Hodgkin's and non-Hodgkin's lymphomas, germ cell tumor, head and
neck cancer, and squamous cell cancer of the skin, cervix, and vulva
• One advantage of this agent is that it can be given subcutaneously,
intramuscularly, or intravenously
• Elimination of bleomycin is mainly via renal excretion; dose
modification is recommended in patients with renal dysfunction
Bleomycin
• Toxicity
• Pulmonary toxicity is dose-limiting for bleomycin and usually
presents as pneumonitis with cough, dyspnea, dry inspiratory crackles
on physical examination, and infiltrates on chest x-ray
• The incidence of pulmonary toxicity is increased in patients older than
70 years of age, in those who receive cumulative doses greater than
400 units, in those with underlying pulmonary disease, and in those
who have received prior mediastinal or chest irradiation
• Other toxicities include skin hyperpigmentation, keratosis and
stomatitis
Miscellaneous anticancer drugs
Miscellaneous anticancer drugs
• A large number of newer anticancer drugs that do not fit traditional
categories will be covered here including targeted therapies
• Targeted cancer therapies are drugs or other substances that block
the growth and spread of cancer by interfering with specific
molecules ("molecular targets") that are involved in the growth,
progression, and spread of cancer
Tyrosine kinase inhibitors (TKIs)
• Imatinib
• Mechanism – it is an inhibitor of the tyrosine kinase domain of the Bcr-Abl
oncoprotein and prevents phosphorylation of the kinase substrate by ATP
• It is indicated for the treatment of chronic myelogenous leukemia (CML),
a pluripotent hematopoietic stem cell disorder characterized by the t(9:22)
Philadelphia chromosomal translocation
• This translocation results in the Bcr-Abl fusion protein, the causative agent
in CML, and is present in up to 95% of patients with this disease
• This agent also inhibits other receptor tyrosine kinases for platelet-derived
growth factor receptor (PDGFR), stem cell factor, and c-kit
Imatinib
• Clinical use – Used in CML (chronic phase and blast crisis); Imatinib is
also effective also for treatment of gastrointestinal stromal tumors
expressing the c-kit (CD117) tyrosine kinase
• Imatinib is well absorbed orally, and it is metabolized in the liver,
with elimination of metabolites occurring mainly in feces via biliary
excretion
• Toxicity - diarrhea, myalgia, fluid retention, and congestive heart
failure
Other TKIs
• Dasatinib and nilotinib are TKIs with similar mechanisms and uses as Imatinib; both
are active against Imatinib resistant CML
• Pharmacokinetics of TKIs
• Imatinib, dasatinib, and nilotinib are all metabolized in the liver, mainly by the
CYP3A4 liver microsomal enzyme. A large fraction of each drug is eliminated in feces
via the hepatobiliary route
• It is important to review the patient's current list of prescription and nonprescription
drugs because these agents have potential drug-drug interactions, especially with
those that are also metabolized by the CYP3A4 system
• In addition, patients should avoid grapefruit products (CYP3A4 inhibitor) and the use
of St. John's wort (CYP3A4 inducer), as they may alter the clinical activity of these
small molecule inhibitors
Growth factor receptor inhibitors
• Trastuzumab, a monoclonal antibody, recognizes a surface protein in
breast cancer cells that overexpress the (human epidermal growth
factor receptor 2) HER-2/neu receptor for epidermal growth factor
(25-30%)
• By binding to the HER-2/neu protein, trastuzumab inhibits growth of
tumour cells and mediates antibody dependent cellular cytotoxicity
(ADCC) in cancer cells overexpressing HER-2/neu
• Acute toxicity of this antibody includes nausea and vomiting, chills,
fevers, and headache
• Trastuzumab may cause cardiac dysfunction, including heart failure
• Several other drugs inhibit an epidermal growth factor receptor
(EGFR) that is distinct from the HER-2/neu receptor for the epidermal
growth factor that is targeted by trastuzumab
• The EGFR regulates signaling pathways involved in cellular
proliferation, invasion and metastasis, and angiogenesis
• It is also implicated in inhibiting the cytotoxic activity of some
anticancer drugs and radiation therapy
• Cetuximab is a chimeric monoclonal antibody directed against the
extracellular domain of the EGFR, and it is presently approved for use
in combination with irinotecan for metastatic colon cancer in the
refractory setting or as monotherapy in patients who are deemed to
be irinotecan-refractory
• Cetuximab is of the G1 isotype, its antitumor activity may be mediated
in part by immunologic-mediated mechanisms
• This agent is also approved for use in combination with radiation
therapy in patients with locally advanced head and neck cancer
Cetuximab
• Administration/pharmacokinetics
• Although this antibody was initially approved to be administered on a
weekly schedule, pharmacokinetic studies have shown that an every-
2-week schedule provides the same level of clinical activity as the
weekly schedule
• Toxicity
• Cetuximab is well tolerated, with the main adverse effects being an
acneiform skin rash, hypersensitivity infusion reaction, and
hypomagnesemia
Panitumumab
• Panitumumab is a fully human monoclonal antibody directed against the
EGFR and works through inhibition of the EGFR signaling pathway
• In contrast to cetuximab, this antibody is of the G2 isotype, and as such,
it would not be expected to exert any immunologic-mediated effects
• Presently, panitumumab is approved for patients with refractory
metastatic colorectal cancer who have been treated with all other active
agents
• As this is a fully human antibody, infusion-related reactions are seen only
rarely, and acneiform skin rash and hypomagnesemia are the two main
adverse effects associated with this agent.
Gefitinib & Erlotinib
• Gefitinib and erlotinib are small molecule inhibitors of the tyrosine
kinase domain associated with the EGFR, and both are used in the
treatment of non-small cell lung cancer that is refractory to at least
one prior chemotherapy regimen
• Patients who are nonsmokers and who have a bronchoalveolar
histologic subtype appear to be more responsive to these agents
• In addition, erlotinib has been approved for use in combination with
gemcitabine for the treatment of advanced pancreatic cancer
Gefitinib & Erlotinib
• Both agents are metabolized in the liver by the CYP3A4 enzyme
system, and elimination is mainly hepatic with excretion in feces
• Caution must be taken when using these agents with drugs that are
also metabolized by the liver CYP3A4 system, such as phenytoin and
warfarin, and the use of grapefruit products should be avoided
• Toxicity
• An acneiform skin rash, diarrhea, and anorexia and fatigue are the
most common adverse effects observed with these small molecules
Agents acting on VEGF signalling
• The vascular endothelial growth factor (VEGF) is one of the most
important angiogenic growth factors
• The growth of both primary and metastatic tumors requires an intact
vasculature
• As a result, the VEGF-signaling pathway represents an attractive target
for cancer treatment
Agents acting on VEGF signalling
• Bevacizumab is a recombinant humanized monoclonal antibody that targets
all forms of VEGF-A; this antibody binds to and prevents VEGF-A from
interacting with the target VEGF receptors
• Clinical uses – metastatic colorectal cancer, non-small lung cancer; breast
cancer
• Use for age-related macular degeneration (ARMD)
• VEGF has been demonstrated in human specimens of choroidal
neovascularization (CNV) and animal models have confirmed that this protein
is capable of inducing CN
• Therefore, targeted inhibition of VEGF is a reasonable approach for the
treatment of CNV in ARMD
Bevacizumab
• Toxicity
• One potential advantage of this antibody is that it does not appear to
exacerbate the toxicities typically observed with cytotoxic
chemotherapy
• The main safety concerns associated with bevacizumab include
hypertension, an increased incidence of arterial thromboembolic
events (transient ischemic attack, stroke, angina, and myocardial
infarction), wound healing complications and gastrointestinal
perforations, and proteinuria
Sorafenib & Sunitinib
• Sorafenib is a small molecule that inhibits multiple receptor tyrosine kinases
(RTKs), especially VEGF-R2 and VEGF-R3, platelet-derived growth factor-
(PDGFR-), and raf kinase
• It was initially approved for advanced renal cell cancer, and recently was
approved for advanced hepatocellular cancer
• Sunitinib is similar to sorafenib in that it inhibits multiple RTKs, although the
specific types are somewhat different; they include PDGFR- and PDGFR-,
VEGFR-R1, VEGF-R2, VEGF-R3, and c-kit
• It is approved for the treatment of advanced renal cell cancer and for the
treatment of gastrointestinal stromal tumors (GIST) after disease
progression on or with intolerance to imatinib
Sorafenib & Sunitinib
• Both sorafenib and sunitinib are metabolized in the liver by the
CYP3A4 system, and elimination is primarily hepatic with excretion in
feces
• Each of these agents has potential interactions with drugs that are
also metabolized by the CYP3A4 system, especially warfarin
• In addition, patients should avoid grapefruit products and the use of
St. John's wort, as they may alter the clinical activity of these agents
Sorafenib, & Sunitinib
• Toxicity
• Hypertension, bleeding complications, and fatigue are the most
common adverse effects seen with both agents
• With respect to sorafenib, skin rash and the hand-foot syndrome are
observed in up to 30–50% of patients
• For sunitinib, there is also an increased risk of cardiac dysfunction,
which, in some cases, can lead to congestive heart failure
Asparaginase
• Asparaginase (L -asparagine amidohydrolase) is an enzyme used to
treat childhood ALL.
• Mechanism - It hydrolyzes circulating L-asparagine to aspartic acid
and ammonia; because tumor cells in ALL lack asparagine synthetase,
they require an exogenous source of L-asparagine
• Thus, depletion of L-asparagine results in effective inhibition of
protein synthesis
• In contrast, normal cells can synthesize L-asparagine and thus are less
susceptible to the cytotoxic action of asparaginase
Asparaginase
• Toxicity
• The main adverse effect of this agent is a hypersensitivity reaction
manifested by fever, chills, nausea and vomiting, skin rash, and
urticarial
• Severe cases can present with bronchospasm, respiratory failure, and
hypotension
• Other adverse effects include an increased risk of both clotting and
bleeding as a result of alterations in various clotting factors,
pancreatitis, and neurologic toxicity with lethargy, confusion,
hallucinations, and in severe cases, coma
Retinoic acid derivatives
• Tretinoin (all-trans-retinoic acid) is active in patients with acute
promyelocytic leukemia (APL) through the induction of terminal
differentiation, in which the leukemic promyelocytes lose their ability
to proliferate
• Clinical use - this agent is approved for use in APL following
progression or relapse with anthracycline-based chemotherapy and
for patients in whom anthracycline-based chemotherapy is
contraindicated
Retinoic acid derivatives
• Toxicity - vitamin A toxicity manifesting as headache, fever, dry skin
and mucous membranes, skin rash, pruritus, and conjunctivitis;
retinoic acid syndrome (fever, leukocytosis, dyspnea, weight gain,
diffuse pulmonary infiltrates, and pleural or pericardial effusions);
increased serum cholesterol and triglyceride levels; central nervous
system toxicity in the form of dizziness, anxiety, depression,
confusion, and agitation; abdominal pain and diarrhea; and transient
elevations in liver function tests
Arsenic trioxide (As2O3)
• Mechanism
• It functions by inducing differentiation through degradation of the
chimeric PML/RAR- protein
• In addition, it induces apoptosis through a mitochondrion-dependent
process, resulting in subsequent release of cytochrome C with
caspase activation
• Clinical use - Arsenic trioxide is used for induction of remission in
patients with APL with the t(15:17) chromosomal translocation
refractory to or relapsed following first-line therapy with all-trans-
retinoic acid- and anthracycline-based chemotherapy
Arsenic trioxide (As2O3)
• Pharmacokinetics/administration
• This drug is administered via the intravenous route, and it is widely
distributed in the body
• Toxicity
• The main toxicities are fatigue, electrocardiographic changes with QT
prolongation, arrhythmias, and a syndrome characterized by fever,
dyspnea, skin rash, fluid retention, and weight gain
Rituximab
• Rituximab is a monoclonal antibody that binds to a surface protein in
non-Hodgkin’s lymphoma cells and induces complement-mediated
lysis, direct cytotoxicity, and induction of apoptosis
• It is currently used with conventional anticancer drugs (eg,
cyclophosphamide plus vincristine plus prednisone) in low-grade
lymphomas
• Rituximab is associated with hypersensitivity reactions and
myelosuppression (with profound neutropenia)
Proteasome Inhibitors
• Bortezomib and carfilzomib are inhibitors of the chymotrypsin like
activity of the 26S proteasome in mammalian cells
• The 26S proteasome is a large protein complex that degrades
ubiquitinated proteins, such as cyclin-dependent kinases
• Inhibition results in down-regulation of the nuclear factor kappa B
(NF-κB) signaling pathway
• Clinical use – multiple myeloma
Proteasome Inhibitors
• Pharmacokinetics – eliminated by the liver; it is advantageous for use
in patients with renal impairment as a result of multiple myeloma
• Toxicity
• Adverse effects include peripheral neuropathy, thrombocytopenia,
heart failure, and hypotension
Hormonal anticancer agents
Gonadal hormone antagonists
• Tamoxifen, a selective estrogen receptor modulator blocks the binding of
estrogen to receptors of estrogen-sensitive cancer cells in breast tissue; other
examples include torimefene, raloxifene
• Clinical use - The drug is used in receptor-positive breast carcinoma and has
been shown to have a preventive effect in women at high risk for breast
cancer
• Toxicity
• Because it has agonist activity in the endometrium, tamoxifen increases the
risk of endometrial hyperplasia and neoplasia
• Other adverse effects include nausea and vomiting, hot flushes, vaginal
bleeding, and venous thrombosis
Gonadal hormone antagonists
• Flutamide is an androgen receptor antagonist used in prostatic
carcinoma
• Adverse effects include gynecomastia, hot flushes, and hepatic
dysfunction
Gonadotropin-Releasing Hormone (GnRH)
Analogs
• Leuprolide, goserelin, and nafarelin are GnRH agonists, effective in
prostatic carcinoma
• When administered in constant doses so as to maintain stable blood
levels, they inhibit release of pituitary luteinizing hormone (LH) and
follicle-stimulating hormone (FSH)
• Physiologic secretion of GnRH is pulsatile; constant serum levels
cause down-regulation of GnRH recpetors and a drop in gonadotropin
levels leading to reduced sex hormone levels to castrate levels
Gonadotropin-Releasing Hormone (GnRH)
Analogs
• Toxicity
• Leuprolide may cause bone pain, gynecomastia, hematuria,
impotence, and testicular atrophy
Immunosuppressive agents
Immunosuppressive agents
• Immunosuppressive agents have proved very useful in minimizing the
occurrence or impact of deleterious effects of exaggerated or
inappropriate immune responses
• Glucocorticoids
• Glucocorticoids (corticosteroids) were the first hormonal agents
recognized as having lympholytic properties
• Administration of any glucocorticoid reduces the size and lymphoid
content of the lymph nodes and spleen, although it has no toxic effect
on proliferating myeloid or erythroid stem cells in the bone marrow
Glucocorticoids
• Anti-inflammatory and immunosuppressive effects
• Glucocorticoids dramatically reduce the manifestations of
inflammation
• This is due to their profound effects on the concentration,
distribution, and function of peripheral leukocytes and to their
suppressive effects on the inflammatory cytokines and chemokines
and on other mediators of inflammation
• Inflammation, regardless of its cause, is characterized by the
extravasation and infiltration of leukocytes into the affected tissue
Anti-inflammatory and immunosuppressive effects
of glucocorticoids
• After a single dose of glucocorticoid, the concentration of neutrophils
in the circulation increases while the lymphocytes (T and B cells),
monocytes, eosinophils, and basophils decrease
• The increase in neutrophils is due both to the increased influx into
the blood from the bone marrow and to the decreased migration
from the blood vessels, leading to a reduction in the number of cells
at the site of inflammation
• The reduction in circulating lymphocytes, monocytes, eosinophils, and
basophils is primarily the result of their movement from the vascular
bed to lymphoid tissue
of glucocorticoids
• Glucocorticoids also inhibit the functions of tissue macrophages and
other antigen-presenting cells by lowering the ability of these cells to
respond to antigens and mitogens is reduced.
• The effect on macrophages is particularly marked and limits their
ability to phagocytose and kill microorganisms and to produce tumor
necrosis factor-, interleukin-1, metalloproteinases, and plasminogen
activator
• Both macrophages and lymphocytes produce less interleukin-12 and
interferon-, important inducers of TH1 cell activity, and cellular
immunity.
of glucocorticoids
• Effect on humoral immunity
• the primary antibody response can be diminished, and with continued
use, previously established antibody responses are also decreased
• Additionally, continuous administration of corticosteroid increases the
fractional catabolic rate of IgG, the major class of antibody
immunoglobulins, thus lowering the effective concentration of
specific antibodies
• Contact hypersensitivity mediated by DTH T cells, for example, is
usually abrogated by glucocorticoid therapy
of glucocorticoids
• In addition to their effects on leukocyte function, glucocorticoids
influence the inflammatory response by reducing the prostaglandin,
leukotriene, and platelet-activating factor synthesis that results from
activation of phospholipase A2
• Finally, glucocorticoids reduce expression of cyclooxygenase-2, the
inducible form of this enzyme, in inflammatory cells, thus reducing
the amount of enzyme available to produce prostaglandins
Clinical uses of glucocorticoids
1. Autoimmune conditions: Idiopathic thrombocytopenic purpura,
rheumatoid arthritis, hemolytic anemia, acute glomerulonephritis,
etc
2. Glucocorticoids modulate allergic reactions and are useful in the
treatment of diseases like asthma or as premedication for other
agents (eg, blood products, chemotherapy) that might cause
undesirable immune responses
3. Glucocorticoids are first-line immunosuppressive therapy for both
solid organ and hematopoietic stem cell transplant recipients, with
variable results
Calcineurin inhibitors
Cyclosporine
• Mechanism
• Cyclosporine is a peptide antibiotic blocks T cell activation by binding to
cyclophilin
• Cyclosporine and cyclophilin (an immunophillin) form a complex that inhibits the
cytoplasmic phosphatase, calcineurin, which is necessary for the activation of a T
cell– specific transcription factor
• This transcription factor, NF-AT, is involved in the synthesis of interleukins (eg, IL-
2) by activated T cells
• Cyclosporine also inhibits the gene transcription of IL-2, IL-3, IFN-γ, and other
factors produced by antigen-stimulated T cells
• Therefore it will inhibit cell mediated immunity
Cyclosporine
• Clinical uses
• Human organ transplantation
• Treatment of graft-versus-host (GVH) disease after hematopoietic stem cell
transplantation
• Treatment of selected autoimmune disorders (RA, psoriasis, asthma)
• Cyclosporine may be given intravenously or orally, though it is slowly and
incompletely absorbed (20–50%)
• Primarily metabolized by the P450 3A enzyme system in the liver with
resultant multiple drug interactions
Cyclosporine
• Toxicity - nephrotoxicity, hypertension, hyperglycemia, liver
dysfunction, hyperkalemia, altered mental status, seizures, and
hirsutism
• Causes little bone marrow toxicity
• Risk of incident malignancies (lymphoma, Kaposi’s sarcoma, skin
cancer)
• Tumors may arise after cyclosporine treatment because the drug
induces TGF-β, which promotes tumor invasion and metastasis
• Tacrolimus - bears similar properties as cyclosporine although it is more
potent
Proliferation signal inhibitors
• Examples –sirolimus (rapamycin), everolimus
• Mechanism
• PSIs bind the circulating immunophilin (FK506-binding protein 12), resulting in an
active complex that blocks the molecular target of rapamycin (mTOR)
• The mTOR is a key component of a complex intracellular signaling pathway
involved in cellular processes such as cell growth and proliferation,
angiogenesis, and metabolism
• Thus, blockade of mTOR ultimately can lead to inhibition of interleukin-driven T-
cell proliferation
• Both everolimus and sirolimus also may inhibit B-cell proliferation and
immunoglobulin production
• Clinical uses
• Prevent rejection of solid organ allografts
• Prophylaxis and as therapy for steroid-refractory acute and chronic
GVH disease in hematopoietic stem cell transplant recipients
• Topical sirolimus - dermatologic disorders and, in combination with
cyclosporine, in the management of uveoretinitis
• Sirolimus-eluting coronary stents have been shown to reduce
restenosis and additional adverse cardiac events in patients with severe
coronary artery disease, due to the drug’s antiproliferativeeffects
• Sirolimus is available only as an oral drug
• Its half-life is about 60 hours, while that of everolimus is about 43
hours. Both drugs are substrates for both cytochrome P450 3A and P-
glycoprotein
• Hence, significant drug interactions can occur e.g. use with
cyclosporine can increase the plasma levels of both sirolimus and
everolimus such that drug levels need to be monitored
• Toxicities
• Profound myelosuppression (especially thrombocytopenia),
hepatotoxicity, diarrhea, hypertriglyceridemia, pneumonitis, and
headache
• Because nephrotoxicity is of major concern when administering
calcineurin inhibitors, and since renal toxicity is less common with
PSIs, there is interest in increased early use of the latter agents
• However, increased use in stem cell transplantation regimens as GVH
disease prophylaxis, particularly when combined with tacrolimus, has
revealed an increased incidence of hemolytic-uremic syndrome
Tofacitinib
• Tofacitinib (Xeljanz) inhibits JAK enzymes that stimulate
hematopoiesis and immune cell function in response to cytokine or
growth factor signaling
• Tofacitinib reduces circulating NK cells, serum immunoglobulins, and
C-reactive protein
• It is approved for adults with moderate to severe RA
• It has a black box warning for serious infections and malignancies,
similar to anti–TNF-α Mabs (see below)
Mycophenolate mofetil
• Mechanism of action—This drug is rapidly converted into
mycophenolic acid, which inhibits inosine monophosphate
dehydrogenase, an enzyme in the de novo pathway of guanosine
triphosphate (GTP) synthesis
• This action suppresses both B- and T-lymphocyte activation
• Lymphocytes are particularly susceptible to inhibitors of the de novo
pathway because they lack the enzymes necessary for the alternative
salvage pathway for GTP synthesis
Mycophenolate mofetil
• Clinical use—Mycophenolate mofetil has been used successfully as a
sole agent in kidney, liver, and heart transplantations
• In renal transplantations, its use with low-dose cyclosporine has
reduced cyclosporine-induced nephrotoxicity
• Toxicity—This drug can cause gastrointestinal disturbances and
myelosuppression, especially neutropenia
Immunomodulatory agents (ImiDs)
• Examples: Thalidomide, lenalidomide, pomalidomide
• Mechanism – Thalidomide inhibits angiogenesis and has anti-
inflammatory and immunomodulatory effects
• It inhibits tumor necrosis factor alpha (TNF-α), reduces phagocytosis
by neutrophils, increases production of IL-10, alters adhesion
molecule expression, and enhances cell-mediated immunity via
interactions with T cells
Thalidomide
• Clinical use – majorly in erythema nodosum leprosum and multiple
myeloma
• Phamacokinetics – It is eliminated renally; renal dose adjustment is
however not necessary
• Toxicity – teratogenicity (phocomelia) peripheral neuropathy,
constipation, rash, fatigue, hypothyroidism, and increased risk of
deep-vein thrombosis (risk is highest when used alongside
dexamethasone)
Lenalidomide
• Lenalidomide has greater efficacy and less risk of VTE and peripheral
neuropathy than thalidomide
• It is myelosuppressive
• However it cannot be used in renal failure and long courses or
treatment (>4 cycles) should not be administered in transplant
candidates because it reduced stem cell yield for autologous
transplant
Cytotoxic agents
• Azathioprine
• Azathioprine is a prodrug of mercaptopurine and, like
mercaptopurine, functions as an antimetabolite
• Mechanism - Azathioprine and mercaptopurine appear to produce
immunosuppression by interfering with purine nucleic acid
metabolism at steps that are required for the wave of lymphoid cell
proliferation that follows antigenic stimulation
Azathioprine
• Clinical use - maintaining renal allografts, acute glomerulonephritis,
systemic lupus erythematosus, rheumatoid arthritis, Crohn’s disease,
and multiple sclerosis, prednisone-resistant antibody-mediated
idiopathic thrombocytopenic purpura and autoimmune hemolytic
anemias
• Toxicity is similar to 6-MP
Cyclophosphamide
• The alkylating agent cyclophosphamide is one of the most efficacious
immunosuppressive drugs available
• Mechanism - destroys proliferating lymphoid cells but also appears to
alkylate some resting cells
• It has been observed that very large doses (eg, >120 mg/kg intravenously
over several days) may induce an apparent specific tolerance to a new
antigen if the drug is administered simultaneously with, or shortly after, the
antigen
• Clinical use - systemic lupus erythematosus), acquired factor XIII antibodies
and bleeding syndromes, autoimmune hemolytic anemia, antibody-induced
pure red cell aplasia, and Wegener’s granulomatosis
Cyclophosphamide
• Although cyclophosphamide appears to induce tolerance for marrow
or immune cell grafting, its use does not prevent the subsequent
GVH syndrome, which may be serious or lethal if the donor is a poor
histocompatibility match (despite the severe immunosuppression
induced by high doses of cyclophosphamide)
• Other toxicities have been discussed under cancer chemotherapy
Other cytotoxic agents
• Other cytotoxic agents, including methotrexate, vincristine, and
cytarabine also have immunosuppressive properties
Pyrimidine synthesis inhibitors
• Leflunomide is a prodrug of an inhibitor of pyrimidine synthesis
• Teriflunomide is the principal active metabolite of leflunomide
• They both reversibly inhibit the mitochondrial enzyme dihydroorotate
dehydrogenase, which is involved in pyrimidine synthesis and
ultimately results in decreased lymphocyte activation
• They have anti-inflammatory activity in addition to
immunomodulatory properties
Leflunomide
• Leflunomide is orally active, and the active metabolite has a long half-
life of several weeks
• Thus, the drug should be started with a loading dose, but it can be
taken once daily after reaching steady state
• Clinical use - rheumatoid arthritis
Leflunomide
• Toxicities include elevation of liver enzymes with some risk of liver
damage and renal impairment
• Patients with severe liver disease should not receive leflunomide
• This drug is teratogenic and contraindicated in pregnancy
• A low frequency of cardiovascular effects (angina, tachycardia) has
been reported
Hydroxychloroquine
• Hydroxychloroquine is an antimalarial agent with immunosuppressant
properties
• Mechanism - It is thought to suppress intracellular antigen processing
and loading of peptides onto MHC class II molecules by increasing the
pH of lysosomal and endosomal compartments, thereby decreasing T-
cell activation
Hydroxychloroquine
• Clinical use - autoimmune disorders e.g. rheumatoid arthritis and
systemic lupus erythematosus, GVH disease after allogeneic stem cell
transplantation
• Toxicity - rash, gastrointestinal disturbance, myopathy, neuropathy,
ocular toxicity
Immunosuppressive antibodies
Antilymphocyte globulin and antithymocyte
globulin (ATG)
• Mechanism of action—Two types of antisera directed against
lymphocytes are available
• Antilymphocyte globulin (ALG) and antithymocyte globulin (ATG) are
produced in horses, sheep, or rabbits by immunization against human
lymphoid cells
• Antibodies in these preparations bind to human T cells involved in
antigen recognition and initiate their destruction by serum complement
• These antibodies selectively block cellular immunity rather than antibody
formation, which accounts for their ability to suppress organ graft
rejection, a cell-mediated process
globulin (ATG)
• Clinical use — ALG and ATG are used before allogeneic stem cell
transplantation to prevent graft-versus-host reaction
• They are also used in combination with other immunosuppressants
for solid organs transplantation
globulin (ATG)
• Toxicity—Because humoral immunity may remain intact, injection of
ALG or ATG can cause type III hypersensitivity reactions, including
serum sickness and anaphylaxis
• Pain and erythema occur at injection sites, and lymphoma has been
noted as a late complication
Immune globulin intravenous (IGIV)
• Mechanism of action—Intravenous use of this immunoglobulin
preparation (usually IgG) prepared from pools of thousands of healthy
donors is believed to have a normalizing effect on an individual’s
immune networks
• Its precise mechanism of action is not known
• Clinical use—IGIV has proved useful in a wide range of conditions
including immunoglobulin deficiencies, autoimmune disorders, HIV
disease, and stem cell transplantation
• Toxicity—Renal toxicity, including acute renal failure, is a particular
concern with IGIV
Rho(D) immune globulin
• Mechanism of action —RhoGAM is a human IgG preparation that
contains antibodies against red cell Rho(D) antigens
• Administration of this antibody to Rho(D)-negative mothers at time of
antigen exposure (ie, birth of an Rho(D)-positive child) blocks the
primary immune response to the foreign cells
Rho(D) immune globulin
• Clinical use—Rho(D) immune globulin is used for prevention of Rh
hemolytic disease of the newborn
• In women treated with Rho(D) immune globulin 24–72 h after
delivery, maternal antibodies to Rh-positive cells are not produced in
subsequent pregnancies, and hemolytic disease of the neonate is
averted
Monoclonal antibodies (MAbs)
• A monoclonal antibody is an antibody made by cloning a unique
clone of B cells
• All subsequent antibodies derived this way trace back to a unique
parent cell
• Monoclonal antibodies can have monovalent affinity, binding only to
the same epitope (part of an antigen that triggers an immune
response)
Monoclonal antibodies (MAbs)
• Monoclonal antibodies (MAbs) have the advantage of high specificity
because they can be developed for interaction with a single molecule
• “Humanization” of murine monoclonal antibodies and wholly human
monoclonal antibodies (based on genetic engineering of transgenic
mice that make human antibodies) have reduced, but not completely
eliminated, the likelihood of formation of neutralizing antibodies and
of immune reactions
Anti-TNF agents
• Infliximab—This chimeric MAb is targeted against TNF-α, a proinflammatory
cytokine, and thereby decreases formation of interleukins and adhesion
molecules involved in leukocyte activation
• Clinical use - Infliximab induces remissions in treatment-resistant Crohn’s
disease In combination with methotrexate, infliximab improves symptoms in
patients with rheumatoid arthritis
• It also is effective in the treatment of ulcerative colitis, ankylosing spondylitis,
and psoriatic arthritis
• Toxicity - Infusion reactions and an increased rate of infection may occur
• Adalimumab is a completely human IgG monoclonal antibody that binds to
TNF-α and is approved for treatment of rheumatoid arthritis
Anti-TNF agents
• Etanercept
• Though not a true MAb, etanercept is an immunoglobulin-based
agent that also binds with high affinity and thereby sequesters TNF-α
• It is a dimer of identical chains of a human TNF receptor fused to a
human IgG constant region
Etanercept
• Clinical use - Etanercept is used in arthritis, psoriasis, and ankylosing
spondylitis, and it is being investigated in other inflammatory diseases
• Toxicity – Injection site reactions and hypersensitivity may occur
• All of the anti-TNF-α agents increase the risk of serious infection,
reactivation of tuberculosis, and lymphoma
• Certolizumab and golimumab are two newer anti-TNF agents
Target IL-2: Daclizumab
• Target IL-2: Daclizumab—Daclizumab is a highly specific MAb that
binds to the alpha subunit of the IL-2 receptor displayed on the
surface of T cells and prevents activation by IL-2
• Clinical use - It is used in combination with other
immunosuppressants to prevent renal transplant rejection
• In contrast to cyclosporine, tacrolimus, or cytotoxic
immunosuppressants, the adverse effects of daclizumab are
equivalent to those of placebo
• Basiliximab is a chimeric human-mouse IgG with an action that is
equivalent to that of daclizumab
Other MAbs
• Target other: Other anti-inflammatory antibodies are alefacept
(targeting CD2), canakinumab (IL-1β), natalizumab (α4 β1-integrin),
omalizumab (IgE), and ustekinumab (IL-12)
Immunomodulation therapy
• Agents that stimulate immune responses represent a newer area in
immunopharmacology with the potential for important therapeutic
uses, including the treatment of immune deficiency diseases, chronic
infectious diseases, and cancer
Aldesleukin
• Aldesleukin
• Aldesleukin is recombinant interleukin-2 (IL-2), an endogenous
lymphokine that promotes the production of cytotoxic T
lymphocytes and activates NK cells
• Aldesleukin is indicated for the adjunctive treatment of renal cell
carcinoma and malignant melanoma
• It is investigational for possible efficacy in restoring immune function
in AIDS and other immune deficiency disorders
Interferons
• Interferon-α-2a inhibits cell proliferation and is used in hairy cell
leukemia, chronic myelogenous leukemia, malignant melanoma
Kaposi’s sarcoma, and hepatitis B and C
• Interferon-a-1b has some beneficial effects in relapsing multiple
sclerosis
• Interferon-f-1b has greater immune-enhancing actions than the other
interferons and appears to act by increasing the synthesis of TNF
• The recombinant form is used to decrease the incidence and severity
of infections in patients with chronic granulomatous disease
Cytokine inhibitors
• Cytokine inhibitors
• An important application of immunomodulation therapy involves the
use of cytokine inhibitors for inflammatory diseases
• Anakinra is a recombinant form of the naturally occurring IL-1
receptor antagonist that prevents IL-1 from binding to its receptor
stemming the cascade of cytokines that would otherwise be released
• Anakinra is approved for use in adult rheumatoid arthritis patients
who have failed treatment with one or more disease-modifying
antirheumatic drugs
Patient monitoring
• Patients must be carefully monitored for serious infections or
malignancies if they are also taking an anti-TNF-α drug, have chronic
infections, or are otherwise immunosuppressed
Dermatologic pharmacology
Agents used in acne
• Topical retinoic acid / tretinoin / all-trans-retinoic acid (acid form of
vitamin A)
• Mechanism and clinical effects
• Its action in acne has been attributed to decreased cohesion between
epidermal cells and increased epidermal cell turnover
• This is thought to result in the expulsion of open comedones and the
transformation of closed comedones into open ones
• These actions are mediated through binding to retinoid receptors
RARs
Topical retinoic acid
• Topically applied retinoic acid remains chiefly in the epidermis, with
less than 10% absorption into the circulation
• The small quantities of retinoic acid absorbed following topical
application are metabolized by the liver and excreted in bile and urine
• Topical retinoic acid should be applied to dry skin only, and care
should be taken to avoid contact with the corners of the nose, eyes,
mouth, and mucous membranes
• Toxicity
• The most common adverse effects of topical retinoic acid are
erythema and dryness that occur in the first few weeks of use, but
these can be expected to resolve with continued therapy
• Animal studies suggest that this drug may increase the tumorigenic
potential of ultraviolet radiation
• In light of this, patients using retinoic acid should be advised to avoid
or minimize sun exposure and use a protective sunscreen
• Retinoic acid appears to worsen acne in the first 4-6 weeks of rx due
to uncovering previously unseen comedones
• This will eventually clear and clinical benefit can be observe after 8-12
weeks of rx
Adapalene
• Adapalene (Differin) is a derivative of naphthoic acid that resembles
retinoic acid in structure and effects
• It is available for daily application as a 0.1% gel, cream, or lotion and a
0.3% gel
• Unlike tretinoin, adapalene is photochemically stable and shows little
decrease in efficacy when used in combination with benzoyl peroxide
Adapalene
• Adapalene is less irritating than tretinoin and is most effective in
patients with mild to moderate acne vulgaris
• Adapalene is also available in a fixed-dose combination gel with
benzoyl peroxide (Epiduo, Epiduo Forte)
Tazarotene
• Tazarotene (Tazorac, Fabior) is an acetylenic retinoid available as a
0.1% gel, cream, and foam for the treatment of mild to moderately
• severe facial acne
• Topical tazarotene should be used by women of childbearing age only
after contraceptive counseling
• It is recommended that tazarotene should not be used by pregnant
women
Isotretinoin
• Isotretinoin is a synthetic retinoid currently restricted to the oral
treatment of severe cystic acne that is recalcitrant to standard
therapies
• The precise mechanism of action of isotretinoin in cystic acne is not
known, although it appears to act by inhibiting sebaceous gland size
and function
• The drug is well absorbed, is extensively bound to plasma albumin,
and has an elimination half-life of 10–20 hours
Isotretinoin
• Toxicity
• Common adverse effects resemble hypervitaminosis A and include dryness
and itching of the skin and mucous membranes
• Less common adverse effects which are are reversible on discontinuance of
therapy include headache, corneal opacities, pseudotumor cerebri,
inflammatory bowel disease, anorexia, alopecia, and muscle and joint pains
• Skeletal hyperostosis has been observed in patients receiving isotretinoin
with premature closure of epiphyses noted in children treated with this
medication
• Lipid abnormalities (triglycerides, high-density lipoproteins) are frequent;
their clinical relevance is unknown at present
Isotretinoin
• Teratogenicity is a significant risk in patients taking isotretinoin;
therefore, the FDA mandates that women of childbearing potential must
use an effective form of contraception for at least 1 month before,
throughout isotretinoin therapy, and for one or more menstrual cycles
following discontinuance of treatment
• A negative serum pregnancy test must be obtained within 2 weeks
before starting therapy in these patients, and therapy should be initiated
only on the second or third day of the next normal menstrual period
• In the USA, health care professionals, pharmacists, and patients must
utilize the mandatory iPLEDGE registration and follow-up system
Benzoyl peroxide
• It has been postulated that the mechanism of action of benzoyl
peroxide in acne is related to its antimicrobial activity against P acnes
and to its peeling and comedolytic effects
• Benzoyl peroxide penetrates the stratum corneum or follicular
openings unchanged and is converted metabolically to benzoic acid
within the epidermis and dermis
• Less than 5% of an applied dose is absorbed from the skin in an 8-hour
period
Benzoyl peroxide
• Toxicity
• Benzoyl peroxide is a potent contact sensitizer in experimental
studies, and this adverse effect may occur in up to 1% of acne patients
• Irritation of the eyes and mucous membranes (avoid contact)
• Benzoyl peroxide is an oxidant and may rarely cause bleaching of the
hair or colored fabrics
Benzoyl peroxide
• Toxicity
• To decrease the likelihood of irritation, application should be limited
to a low concentration (2.5%) once daily for the first week of therapy
and increased in frequency and strength if the preparation is well
tolerated
Azelaic acid
• Mechanism
• Its mechanism of action has not been fully determined, but
preliminary studies demonstrate antimicrobial activity against P
acnes as well as in vitro inhibitory effects on the conversion of
testosterone to dihydrotestosterone
• Used for acne vulgaris and acne rosacea
Azelaic acid
• Administration
• Initial therapy is begun with once-daily applications of the 20% cream,
15% gel, or 15% foam to the affected areas for 1 week and twice-daily
applications thereafter
• Toxicity
• Most patients experience mild irritation with redness and dryness of
the skin during the first week of treatment
• Clinical improvement is noted in 6–8 weeks of continuous therapy
Brimonidine
• Brimonidine is an α2-adrenergic agonist indicated for the topical
treatment of persistent facial erythema of rosacea in adults 18 years
of age or older
• Daily topical application of brimonidine 0.33% gel may reduce
erythema through direct vasoconstriction
Brimonidine
• Toxicity
• Exacerbation of facial erythema and flushing may occur, ranging from
30 minutes to several hours after application
• Alpha2 agonists can lower blood pressure therefore, brimonidine
should be used with caution in patients with severe, unstable, or
uncontrolled cardiovascular disease
Antimicrobial agents used in acne
• These include clindamycin, metronidazole, erythromycin, dapsone
for acne vulgaris and sodium sulfacetamide and ivermectin for acne
rosacea
• Both topical and systemic agents may be used; the latter being more
potent albeit with increased systemic adverse effects
• Their mechanisms generally involve antimicrobial effect on implicated
organisms such as Propionibacterium acnes in vulgaris and demodex
mites in rosacea
• The toxicities of the topical antimicrobials may involve skin irritation
Drugs for psoriasis
• Acitretin
• Its mechanism is similar to other retinoid derivatives
• Clinical use
• Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate,
is effective in the treatment of psoriasis, especially pustular forms
• It is given orally at a dosage of 25–50 mg/d
Acitretin
• Toxicity
• Adverse effects attributable to acitretin therapy are similar to those seen with
isotretinoin and resemble hypervitaminosis A
• Elevations in cholesterol and triglycerides may be noted with acitretin, and
hepatotoxicity with liver enzyme elevations has been reported
• Acitretin is more teratogenic than isotretinoin in the animal species studied to
date, which is of special concern in view of the drug’s prolonged elimination
time (more than 3 months) after chronic administration
• In cases where etretinate is formed by concomitant administration of acitretin
and ethanol, etretinate may be found in plasma and subcutaneous fat for
many years
Acitretin
• Acitretin safety considerations
• Acitretin must not be used by women who are pregnant or may
become pregnant while undergoing treatment or at any time for at
least 3 years after treatment is discontinued
• Ethanol must be strictly avoided during treatment with acitretin and
for 2 months after discontinuing therapy
• Patients must not donate blood during treatment and for 3 years after
acitretin is stopped.
Tazarotene
• Mechanism
• Tazarotene is a topical acetylenic retinoid prodrug that is hydrolyzed
to its active form by an esterase. The active metabolite, tazarotenic
acid, binds to retinoic acid receptors, resulting in modified gene
expression
• The precise mechanism of action in psoriasis is unknown but may
relate to both anti-inflammatory and antiproliferative actions
• Pharmacokinetics, administration and safety
• Tazarotene is absorbed percutaneously, and teratogenic systemic
concentrations may be achieved if applied to more than 20% of total
body surface area
• Women of childbearing potential must therefore be advised of the
risk prior to initiating therapy, and adequate birth control measures
must be utilized while on therapy
• Treatment of psoriasis should be limited to once-daily application of
either 0.05% or 0.1% gel not to exceed 20% of total body surface area
• Toxicity
• Adverse local effects include a burning or stinging sensation (sensory
irritation) and peeling, erythema, and localized edema of the skin
(irritant dermatitis)
• Potentiation of photosensitizing medication may occur, and patients
should be cautioned to minimize sunlight exposure and to use
sunscreens and protective clothing
Calcipotriene & calcitriol
• Calcipotriene (Dovonex, Sorilux) is a synthetic vitamin D3 derivative
(available as a 0.005% cream, scalp lotion, and foam) that is effective
in the treatment of plaque-type psoriasis vulgaris of moderate
severity
• Mechanism – inhibition of epidermal proliferation and stimulation of
differentiation of epidermal cells; it also increases the number of
vitamin D receptors in epidermal nuclei
Calcipotriene
• Toxicity
• Adverse effects include burning, itching, and mild irritation, with
dryness and erythema of the treatment are
• Care should be taken to avoid facial contact, which may cause ocular
irritation
• The combination of calcipotriene and betamethasone dipropionate
are available is more effective than its individual ingredients and is
well tolerated
Calcitriol
• Calcitriol (Vectical) contains 1,25-dihydroxycholecalciferol, the
hormonally active form of vitamin D3
• Calcitriol 3 mcg/g ointment is similar in efficacy to calcipotriene
0.005% ointment for the treatment of plaque-type psoriasis on the
body and is better tolerated in intertriginous and sensitive areas of
the skin
• Clinical studies show comparable safety data regarding adverse
cutaneous and systemic reactions between topical calcitriol and
calcipotriene ointment
Tar compounds
• Tar preparations are used mainly in the treatment of psoriasis,
dermatitis, and lichen simplex chronicus
• The phenolic constituents endow these compounds with antipruritic
properties, making them particularly valuable in the treatment of
chronic lichenified dermatitis
• Acute dermatitis with vesiculation and oozing may be irritated by
even weak tar preparations, which should be avoided
• However, in the subacute and chronic stages of dermatitis and
psoriasis, these preparations are quite useful and offer an alternative
to the use of topical corticosteroids
Coal tar compounds
• Toxicity
• The most common adverse reaction to coal tar compounds is an
irritant folliculitis, necessitating discontinuance of therapy to the
affected areas for a period of 3–5 days
• Photoirritation and allergic contact dermatitis may also occur
• Tar preparations should be avoided in patients who have previously
exhibited sensitivity to them
Salicylic acid
• Salicylic acid has been extensively used in dermatologic therapy as a
keratolytic agent
• The mechanism by which it produces its keratolytic and other
therapeutic effects is poorly understood
• The drug may solubilize cell surface proteins that keep the stratum
corneum intact, thereby resulting in desquamation of keratotic debris
• Salicylic acid is keratolytic in concentrations of 3–6%
• In concentrations greater than 6%, it can be destructive to tissue
Salicylic acid
• Toxicity
• Topical use may be associated with local irritation, acute
inflammation, and even ulceration with the use of high
concentrations of salicylic acid
• Particular care must be exercised when using the drug on the
extremities of patients with diabetes or peripheral vascular disease
• Urticarial, anaphylactic, and erythema multiforme reactions may
occur in patients who are allergic to salicylates
Salicylism
• Salicylism and death have occurred following topical application
• Presents with increased respiratory drive, tinnitus, nausea/vomiting,
neuroglycopenia (with seizures and coma), and acidosis
• In cases of severe intoxication, hemodialysis is the treatment of
choice
• It is advisable to limit both the total amount of salicylic acid applied
and the frequency of application
Agents used to treat glaucoma
Cholinomimetics
• Cholinomimetics:
1. Direct acting cholinomimetics
2. Indirectly acting cholinomimetics
Direct acting cholinomimetics
• Examples: carabachol (choline ester), pilocarpine (cholinomimetic alkaloid)
• Involves activating muscarinic receptors on effector cells to alter organ function
directly
• In the eye muscarinic agonists instilled into the conjunctival sac cause
contraction of the smooth muscle of the iris sphincter (resulting in miosis) and of
the ciliary muscle (resulting in accommodation)
• As a result, the iris is pulled away from the angle of the anterior chamber, and
the trabecular meshwork at the base of the ciliary muscle is opened
• Both effects facilitate aqueous humor outflow into the canal of Schlemm, which
drains the anterior chamber
Indirectly acting cholinomimetics
(cholinesterase inhibitors)
• Examples: Physostigmine (a carbamate); echothiphate (an
organophosphate)
• Mechanism - cholinesterase inhibitors increase the concentration of
endogenous acetylcholine at cholinoceptors by inhibiting
acetylcholinesterase
• The effects of the cholinesterase inhibitors on the eye, which is well
innervated by the parasympathetic nervous system, is qualitatively
quite similar to the effects of the direct-acting cholinomimetics
Cholinomimetics
• Toxicity
• Signs of muscarinic excess when given systemically in overdosage
• These effects include nausea, vomiting, diarrhea, urinary urgency,
salivation, sweating, cutaneous vasodilation, and bronchial
constriction
• The effects are all blocked competitively by atropine and its congeners
• Topical use in the eye is unlikely to produce the above systemic effects
Agents acting on the sympathetic nervous
system
• Alpha agonists
• Non-selective e.g. epinephrine and dipivefrin
• Alpha 2 selective e.g. apraclonodine and brimonidone
• Mechanism - Alpha2 agonists increase the outflow of aqueous humor
from the eye and can be used clinically to reduce intraocular pressure
in glaucoma
Agents acting on the sympathetic nervous
system
• Beta antagonists (blockers) e.g. timolol, betaxolol, carteolol
• β antagonists decrease the production of aqueous humor and are
used in the treatment of glaucoma
Carbonic anhydrase inhibitors
• Examples: acetazolamide (oral), dorzolamide (topical), brinzolamide
(topical)
• Mechanism - the reduction of aqueous humor formation by carbonic
anhydrase inhibitors decreases the intraocular pressure
• Toxicity – metabolic acidosis, renal K+ wasting, renal stones,
drowsiness, parastheisas, hypersensitivity
• Topically active agents, reduce intraocular pressure without producing
renal or systemic effects
Prostaglandin analogs
• Examples: latanoprost, tafluprost, bimatoprost
• Mechanism: Prostaglandin F2α induces constriction of the iris
sphincter muscle, but its overall effect in the eye is to decrease
intraocular pressure by increasing the aqueous humor outflow
• Supplied as ophthalmic emulsion and ophthalmic solution
• Toxicity – blurred vision, burning sensation, conjuctival hyperemia, iris
colour change, itching
Agents used for fundoscopic
examination
Alpha adrenergic agonists
• Examples: Phenylephrine, epinephrine
• In the eye, the radial pupillary dilator muscle of the iris contains α
receptors; activation by drugs such as phenylephrine causes
mydriasis; phenylephrine has little beta effect
• Toxicity (local) – pain in the eye
• Systemic toxicity of the sympathomimetics are related to the systemic
effects on the particular organ systems with the different types of
adrenergic receptors
Antimuscarinics
• Examples: Atropine, tropicamide
• Mechanism - The pupillary constrictor muscle depends on muscarinic
cholinoceptor activation
• This activation is blocked by topical atropine and other tertiary
antimuscarinic drugs and results in unopposed sympathetic dilator
activity and mydriasis
• Local toxicity – blurred vision, burning sensation in the eye,
photophobia, raised intraocular pressure
Other indications of atropine
1. Treatment of organophosphate poisoning
2. Cardiac arrest
3. Premedication for anesthesia
4. Irritable bowel syndrome
5. Nasal discharge
6. Neuromuscular blockade reversal
7. Urinary incontinence
Systemic toxicity of the antimuscarinics
• Cardiovacular: palpitations, tachycardia, arrhythmias
• GI: constipation, nausea
• Ophthalmic: blurred vision, decreased lacrimation, angle closure
glaucoma
• Renal: urinary retention
• Reproductive: erectile dysfunction
• Neurologic: coma
• Endocrine metabolic: anhidrosis
References
• Katzung B. G. (2017), Basic and clinical pharmacology, (14th.ed); McGraw-Hill
• Brunton L. L. et al (2017), Goodman & Gilman’s The pharmacological basis of
therapeutics (13th.ed.); McGraw-Hill
• Ritter J. et al (2019). Rang and Dale’s Pharmacology (9th Edition); Elsevier
• Satoskar et al (2013). Pharmacology and Pharmacotherapeutics (23rd edition).
• Tripathi K.D. (2013), Essentials of Medical Pharmacology (7th Ed), Jaypee Brothers
• Whittlesea C. (2018), Clinical Pharmacy and Therapeutics (6th Edition); Elservier
• Ritter J. M. et al. (2008), A Textbook of Clinical Pharmacology and Therapeutics;
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