NCM 106: PHARMACOLOGY
CHAPTER #: DRUGS FOR IMMUNE SYSTEM MODULATION
SOURCE: GROUP 2 PPT
TRANSCRIBERS: ANDREA REYES
CHECKER: PRINCESS ASHLEY M. YLAGAN, ALEC DIANZON & JEWEL SHTONE
SECOND YEAR
FIRST SEM
TOPIC OUTLINE
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Antigens
Innate Body Defenses vs. Adaptive Defenses
Humoral Immune Response and Antibodies
Cell Mediated Immunity
Immunosuppressant Drugs
Cytotoxic Drugs
Antibodies
Clinical Uses of Immunosuppressive Agents
Disease modifying anti-rheumatic drugs (DMARDs)
Biological therapies in RA
ANTIGENS
• Antigens are microbes and foreign substances that elicit
an immune response.
• Strongest antigens (present on the surfaces of):
• Pollen grains
• Bacteria
• Nonhuman cells
• Viruses
INNATE BODY DEFENSES VS. ADAPTIVE
DEFENSES
INNATE (NONSPECIFIC) BODY DEFENSES
• Non specific
• First line of protection from pathogens
ADAPTIVE (SPECIFIC) BODY DEFENSES)
• Specific
• Second line of protection
• Immune response
• More complexed
HUMAN IMMUNE RESPONSE AND ANTIBODIES
•
•
•
•
•
•
•
•
Is initiated when an antigen encounters a type of
lymphocyte known as B cell
B cells becomes activated and clones itself rapidly,
most cells are called plasma cells
Plasma cells secrete antibodies specific to the antigen
Circulating through the body are Antibodies also known
as Immunoglobulins
Immunoglobulins physically interact with the antigens to
neutralize or mark for destruction by other cells or in
this case the cytotoxic cells.
Peak production of antibodies occurs around 10 days
after the antigen challenge.
After the antigen challenge, Memory B cells are formed
that will remember the antigen- antibody interaction.
The body will able to manufacture even higher level of
antibodies approximately 2-3 days.
CELL MEDIATED IMMUNITY
• T cells rapidly form clones after they are activated or
sensitized by an encounter with their specific antigen.
• T cells do not produce antibodies.
• Activated T cells produce huge amounts of cytokines,
which are hormone-like proteins that regulate the intensity
and duration of the immune response.
• Like B cells, some sensitized T cells become memory
cells.
KINDS OF T CELLS
HELPER T CELLS
responsible for activating most other immune cells.
CYTOTOXIC T CELLS
direct killers of antigens
MACROPHAGES
kill bacteria
IMMUNOSUPPRESSANT DRUGS
• Immunosuppressant drugs suppress primary immune
responses (i.e. antigen processing, cell proliferation,
lymphokine synthesis, etc.) more effectively than
secondary immune responses (i.e. those related to reencountering antigen, that is those related to immunologic
memory)
• are highly effective in treating conditions such as organ
transplant rejection and severe autoimmune disorders. •
work better if they are given before rather than after the
exposure of the body to the antigen (unfortunately most
autoimmune diseases are treated after autoimmunity is
established).
• • Therapies with these drugs often require lifelong use, so
exposing the patient to increased risk of infections and
some cancers (lymphomas, Kaposi’s sarcoma, skin cancer)
CYCLOSPORINE
MECHANISM OF ACTION:
• The drug binds to cyclophilin to form a complex which in turn
binds to calcineurin, a cytoplasmic phosphatase, and inhibits
its action.
• Since calcineurin regulates the ability of a nuclear factor of
activated T cells (NFAT) to translocate to the nucleus and
increase the production of interleukin-2, the production of IL-2
is suppressed.
• As a consequence, T-helper cells cannot proliferate and die
by apoptosis
PHARMACOKINETICS:
• The drug is given PO or IV.
• It is totally metabolized by the CYP3A system (its
metabolism is affected by a lot of drugs that inhibit or induce
the p450 system).
TOXICITY:
• Nephrotoxicity (up to 80%).
• Neurotoxicity, including paresthesias (up to 50%) tremor (up
to 55%), hallucinations and seizures
• Hypertension (up to 50%)
• Hirsutism (common), gingival hyperplasia (up to 20%)
CLINICAL USES:
• Organ transplantation (to prevent rejection) (Graft-versushost disease).
• Selected autoimmune disorders (psoriasis, rheumatoid
arthritis, IBD, SLE)
TACROLIMUS (FK506)
• A fungal macrolide antibiotic.
• Chemically not related to cyclosporine
• Both drugs have similar mechanism of action.
• The internal receptor for tacrolimus is immunophilin
(FK-binding protein, FK-BP).
• Tacrolimus-FKBP complex inhibits calcineurin.
SIROLIMUS (RAPAMYCIN)
MECHANISM OF ACTION:
• The drug resembles tacrolimus and binds to the same
intracellular Fk binding proteins. However, whereas
tacrolimus and cyclosporine block IL-2 gene transcription,
sirolimus acts later to block IL-2 dependent lymphocyte
proliferation.
• This blockade is likely due to the inhibition of mammalian
kinase, an enzyme which is essential for cell-cycle
progression. Therefore, the drug inhibits substantially T and
B cell proliferation.
PHARMACOKINETICS:
• The drug is given orally.
• It is totally metabolized by the CYP3A4 system.
TOXICITY:
• Hyperlipidemia (up to 50%).
• Hypertension (up to 50%).
• Anemia, leukopenia, thrombocytopenia.
CLINICAL USES:
• Organ transplantation (to prevent rejection)
• Atopic dermatitis, psoriasis
CYTOTOXIC DRUGS
Inhibitors of purine or pyrimidine synthesis (Antimetabolites):
• Azathioprine
• Mycophenolate Mofetil
• Leflunomide
• Methotrexate
AZATHIOPRINE
CHEMISTRY:
• Derivative of mercaptopurine.
• Prodrug.
• Cleaved to 6-mercaptopurine then to 6-mercaptopurine
nucleotide, thioinosinic acid (nucleotide analog).
• Inhibits de novo (new) synthesis of purines required for
lymphocytes proliferation.
• Prevents clonal expansion of both B and T lymphocytes.
PHARMACOKINETICS:
• orally or intravenously.
• Widely distributed but does not cross BBB.
• Metabolized in the liver to 6-mercaptopurine or to thiouric
acid (inactive metabolite) by xanthine oxidase.
• excreted primarily in urine.
DRUG INTERACTIONS:
• Co-administration of allopurinol with azathioprine may lead to
toxicity due to inhibition of xanthine oxidase by allopurinol.
USES:
• Acute glomerulonephritis
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Crohn’ s disease.
ADVERSE EFFECTS:
• Bone marrow depression: leukopenia, thrombocytopenia.
• Gastrointestinal toxicity.
• Hepatotoxicity.
• Increased risk of infections.
MYCOPHENOLATE MOFETIL
• Is a semisynthetic derivative of mycophenolic acid from
fungus source.
• Prodrug; is hydrolyzed to mycophenolic acid
MECHANISM OF ACTION:
• Inhibits de novo synthesis of purines.
• Mycophenolic acid is a potent inhibitor of inosine
monophosphate dehydrogenase (IMP), crucial for purine
synthesis deprivation of proliferating T and B cells of nucleic
acids
PHARMACOKINETICS:
• Given orally, i.v. or i.m.
• rapidly and completely absorbed after oral administration
CLINICAL USES:
• Solid organ transplants for refractory rejection.
• Steroid-refractory hematopoietic stem cell transplant patients.
• Combined with prednisone as alternative to cyclosporine or
tacrolimus.
• Rheumatoid arthritis, & dermatologic disorders
ADVERSE EFFECTS:
• GIT toxicity: > 10%. nausea, vomiting, diarrhea, abdominal
pain.
• Bone marrow suppression > 20%
Contraindicated during pregnancy
ANTIBODIES
Block T cell surface molecules involved in signaling
immunoglobulins
• antilymphocyte globulins (ALG)
• antithymocyte globulins (ATG)
• Rho (D) immunoglobulin
• Basiliximab
• Daclizumab
MUROMONAB – CD3
• Is a murine monoclonal antibody
• Prepared by hybridoma technology
• Directed against glycoprotein CD3 antigen of human T cells.
• Given I.V.
• Metabolized and excreted in the bile
MECHANISM OF ACTION:
• The drug binds T to CD3 proteins on T lymphocytes (antigen
recognition site) leading to disruption of T-lymphocyte
function, their depletion and decreased immune response.
• Prednisolone, diphenhydramine are given to reduce
cytokine release syndrome
USES:
• Used for treatment of acute renal allograft rejection & steroid
resistant acute allograft
• To deplete T cells from bone marrow donor prior to
transplantation.
ADVERSE EFFECTS:
• Anaphylactic reactions (infusion related)
• Pulmonary edema
• Secondary malignancy
• Infection
• Cytokine release syndrome (Flu-like illness to shock like
reaction).
MUROMONAB – CD3
• Rho (D) is a concentrated solution of human IgG containing
higher titer of antibodies against Rhٕ (D) antigen of red cells
• Given to Rh-negative mother within 24-72 hours after
delivery of Rh-positive baby (2 mL, I.M.) to prevent
hemolytic disease of the next Rh-positive babies
(erythroblastosis fetalis)
Adverse Effects:
• Local pain
• Fever
THALIDOMIDE
• A sedative drug
• Teratogenic
• Given orally
• Has immunomodulatory actions
• Inhibits TNF-α
• Reduces phagocytosis by neutrophils
• Increases IL-10 production
• Inhibits angiogenesis
• Used in multiple myeloma
USES:
• Myeloma
• Rheumatoid arthritis
• Graft versus host diseases
• Leprosy reactions
• Treatment of skin manifestations of lupus erythematosus
CLINICAL USES OF IMMUNOSUPPRESSIVE AGENTS
DISEASE
AGENT USED
Autoimmune Disease:
Prednisone,
mercaptopurine,
Acute
cyclophosphamide
glomerulonephritis
Autoimmune
Prednisone,
cyclophosphamide,
hemolytic anemia
mercaptopurine, azathioprine, high
dose ᶞ-globulin
Organ transplant:
Cyclosporine,
azathioprine,
Renal
prednisone, ALG (antilymphocyte
globulin)
Heart
Tacrolimus
Liver
Cyclosporine,
Prednisone,
Azathioprine, Tacrolimus
Bone Marrow
Cyclosporine, Cyclophosphamide,
Prednisone, Methotrexate, ALG, total
body radiation
IMMUNOSTIMULANTS
INTERFERONS
Three families:
Type I IFNs (IFN-α, β);
• Acid-stale proteins
• Induced by viral infections
• Leukocyte produces IFN-α
• Fibroblasts & endothelial cells produce IFN-β
Type II IFN (IFN-ꭚ)
• Acid-labile
• Produced by Activated T lymphocytes
INTERFERON EFFECTS:
IFN-ꭚ: IMMUNE INHANCING
Increased antigen presentations with macrophage,
natural killer cell, cytotoxic T lymphocyte activation
IFN-α, β
Effective in inhibiting cellular proliferation (more effective
than IFN-ꭚ in this regard)
INTERFERONS
• Recombinant DNA cloning technology
• Antiproliferative activity
• Antiviral infection
• Immunomodulatory effect
USES:
• treatment of certain infections e.g., Hepatitis (IFN-α)
• Autoimmune diseases e.g. Rheumatoid arthritis
• Certain forms of cancer e.g. melanoma, renal cell carcinoma
• Multiple sclerosis (IFN-β): reduced rate of exacerbation
SIDE EFFECTS:
• Fever
• Chills
• Myelosuppression
ADLESLEUKIN
MODE OF ACTION:
• The drug is a recombinant version of interleukin-2
• It induces proliferation of B and T cells (including cytotoxic
T cells) and activation of natural killer cells and lymphokineactivated killer cells.
• The mechanism of antitumor activity is unknown but is
probably related to the activation of cytotoxic T cells
TOXICITY:
• Hypotension (70%), sinus tachycardia (70%), pulmonary
congestion (50%) and edema (50%)
• Acute renal failure 60%)
• Mental status change (70%)
• Nausea/vomiting and diarrhea (70%)
• Anemia, thrombocytopenia (70%)
CLINICAL USES:
• Renal cell carcinoma
• Malignant melanoma
DISEASE MODIFYING ANTI-RHEUMATIC
DRUGS (DMARDS)
DMARDs are used in the treatment of Rheumatoid
Arthritis (RA) and have been shown to slow the course
of the disease and prevent further destruction of the
joints and involved tissues
LEFLUNOMIDE
• A prodrug
• Active metabolite undergoes enterohepatic circulation
• Has long duration of action
• Can be given orally
• Antimetabolite immunosuppressant
• Pyrimidine synthesis inhibitor
• Approved only for rheumatoid arthritis
ADVERSE EFFECTS:
• Elevation of liver enzymes
• Renal impairment
• Teratogenicity
• Cardiovascular effects (tachycardia)
METHOTREXATE
• a folic acid antagonist
• orally, parenterally (I.V., I.M.)
• excreted in urine
• inhibits dihydrofolate reductase required for folic acid
activation (tetrahydrofolic)
• inhibition of DNA, RNA & protein synthesis
• interferes with T cell replication
• Rheumatoid arthritis & psoriasis and Crohn disease
• Graft versus host disease
ADVERSE EFFECTS:
• Nausea-vomiting-diarrhea
• Alopecia
• Bone marrow depression
• Pulmonary fibrosis
HYDROXYCHLOROQUINE
• Used for early, mild RA and has relatively few sides
effects
• Does not slow joint damage, therefore it is often used in
combination with methotrexate
• Mechanism of action may include inhibition of
phospholipase A2, platelet aggregation and effects on the
immune system
GOLD SALTS
• Cannot repair existing damage, only prevent further injury
• Gold compounds are used infrequently due to constant
monitoring for serious toxicity
• Currently available gold preparation is auranofin, given
orally
• Auranofin is taken up by macrophages and suppresses
phagocytosis and lysosomal enzyme activity resulting in
slower progression of bone and articular destruction
BIOLOGICAL THERAPIES IN RA
• IL-1 and TNF-a are proinflammatory cytokines involved in
the pathogenesis of RA
• TNF inhibitors (etanercept, adalimumab and infliximab)
• IL-1 receptor antagonist (anakinra)
INFLIXIMAB
• Monoclonal antibody that bins specifically to TNF-a,
thereby neutralizing the cytokine
• Approved for use in combination in patients with RA who
have had inadequate response to methotrexate
monotherapy
• Not indicated for use alone, because it allows the body to
develop anti-infliximab antibodies which reduces efficacy
NCM 106: PHARMACOLOGY
DAIS #2: DRUGS FOR INFLAMATION AND FEVER
SOURCE: GROUP 2 PPT
TRANSCRIBERS: JOHN MICHAEL MURILLO
CHECKER: PRINCESS ASHLEY M. YLAGAN, ALEC DIANZON
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TOPIC OUTLINE
Inflammation
Function of Inflammation
Classification of Inflammation
Role of Chemical Mediators
General Strategies for Treating Inflammation
Anti-Inflammatory Drugs
Two Primary Drug Classes Used For Inflammation
Nonsteroidal Anti-Inflammatory Drugs (NSIADs)
Corticosteroids (Glucocorticorticoids)
Fever
Treating Fever with Antipyretics
Acetaminophen
Prototype Drug
Evidence-Based Practice
SECOND YEAR
FIRST SEM
GENERAL STRATEGIES FOR TREATING
INFLAMMATION
When treating inflammation, the following general principles
apply:
•
Inflammation is a natural process for ridding the body of
antigens, and it is usually self-limiting.
•
For mild symptoms, non-pharmacologic treatments such
as ice packs and rest should be used whenever
applicable.
•
Topical drugs should be used when applicable because
they cause few adverse effects.
Inflammation of the skin and mucous membranes of the mouth,
nose, rectum, and vagina are best treated with this.
These include anti-inflammatory creams, ointments,
patches, suppositories, and intranasal sprays.
(available over the counter (OTC))
DRUGS FOR INFLAMMATION AND FEVER
INFLAMMATION
•
•
A body defense mechanism that occurs in response to
many different stimuli, including physical injury, exposure
to toxic chemicals, extreme heat, invading microorganisms,
or death of cells
Considered an innate (nonspecific) defense mechanism
because inflammation proceeds in the same manner,
regardless of the cause that triggered it
ANTI-INFLAMMATORY DRUGS
•
•
•
FUNCTION OF INFLAMMATION
•
•
To contain the injury or destroy the microorganism.
By neutralizing the foreign agent and removing cellular
debris and dead cells, repair of the injured area is able to
proceed at a faster pace.
CLASSIFICATION OF INFLAMMATION
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2
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TWO PRIMARY DRUG CLASSES USED FOR
INFLAMMATION
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ACUTE INFLAMMATION
Has an immediate onset and 8 to 10 days been normally
needed for the symptoms to resolve and for repair to begin.
Examples: acute bronchitis, sore throat from a cold/flu
•
•
•
•
ROLE OF CHEMICAL MEDIATORS
BRADYKININ
Present in an inactive form in plasma and mast cells; vasodilator
that causes pain; effects are similar to those of histamine;
broken down by angiotensin-converting enzyme (ACE).
COMPLEMENT
Series of at least 20 proteins that combine in a cascade fashion
to neutralize or destroy an antigen; stimulates histamine release
by mast cells.
HISTAMINE
Stored and released by mast cells; causes vasodilation,
smooth-muscle constriction, tissue swelling, and itching.
LEUKOTRIENES
Stored and released by mast cells: effects are similar to those
of histamine: contributes to symptoms of asthma and allergies.
PROSTAGLANDINS
Present in most tissues and stored and released by mast cells;
increase capillary permeability, attract white blood cells to site
of inflammation, cause pain and induce fever.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Corticosteroids
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
(NSAIDS)
CHRONIC INFLAMMATION
Has a slower onset and may continue for prolonged
periods.
Examples: chronic peptic ulcer, rheumatoid arthritis
The goal of pharmacotherapy with anti- inflammatory drugs
is to prevent or decrease the intensity of the
inflammatory response and reduce fever, if present.
Most anti-inflammatory medications are nonspecific; the
drug will exhibit the same inhibitory actions regardless of
the cause of the inflammation.
Common diseases that benefit from anti-inflammatory
therapy include: allergic rhinitis, anaphylaxis,
ankylosing spondylitis, contact dermatitis, Crohn's
disease, glomerulonephritis, Hashimoto ' s thyroiditis,
peptic ulcer disease, RA, SLE, and ulcerative colitis.
•
For mild to moderate pain, inflammation, and fever,
NSAIDs are the drugs of choice
Commonly used to manage the pain and inflammation
associated with arthritis and other musculoskeletal
disorders.
NSAIDs should always be used cautiously, for the shortest
time possible and at the lowest effective dose.
NSAIDs block a specific enzyme called cyclooxygenase (or
COX) used by the body to make prostaglandins.
By reducing production of prostaglandins, NSAIDs help
relieve the discomfort of fever and reduce inflammation
and the associated pain
SELECTED NSAIDss
SALICYLATE (ASPIRIN)
Mode of Action
Inhibit the activity of the enzyme now called cyclooxygenase
(COX) which leads to the formation of prostaglandins (PGs) that
cause inflammation, swelling, pain and fever.
Adverse Effect
• Stomach pain, heartburn, nausea, vomiting, tinnitus,
prolonged bleeding time
• Severe Gl bleeding, bronchospasm, anaphylaxis,
hemolytic anemia, Reye's syndrome in children, metabolic
acidosis
Other Notes
• Best to take aspirin with after meals. That will reduce
stomach discomfort and pain.
• Unless prescribed by a doctor, never give aspirin to
children under 16. It can increase children's risk of Reye's
syndrome.
• You should feel better 20– 30 minutes after taking aspirin.
•
SELECTED NSAID
SELECTIVE COX-2 INHIBITOR
• CELECOXIB (CELEBREX)
Mode of Action
•
Works by blocking an enzyme called cyclooxygenase-2 (COX2). This enzyme is responsible for converting arachidonic acid
into prostaglandin, which plays a role in inflammation. By
blocking COX-2, celecoxib reduces inflammation in the body
and pain.
•
Adverse Effect
•
•
•
Back pain, peripheral edema, abdominal pain, dyspepsia,
flatulence, dizziness, headache, insomnia, hypertension
(HIN).
Increased risk of cardiovascular events, acute renal
failure.
Like the NSAIDs, corticosteroids inhibit the biosynthesis
of prostaglandins. Corticosteroids, however, affect
inflammation by multiple mechanisms.
They have the ability to suppress histamine release and
can inhibit certain functions of phagocytes and
lymphocytes.
These multiple actions markedly reduce inflammation,
making corticosteroids the most effective medications
available for the treatment of severe inflammatory
disorders.
During long-term therapy, nurses must be alert for signs
of overtreatment with corticosteroids, a condition known
as Cushing’s syndrome. Because the body becomes
accustomed to high doses of corticosteroids, patients
must discontinue these drugs gradually; abrupt
withdrawal can result in acute lack of adrenal function
Other Notes
•
•
Celecoxib capsules are usually taken once or twice a day.
If you are taking up to 200 mg of celecoxib capsules at a
time.
You may take the medication with or without food. If you
are taking more than 200 mg of celecoxib capsules at a
time, you should take the medication with food.
SELECTED NSAID
IBUPROFEN AND SIMILAR DRUGS
•
•
•
•
•
•
•
•
•
diclofenac (Cataflam, Voltaren, others)
diflunisal
etodolac
fenoprofen (Nalfon)
flurbiprofen (Ansaid)
ibuprofen (Advil, Motrin, others)
indomethacin (Indocin)
Mode of Action
Works by blocking the effects of cyclooxygenase (COX)
enzymes.
This
prevents
prostaglandin
synthesis
(prostaglandins elevate body temperature and make nerve
endings more sensitive to pain transmission).
Adverse Effect
Dyspepsia, dizziness, headache, drowsiness, tinnitus, rash,
pruritus, increased liver enzymes, prolonged bleeding time,
edema, nausea, vomiting, occult blood loss
Peptic ulcer, Gl bleeding, anaphylactic reactions with
bronchospasm, blood dyscrasias, renal impairment, MI, heart
failure (HF). hepatotoxicity
Other Notes
•
Give the drug on an empty stomach as tolerated. If nausea,
vomiting, or abdominal pain occurs, give with food.
•
Be aware that patients with asthma or who have allergies
to aspirin are more likely to exhibit a hypersensitivity
reaction to ibuprofen.
•
Relieves minor aches and pain in children aged 6 months
or older.
•
Available as tablets, capsules, chewable tablets,
suspension, and in an injectable form.
CORTICOSTEROIDS
(GLUCOCORTICORTICOIDS)
Have the ability to suppress severe inflammation.
•
Because of potentially serious adverse effects, however,
systemic corticosteroids are reserved for the short-term
treatment of severe disease.
•
Corticosteroids are often referred to as glucocorticoids.
Corticosteroids are natural hormones released by the
adrenal cortex that have powerful effects on nearly every
cell in the body. When corticosteroids are used as drugs
to treat inflammatory disorders, the doses are many times
higher than the amount naturally present in the blood.
•
The uses of corticosteroids include the treatment of
neoplasia, asthma, arthritis and corticosteroid deficiency.
SELECTED CORTECOSTEROID
PREDNISONE
TRIAMCINOLONE (ARISTOSPAN, KENALOG,
OTHERS)
Mode of Action
Decreases inflammation via suppression of the migration of
polymorphonuclear leukocytes and reversing increased
capillary permeability. It also suppresses the immune system by
reducing the activity and the volume of the immune system.
Adverse Effect
• Mood swings, weight gain, acne, facial flushing, nausea,
insomnia, sodium and fluid retention, impaired wound
healing, menstrual abnormalities
• Peptic ulcer, hypocalcemia, osteoporosis with possible
bone fractures, loss of muscle mass, decreased growth in
children, possible masking of infections
Other Notes
• Tell your doctor right away if you have depression; mood
swings; a false or unusual sense of well-being; trouble
with sleeping; or personality changes while taking this
medicine.
• This medicine might cause thinning of the bones
(osteoporosis) or slow growth in children if used for a long
time.
FEVER
•
•
•
Like inflammation, fever is a natural defense mechanism
for neutralizing foreign organisms.
Many species of bacteria are killed by high fever. Often, the
health care provider must determine whether the fever
needs to be dealt with aggressively or allowed to run its
course.
Drugs used to treat fever are called antipyretics.
TREATING FEVER WITH ANTIPYRETICS
•
•
•
The goal of antipyretic therapy is to lower body
temperature while treating the underlying cause of the
fever, usually an infection.
Aspirin, ibuprofen, and acetaminophen are safe,
inexpensive, and effective drugs for reducing fever.
Aspirin and acetaminophen are also available as
suppositories. The antipyretics come in various dosages
and concentrations, including extra strength.
ACETAMINOPHEN
•
•
•
•
Acetaminophen, also called paracetamol, is a pain reliever
and a fever reducer (analgesic/antipyretic).
Used to treat mild to moderate pain (from headaches,
menstrual periods, toothaches, backaches, osteoarthritis,
or cold/flu aches and pains) and to reduce fever.
Taking too much acetaminophen may cause serious
(possibly fatal) liver disease.
Adults should not take more than 4000 milligrams (4
grams) of acetaminophen a day. People with liver problems
and children should take less acetaminophen.
✓
✓
✓
✓
✓
SOME AVAILABLE BRANDS FOR ACETAMINOPHEN
Acetadol (Medi-Rx)
Biogesic (Unilab)
Tempra(Taisho)
Alvedon (Multicare)
Calpol (GlaxoSmithKline)
EVIDENCE-BASED PRACTICE
PROTOTYPE DRUG
ACETAMINOPHEN (TYLENOL, OTHERS)
ANTIPYRETIC AND ANALGESIC
ACTION AND USES
•
•
•
•
•
•
Acetaminophen reduces fever by direct action at the level
of the hypothalamus and dilation of peripheral blood
vessels, which enables sweating and dissipation of heat.
Acetaminophen, ibuprofen, and aspirin have equal
efficacy in relieving pain and reducing fever.
Acetaminophen has no anti-inflammatory properties;
therefore, it is not effective in treating arthritis or pain
caused by tissue swelling following injury.
The primary therapeutic usefulness of acetaminophen is
for the treatment of fever in children and for relief of mild to
moderate pain when aspirin is contra- indicated. In the
treatment of severe pain, acetaminophen may be
combined with opioids.
This allows the dose of opioid to be reduced, thus
decreasing the risk of dependence and serious opioid
toxicity. It is available as tablets, caplets, solutions, and
suppositories.
Has no effect on platelet aggregation and does not exhibit
cardiotoxicity. Most importantly, it does not cause GI
bleeding or ulcers, as do the NSAIDs.
ADMINISTRATION ALERT
•
•
•
Liquid forms are available in varying concentrations. Use
the appropriate strength product in children to avoid
toxicity.
Never administer to patients who consume alcohol
regularly due to the potential for hepatotoxicity.
Advise patients that acetaminophen is found in many OTC
products and that extreme care must be taken to not
duplicate doses by taking several of these products
concurrently.
ADVERSE EFFECTS
•
•
•
•
•
Acetaminophen is generally safe, and adverse effects are
uncommon at therapeutic doses.
Acetaminophen causes less gastric irritation than aspirin
and Does not affect blood coagulation.
It is not recommended in patients who are malnourished.
In such cases, acute toxicity may result, leading to renal
failure, which can be fatal.
Other signs of acute toxicity include nausea, vomiting,
chills, abdominal discomfort, and fatal hepatic necrosis.
A major concern with the use of high doses of
acetaminophen is the risk for liver damage, which is
especially important for patients who consume alcohol.
REFERENCE
•
Pharmacology for Nurses –A Pathophysiologic
Approach, 6thEd., Adams, Holland & Urban.
NCM 106: PHARMACOLOGY
CHAPTER #: DRUGS FOR BACTERIAL INFECTIONS
SOURCE: GROUP 2 PPT
TRANSCRIBERS: GONZALES, CHARLEEN NICOLE C.
CHECKER: ALEC DIANZON & DE CASTRO
TOPIC OUTLINES
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Drugs for Bacterial Infection
Describing and Classifying Bacteria
Classification of Anti-Infective Drugs
Actions of Anti-Infective Drugs
Acquired Resistance
Selection of an Effective Antibiotic
Host Factors
Drugs for Antibacterial Infections
Chemical Modifications to the Natural Penicillin
Molecule
Cephalosporins
Tetracyclines, Macrolides, Aminoglycosides,
Fluoroquinolones
Sulfonamides and Urinary Antiseptics
Carbapenems and Miscellaneous Antibacterials
Anti-tubular Drugs
Other Types of Mycobacterium
SECOND YEAR
FIRST SEM
•
SELECTION OF AN EFFECTIVE ANTIBIOTIC
•
•
HOST FACTORS
Common word used to describe a pathogen
DESCRIBING AND CLASSIFYING BACTERIA
GRAM-POSITIVE BACTERIA
•
Bacteria contain a thick cell wall and retain a purple
color after staining staphylococci, streptococci, and
enterococci
•
Bacteria that have thinner cell walls will lose the violet
stain
bacteroides, Escherichia coli, klebsiella, pseudomonas,
and salmonella
GRAM-NEGATIVE BACTERIA
•
CLASSIFICATION OF ANTI-INFECTIVE
DRUGS
ANTI-INFECTIVE
•
•
general term that applies to any drug that is effective
against pathogens. In its broadest sense, an antiinfective drug may be used to treat bacterial, fungal,
viral, or parasitic infections.
The most frequent term used to describe an antiinfective drug is antibiotic.
ACTIONS OF ANTI-INFECTIVE DRUGS
The primary goal of antimicrobial therapy is to assist the
body’s defenses in eliminating a pathogen
BACTERIOCIDAL
medications that accomplish this goal by killing bacteria
BACTERIOSTATIC
do not kill the bacteria but instead slow their growth, allowing
the
body’s
natural
defenses
to
eliminate
the
microorganisms.
ACQUIRED RESISTANCE
•
•
Killing populations of bacteria that are sensitive to the
drug leaves behind those microbes that possess
mutations that made them insensitive to the effects of
the antibiotic.
These drug-resistant bacteria are then free to grow,
unrestrained by their neighbors that were killed by the
antibiotic.
Host Defenses
Local Tissue Conditions
Allergy History
Other Patient Variables
DRUGS FOR ANTIBACTERIAL INFECTIONS
PENICILLINS
PATHOGENICITY
VIRULENCE
Organisms isolated from the specimens are grown in the
laboratory and identified. After identification, the
laboratory tests different antibiotics to determine which
is most effective against the infecting microorganism.
This process of growing the pathogen and identifying the
most effective antibiotic is called culture and
sensitivity (C&S) testing cells.
1.
2.
3.
4.
DRUGS FOR BACTERIAL INFECTIONS
Ability of an organism to cause infection, depends on an
organism’s ability to evade or overcome body defenses.
The patient soon develops an infection that is resistant
to conventional drug therapy DNA, a process called
alkylation.
•
•
Penicillin kills bacteria by disrupting their cell walls.
Many bacterial cell walls contain a substance called
penicillin-binding protein that serves as a receptor for
penicillin.
•
Upon binding, penicillin weakens the cell wall and allows
water to enter, thus killing the organism.
•
Gram-positive bacteria are the most commonly affected
by the penicillins, including streptococci and
staphylococci.
Penicillins; indicated for treatment of:
1. pneumonia
2. gas gangrene
3. meningitis
4. tetanus
5. skin, bone, and join infections
6. anthrax
7. stomach infections
8. Sickle-cell anemia in infants
9. blood and valve infections
BETA-LACTAM RING
•
•
is a portion of the chemical structure of penicillin, is
responsible for its antibacterial activity.
Some bacteria secrete an enzyme, called betalactamase or penicillinase, which splits the betalactam ring.
PENICILLIN G
Adverse Effects
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
rash
pruritus
diarrhea
nausea
fever
drowsiness
anaphylaxis symptoms
angioedema
circulatory collapse
cardiac arrest
nephrotoxicity
CHEMICAL MODIFICATIONS TO THE
NATURAL PENICILLIN MOLECULE
•
produced drugs offering several advantages.
•
Oxacillin and dicloxacillin are examples of drugs that are
effective against penicillinase-producing bacteria.
These are sometimes called antistaphylococcal
penicillins.
PENICILLINASE-RESISTANT PENICILLINS
•
CEPHALOSPORINS
PHARMACOTHERAPY
•
BROAD-SPECTRUM PENICILLINS
•
Ampicillin (Principen) and amoxicillin (Amoxil,
Trimox) are effective against a wide range of
microorganisms and are called broadspectrum
penicillins.
EXTENDED-SPECTRUM PENICILLIN
•
•
Piperacillin is effective against even more microbial
species
than
the
aminopenicillins,
including
Enterobacter, Klebsiella, and Bacteroides fragilis.
Their primary advantage is activity against
Pseudomonas aeruginosa, an opportunistic pathogen
responsible for a large number of HAIs.
✓ The
three
beta-lactamase
inhibitors,
clavulanate, sulbactam, and tazobactam
•
available only in fixed-dose combinations with
specific penicillins.
•
These include Augmentin (amoxicillin plus
clavulanate),
Timentin
(ticarcillin
plus
clavulanate),
Unasyn
(ampicillin
plus
sulbactam), and Zosyn (piperacillin plus
tazobactam).
The cephalosporins are bacteriocidal and act by
attaching to penicillin-binding proteins to inhibit bacterial
cell-wall synthesis
GENERALIZATIONS; REGARDING THE
GENERATIONS
FIRST-GENERATION CEPHALOSPORINS
First-generation cephalosporins are the most effective drugs
in this class against gram-positive organisms including
staphylococci and streptococci.
SECOND-GENERATION CEPHALOSPORINS
•
•
Second-generation cephalosporins are more potent
they more resistant to beta-lactamase, and exhibit a
broader spectrum against gram-negative organisms than
the first-generation drugs
THIRD-GENERATION CEPHALOSPORINS
•
•
Third-generation cephalosporins exhibit an even
broader spectrum against gram-negative bacteria than the
second-generation drugs.
These cephalosporins are sometimes drugs of choice
against infections by Pseudomonas, Klebsiella, Neisseria,
Salmonella, Proteus, and H. influenza.
FORTH-GENERATION CEPHALOSPORINS
Fourth-generation agents are capable of entering the
cerebrospinal fluid (CSF) to treat central nervous system
(CNS) infections.
FIFTH-GENERATION CEPHALOSPORINS
The fifth-generation drugs are designed to be effective
against MRSA (Methicillin-resistant Staphylococcus aureus)
infections.
PHARMACOTHERAPY
Adverse Effects
1.
2.
3.
4.
5.
allergic reactions
skin rashes
cross hypersensitivity
GI complaints
kidney toxicity
MACROLIDES
TETRACYCLINES
•
•
•
Tetracyclines act by inhibiting bacterial protein
synthesis.
By binding to the bacterial ribosome, the tetracyclines
slow microbial growth and exert a bacteriostatic effect.
Doxycycline (Vibramycin, others) and minocycline
(Minocin, others) have longer durations of actions and
are more lipid soluble, permitting them to enter the CSF
PHARMACOTHERAPY
They are drugs of choice for only a few diseases:
1.
2.
3.
4.
5.
6.
7.
Rocky Mountain spotted fever
typhus
cholera
Lyme disease
peptic ulcers caused by H. pylori
chlamydial infections
acne vulgaris
1.
2.
3.
gastric distress
severe photosensitivity
permanent yellow-brown discoloration of the permanent
teeth in young children
affect fetal bone growth and teeth development and are
pregnancy category D drugs
superinfection
hepatoxicity
PHARMACOTHERAPY
•
•
•
•
•
Erythromycin (EryC, Erythrocin, others), the first
macrolide
antibiotic,
was
isolated
from
Streptomyces in a soil sample in 1952.
The macrolides inhibit protein synthesis by binding
to the bacterial ribosome.
At low doses, this inhibition produces a
bacteriostatic effect.
At higher doses, and in susceptible species,
macrolides may be bacteriocidal.
Macrolides are effective against most gram-positive
bacteria and many gram-negative species.
Adverse Effects
4.
5.
6.
TIGERCYLINE (TYGACIL)
•
•
•
•
indicated for drug-resistant intra-abdominal
infections and complicated skin and skinstructure infections
especially those caused by MRSA.
Nausea and vomiting may be severe with this
drug.
Tigecycline is available by IV infusion.
ERYTHROMYCIN (Eryc, Erthrocin, others)
AZITHROMCYIN
✓
✓
•
Azithromycin (Zithromax, Zmax) has such an
extended half-life that it is administered for only 5 days,
rather than the 10 days required for most antibiotics.
A single dose of azithromycin is effective against N.
gonorrhoeae.
The shorter duration of therapy is thought to increase
patient adherence
FIDAXOMICIN
•
•
•
•
The newest of the macrolides.
Approved in 2011 specifically for infections caused by C.
difficile.
The drug should be prescribed only for this indication
because other uses could encourage the development
of resistant strains.
Taken as an oral tablet, the drug is not absorbed and
remains in the digestive tract where it produces its
effects on C. difficile.
Adverse Effects
1.
2.
3.
4.
5.
mild GI upset
diarrhea
abdominal pain
superinfections
macrolide-resistant strains
•
Aminoglycosides are bacteriocidal and act by
inhibiting bacterial protein synthesis.
They are normally reserved for serious systemic
infections
caused
by
aerobic
gram-negative
organisms, including those caused by E. coli, Serratia,
Proteus, Klebsiella, and Pseudomonas.
They are sometimes administered concurrently with a
penicillin, cephalosporin, or vancomycin for treatment
of enterococcal infections
AMINOGLYCOSIDES
•
•
STREPTOMYCIN
•
•
•
The first aminoglycoside
It was named after Streptomyces griseus, the soil
organism from which it was isolated in 1942.
Aminoglycolsides
have
important
therapeutic
applications for the treatment of aerobic gramnegative bacteria, mycobacteria, and some protozoan
Adverse Effects
1.
2.
Damage to the inner ear, or ototoxicity, is
recognized by hearing impairment, dizziness, loss of
balance, persistent headache, and ringing in the ears.
Aminoglycoside nephrotoxicity may be severe,
affecting up to 26% of patients receiving these
antibiotics
FLUOROQUINOLONES
•
•
•
•
•
PHARMACOTHERAPY
This were once reserved only for UTIs because of their
toxicity.
Development of safer drugs in this class began in the
late 1980s and has continued to the present day.
Newer fluoroquinolones have a broad spectrum of
activity and are used for a variety of infections.
All fluoroquinolones have activity against gram-negative
pathogens ; the newer ones are significantly more
effective against gram-positive microbes, such as
staphylococci, streptococci, and enterococci.
The fluoroquinolones are bacteriocidal and affect DNA
synthesis by inhibiting two bacterial enzymes: DNA
gyrase and topoisomerase IV.
PHARMACOTHERAPY
NEOMYCIN
available for topical infections of the skin, eyes, and ears
PAROMOMYCIN (HUMANTIN)
given orally for the treatment of parasitic infections
STREPTOMYCIN
is now usually restricted to the treatment of tuberculosis
because of the emergence of a large number of strains
resistant to the antibiotic.
Adverse Effects
1.
2.
Fluoroquinolones are well tolerated by most patients,
with nausea, vomiting, and diarrhea being the most
common adverse effects.
The most serious adverse effects are dysrhythmias
(moxifloxacin) and potential hepatotoxicity. CNS
effects such as dizziness, headache, and sleep
disturbances affect 1% to 8% of patients
SULFONAMIDES AND URINARY
ANTISEPTICS
•
•
•
•
•
Sulfonamides are older drugs that have been
prescribed for a variety of infections over the past 70
years.
Although their use has declined, sulfonamides are still
useful in treating susceptible UTIs, along with several
other medications called urinary antiseptics.
Sulfonamides suppress bacterial growth by
inhibiting the synthesis of folic acid, or folate.
These drugs are sometimes referred to as folic acid
inhibitors. In human physiology, folic acid is a Bcomplex vitamin that is essential during periods of
rapid growth, especially during childhood and
pregnancy.
Bacteria also require this substance during periods of
rapid cell division and growth.
PHARMACOTHERAPY
•
•
•
These are drugs given by the PO route for their
antibacterial action in the urinary tract.
The kidney concentrates the drugs; thus, their actions
are specific to the urinary system.
Urinary antiseptics reach therapeutic levels in the
kidney tubules, and their anti-infective action continues
as they travel to the urinary bladder.
CARBAPENEMS AND MISCELLANEOUS
ANTIBACTERIALS
✓
•
•
•
Imipenem (Primaxin), ertapenem (Invanz),
doripenem (Doribax), and meropenem (Merrem IV)
Belong to a relatively new class of antibiotics called
carbapenems.
These drugs are bacteriocidal and have some of the
broadest antimicrobial spectrums of any class of
antibiotics.
They contain a beta-lactam ring and kill bacteria by
inhibiting construction of the cell wall
CLINDAMYCIN (CLEOCIN, OTHERS)
•
•
•
•
It is effective against both gram-positive and gramnegative bacteria.
Considered to be appropriate treatment when less toxic
alterna tives are not effective options.
Susceptible bacteria include Fusobacterium and
Clostridium perfringens.
Clindamycin is sometimes the drug of choice for
abdominal infections caused by bacteroides
METRONIDAZOLE (FLAGYL)
•
•
•
It is another older anti-infective that is effective
against anaerobes that are common causes of
abscesses, gangrene, diabetic skin ulcers, and deep
wound infections.
A relatively new use is for the treatment of H. pylori
infections of the stomach associated with peptic ulcer
disease .
It is one of only a few drugs that have dual activity
against both bacteria and multicellular parasites; it is a
prototype for the antiprotozoal medications
QUINUPRISTIN / DALFOPRISTIN (SYNERCID)
•
•
•
A combination drug that belongs to a class of
antibiotics called streptogramins.
This drug is primarily indicated for treatment of
vancomycin-resistant Enterococcus faecium infections.
It is contraindicated in patients with hypersensitivity to
the drug and should be used cautiously in patients with
renal or hepatic dysfunction
LIST OF DRUGS
Adverse Effects
1.
The formation of crystals in the urine, hypersensitivity
reactions, nausea, and vomiting.
•
Although not common, potentially fatal blood
abnormalities, such as;
A. aplastic anemia
-Loss of bone marrow function
B.
acute hemolytic anemia
C.
agranulocytosis
-a severe reduction in leukocytes
PHARMACOTHERAPY
•
•
Approved for the treatment of serious abdominopelvic and
skin infections, community acquired pneumonia, and
complicated UTI.
A disadvantage of the carbapenems is that they can only
be given parenterally.
Adverse Effects
1.
2.
3.
4.
Diarrhea
Nausea
Rashes
Thrombophlebitis at injection sites
ANTITUBULAR DRUGS
TUBERCULOSIS
•
•
•
A highly contagious infection caused by the organism
Mycobacterium tuberculosis.
The incidence is staggering:
➢ More than 1.8 billion people, or 32% of the world
population, are believed to be infected.
It is treated with multiple anti-infectives for a prolonged period
PHARMACOTHERAPY
•
•
•
•
•
•
Mycobacteria have a cell wall that is resistant to penetration
by anti-infective drugs.
For medications to reach the microorganisms isolated in the
tubercles, therapy must continue for 6 to 12 months.
Some patients develop multidrug-resistant infections and
require therapy for as long as 24 months
During the 6- to 24-month treatment period, different
combinations of drugs may be used.
Multiple drug therapy is necessary because the
mycobacteria grow slowly, and resistance is common.
Using multiple drugs in different combinations during the long
treatment period lowers the potential for resistance and
increases therapeutic success.
FIRST FEATURE
Although many different drug combinations are used, a typical
regimen for patients with no complicating factors includes the
following:
THIRD FEATURE
CHEMOPROPHYLAXIS
•
•
•
INITIAL PHASE
•
•
2 months of daily therapy with;
a. isoniazid,
b. rifampin (Rifadin, Rimactane),
c. pyrazinamide (PZA)
d. ethambutol (Myambutol)
If C&S testing reveals that the strain is sensitive to the first
three drugs, ethambutol is dropped from the regimen
•
for close contacts of patients recently infected with
tuberculosis or for those who are susceptible to infections
because they are immunosuppressed.
Therapy usually begins immediately after a patient
receives a positive tuberculin test.
Patients with immunosuppression, such as those with
AIDS or those who are receiving immunosuppressant
drugs, may receive chemoprophylaxis with
antituberculosis drugs.
A short-term therapy of 2 months, consisting of a
combination treatment with isoniazid (INH) and
pyrazinamide (PZA), is approved for tuberculosis
prophylaxis in patients who are HIV positive.
CONTINUATION PHASE
•
4 months of therapy with;
a. isoniazid and rifampin
- two to three times per week.
SECOND FEATURE
TWO BROAD CATEGORIES OF
ANTITUBERCULAR DRUGS
PRIMARY
First-line drugs, which are generally the most effective and
best tolerated by patients.
OTHER TYPES OF MYCOBACTERIUM
SECONDARY
MYCOBACTERIUM LEPRAE
Second-line drugs, more toxic and less effective than the firstline agents, are used when resistance develops.
NOTE: Infections due to multidrug-resistant M. tuberculosis can be
rapidly fatal and can cause serious public health problems in some
communities.
•
•
responsible for leprosy, a disease rarely seen in the
United States.
M. leprae is treated with multiple drugs, usually
beginning with dapsone (DDS).
MYCOBACTERIUM AVIUM COMPLEX (MAC)
•
causes an infection of the lungs, most commonly
observed in patients with AIDS.
The most effective drugs against MAC are the macrolides
azithromycin (Zithromax) and clarithromycin (Biaxin).
NCM 106: PHARMACOLOGY
CHAPTER #: DRUGS FOR FUNGAL, PROTOZOAN, AND HELMINTIC INFECTIONS
SOURCE: GROUP 2 PPT
TRANSCRIBERS: PRINCES SARAH METAS
CHECKER: GONZALES, JOHN ANTHONY M., DIANZON, ALEC & JEWEL SHTONE
TOPIC OUTLINE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Fungi
Fungal Infections
Mycoses and Its Classification of Mycoses
Mechanism of Action of Antifungal Drugs
Antifungal Drugs
Drugs for Systemic Fungal Infections Pharmacotherapy of Systemic Fungal Diseases
Drugs for Systemic Mycoses
Pharmacotherapy with the Azole Antifungals
Pharmacotherapy of Superficial Fungal Infections
Selected Drug for Superficial Mycoses
Protozoa
Protozoan Infections
Antiprotozoan Drugs
Pharmacotherapy of Malaria
Pharmacotherapy on Nonmalarial Protozoan
Infections
Selected Drugs for Nonmalarial Protozoan
Infections
Helminthic Infections
Pharmacotherapy of Helminthic Infections
Selected Drugs for Helminthic Infections
FUNGI
•
•
•
are single-celled or multicellular organisms whose
primary role on the planet is to serve as decomposers
of dead plants and animals, returning their elements to
the soil for recycling.
Include mushrooms, yeasts, and molds.
Yeasts, including the common pathogen Candida
albicans, are unicellular fungi.
FUNGAL INFECTION
•
•
•
•
Most exposure to pathogenic fungi occurs through
inhalation of fungal spores or by handling
contaminated soil. Thus, many fungal infections
involve the respiratory tract, the skin, the hair, and
nails. An additional common source of fungal
infections, especially of the mouth or vagina, is
overgrowth of normal flora
Fungi cause disease by replication; only a few secrete
toxins like some bacterial species. In addition to
causing infections, fungal spores may trigger a
hypersensitivity response in susceptible patients,
resulting in allergies to mold or mildew.
The human body is remarkably resistant to infection by
these organisms, and patients with healthy immune
systems experience few serious fungal diseases.
Patients who have a suppressed immune system,
however, such as those infected with HIV, may
experience frequent fungal infections, some of which
may require aggressive pharmacotherapy.
The species of pathogenic fungi that attack a person
with a healthy immune system are often distinct from
those
that
infect
patients
who
are
immunocompromised.
SECOND YEAR
FIRST SEM
Fungal Pathogens
Fungi, Protozoan, and Multicellular
Fungi, protozoans, and multicellular parasites are more
complex than bacteria. Because of structural and functional
differences, most antibacterial drugs are ineffective against
these organisms.
MYCOSES
•
•
•
•
fungal infections
2 classifications: Superficial or Systemic
CLASSIFICATION OF MYCOSES
Superficial mycoses
Systemic mycoses
SUPERFICIAL MYSOSES
•
•
•
Affect the scalp, skin, nails, and mucous membranes
such as the oral cavity and vagina.
Often treated with topical drugs because the incidence
of adverse effects is much lower using this route of
administration.
Topical antifungal preparations may not penetrate
deep enough to reach the pathogen, infections in the
cutaneous and subcutaneous layer may require oral
(PO) antifungal therapy.
FUNGI
•
•
•
Are those affecting the internal organs, typically the
lungs, brain and digestive organs.
Require aggressive oral or parenteral medications that
produce more adverse effects than the topical agents
Historically, the antifungal drugs used for superficial
infections where clearly distinct from those prescribed
for systemic infections. In recent years, some of the
newer antifungal medications may be used for either
superficial or systemic infections. Some superficial
infections may be treated with oral, rather than topical
drugs.
MECHANISM OF ACTION OF ANTIFUNGAL
DRUGS
•
•
•
Fungi are classified as eukaryotes; their cellular
structure and metabolic pathways are more similar to
those of humans than to bacteria.
One important difference between fungal cells and
human cells is the steroid used in constructing plasma
membranes. Whereas cholesterol is essential for
animal cell membranes, ergosterol is present in fungi.
The largest class of antifungal drugs, the azoles,
inhibits ergosterol biosynthesis, causing the fungal
plasma membrane to become porous or leaky.
Amphotericin B (Fungizone), terbinafine (Lamisil),
and nystatin (Mycostatin) also act by this
mechanism.
•
•
Some antifungals take advantage of enzymatic
differences between fungi and humans.
For example, in fungi, flucytosine (Ancobon) is
converted to the toxic antimetabolite 5-fluorouracil,
which inhibits both DNA and RNA synthesis in the
pathogen.
ANTIFUNGAL DRUGS
•
•
Amphotericin B (Fungizone)
fluconazole (Diflucan)
PHARMACOTHERAPY OF SYSTEMIC
FUNGAL DISEASE
•
•
•
Serious fungal infections are rarely encountered in
persons with healthy body defenses.
The AID epidemic has resulted in the frequent
occurrence of previously rare mycoses, such as
cryptococcosis and coccidioidomycosis
Others who may experience systemic mycoses
include those patients who are receiving prolonged
therapy with corticosteroids, experiencing extensive
burns, receiving antineoplastic drugs, having
indwelling vascular catheters, or having recently
received organ transplants.
AMPHOTERICIN B
has been the preferred drug for systemic fungal infections
since the 1960s, however the medication can cause a
number or serious side effects
ITRACONAZOLE
Selected Drugs for Superficial Mycoses
A. AMPHOTERICIN B9 (FUNGIZONE)
Therapeutic Class: Antifungal (systemic type)
Pharmacologic Class: Polyene
Action and Uses
•
Has a broad spectrum of activity and is effective against
most of the fungi pathogenic to humans.
•
Preferred drug for many systemic mycoses.
•
May also be indicated as prophylactic antifungal therapy
for patients with severe immunosuppression.
•
Is not absorbed from the gastrointestinal (IG) tract, it is
usually given by intravenous (IV) infusion, although
topical preparations are available for superficial
mycoses. Resistance to amphotericin B is not common.
To reduce the toxicity of amphotericin B, the original
drug molecule has been formulated with several lipid
molecules:
•
Liposomal amphotericin B (AmBisome)
•
Amphotericin B lipid complex (Abelcet)
•
Amphotericin B cholesteryl sulfate complex (Amphotec)
The principal advantage of the lipid formulation is reduced
nephrotoxicity and less infusion- related fever and chills.
Because of their expense, the lipid preparations are generally
used only after therapy with other antifungals has failed.
Azole Drugs
•
newer azole drugs that are considerably safer and have
become preferred drugs for less severe infections
•
FLUCYTOSINE (ANCOBON)
•
sometimes combined with amphotericin B to treat
septicemia or pulmonary and urinary tract infections due to
Candida and Cryptococcus species
PHARMACOTHERAPY WITH THE AZOLE
ANTIFUNGALS
FLUCYTOSINE
can cause immunosuppression, renal impairment, and liver
toxicity
Β – GLUCAN SYNTHESIS INHIBTORS
has been added to the treatment options for systemic
mycoses
Caspofungin (Cancidas), anidulafungin (Eraxis), and
micafungin (Mycamine)
o These drugs are expensive and usually
o Important alternatives to amphotericin B in the
treatment of invasive candidiasis.
o prescribed after other antifungal therapy has been
unsuccessful.
o Adverse effect: phlebitis, headaches, and
possible renal or hepatic impairment.
AZOLE CLASS
•
•
•
Largest and most versatile group of antifungals.
Have a broad spectrum and are used to treat nearly any
systemic, cutaneous, or superficial fungal infection
Fluconazole (Diflucan), itraconazole (Sporanox),
ketoconazole (Nizoral), and voriconazole (Vfend) are
used for both systemic and topical infections.
SYSYEMIC AZOLE CLASS
•
•
•
•
DRUGS FOR SYSTEMIC MYCOSES
Has two different chemical classes, (1) imidazoles and
the (2) triazoles.
Interfere with the biosynthesis of ergosterol, which is
essential for fungal cell membranes.
Depleting fungal cells of ergosterol impairs their growth.
Have a spectrum of activity similar to that of
amphotericin B
Considered less toxic and have the major advantage that
they can be administered PO.
Azoles have replaced amphotericin B in the
pharmacotherapy of less serious systemic fungal
infections.
Most common adverse effect: nausea and vomiting;
Anaphylaxis and rash
KETOCONAZOLE
fatal drug-induced hepatitis has occurred although the
incidence is rare and has not been reported with other
systemic azoles
ITRACONAZOLE
has begun to replace ketoconazole in the therapy of systemic
mycoses because it is less hepatotoxic and may be given
either orally or intravenously
POSACONAZOLE (NOXAFIL)
used to prevent invasive Candida and Aspergillus infections
in immunosuppressed patients
AZOLE ANTIFUNGAL DRUGS
TOPICAL AZOLES
•
•
•
•
•
10 topical formulations are available for superficial
mycoses.
Clotrimazole (Mycelex, others): preferred drug for
superficial fungal infections of the skin, vagina, and
mouth.
Fluconazole and itraconazole: additional options for oral
candidiasis.
Tioconazole, butoconazole, and miconazole: available to
treat vulvovaginal candidiasis
Most common adverse effects of the superficial azoles:
transient burning and irritation at the application sites.
PHARMACOTHERAPY OF SUPERFICIAL
FUNGAL INFECTION
•
Superficial mycoses are generally not severe and
patients are often treated with topical medications
Selected Drugs for Superficial Mycoses
A. Fluconazole (Diflucan)
Therapeutic Class: Antifungal
Pharmacologic Class: Inhibitor of fungal cell membrane
synthesis; azole
Action and Uses
•
Acts by interfering with the synthesis of ergosterol
•
It is rapidly and completely absorbed when given orally,
and is particularly effective against Candida albicans.
•
Able to penetrate most body membranes to reach
infections in the central nervous system, bone, eye,
urinary tract, and respiratory tract.
•
Major disadvantage: relatively narrow spectrum of
activity; not as effective against non-albicans Candida
species.
•
Approved for prophylaxis of fungal infections in patients
with AIDS, those undergoing bone marrow transplants,
or those receiving antineoplastic drugs.
B. Nystatin (Mycostatin, Nystop, others)
Therapeutic Class: Superficial antifungal
Pharmacologic Class: Polyene
Action and Uses
•
Nystatin binds to sterols in the fungal cell membrane,
causing leakage of intracellular contents as the
membrane becomes weakened.
•
Available in a wider variety of formulations, including
cream, ointment, powder, tablet and lozenge.
•
Primarily used topically for candida infections of te
vagina, sikin, and mouth. It may also be administered
PO to treat candidiasis of the intestine.
•
Mytrex and Mycolog II cream: combine nystatin with
triamcinolone (a corticosteroid) for treating inflamed
subcutaneous lesions.
SELECTED DRUGS FOR SUPERFICIAL MYCOSES
SUPERFICIAL FUNGAL INFECTION
•
•
may occur in any patient, not just those who have
suppressed immune systems.
Two commonly experienced skin mycoses: Athlete’s
foot (tinea pedis) and jock itch (tinea cruris)
ANTIFUNGAL DRUGS
•
•
Antifungal drugs applied topically are much safer than
their systemic counterparts because penetration into the
deeper layers of the skin or mucous membrane is poor
and only small amounts are absorbed into the circulation.
Adverse Effect: burning or stinging at the site of
application, drying of the skin, rash, or contact dermatitis
Selection of a particular antifungal drug is based
on the location of the infection and characteristics
of the lesion.
A. Griseofulvin
(Fulvicin)
B. Itraconazole
(Sporanox)
and
terbinafine
(Lamisil)
C. Miconazole
and
clotrimazole
D. Tolnaftate and
undecylenic
acid
Inexpensive, older agent given by the
oral route that is indicated for mycoses
of the hair, skin, and nails that have not
responded to conventional topical
preparations.
oral preparations that have the
advantage of accumulating in nail
beds, allowing them to remain active
many months after therapy is
discontinued.
OTC drugs of choice for vulvovaginal
candida infections
frequently used to treat athlete’s foot
and jock itch
PROTOZOA
•
•
•
are single-celled organisms that inhabit water, soil,
and animal hosts
these parasites often thrive in conditions where
sanitation and personal hygiene are poor and
population density is high.
protozoan infections often occur in patients who are
immunosuppressed, such as those with AIDS or who
are receiving antineoplastic drugs
PHARMACOTHERAPY OF MALARIA
•
•
•
SELECTED DRUGS FOR MALARIA
When faced with adverse conditions, protozoans can
form cysts that allow the pathogen to survive in harsh
environments and infect other hosts.
Pharmacotherapy of malaria attempts to interrupt the
complex life cycle of Plasmodium. Although
successful early in the course of the disease, therapy
becomes increasingly difficult as the parasite enters
different stages of its life cycle.
When cysts occur inside the host, the parasite is often
resistant to pharmacotherapy. With few exceptions,
antibiotic, antifungal, and antiviral drugs are ineffective
against protozoans.
MALARIA
is caused by four species of the protozoan Plasmodium
Goals of antimalarial therapy include the following:
Prevention
TRAVELERS TO INFESTED AREAS
of the
RECEIVE PROPHYLACTIC ANTIdisease
MALARIAL DRUGS PRIOR TO AND
DURING THEIR VISIT, AND FOR 1
WEEK AFTER LEAVING.
Chloroquine (Aralen)
atovaquone-proguanil (Malarone)
doxycycline
mefloquine
primaquine.
Treatment of DRUGS ARE USED TO I NTERRUPT
acute
THE ERYTHROCYTIC STAGE AND
attacks
ELIMINATE THE MEROZOITES FROM
RED BLOOD
CELLS
CHLOROQUINE is the traditional antimalarial for treating
the acute stage
Prevention
DRUGS ARE GIVEN TO
of relapse
ELIMINATE THE LATENT
FORMS OF PLASMODIUM
RESIDING IN THE LIVER.
PRIMAQUINE PHOSPHATE - is one of
the few drugs able to eliminate hepatic
cysts and achieve a total cure
DRUGS FOR SYSTEMIC MALARIA
A. CHLOROQUINE (ARALEN)
Therapeutic Class: Antimalarial drug
Pharmacologic Class: Heme complexing agent
Actions and Uses:
•
chloroquine has been the prototype medication for the
prophylaxis treating the erythrocytic stage but has no
activity against latent Plasmodium
•
Both
chloroquine
and
the
closely
related
hydroxychloroquine (Plaquenil) are also used off-label
for the treatment of rheumatic and inflammatory
disorders, including lupus erythematosus and
rheumatoid arthritis
METRONIDAZOLE (FLAGYL)
has been the traditional drug of choice for nonmalarial
protozoan infections
TINIDAZOLE (TINDAMAX)
was approved by the FDA for treatment of trichomoniasis,
giardiasis, and amebiasis
SELECTED DRUGS FOR NONMALARIAL
PROTOZOAN INFECTION
SELECTED DRUGS FOR MALARIA
Fixed-dose combination of artemether/ lumefantrine
(Coartem) treat acute, uncomplicated malaria infections
ARTEMETHER
had been known to have antimalarial properties for over a
thousand years
LUMEFANTRINE
extends the half-life of the combination drug
COARTEM
very effective and offers an additional option for treating
chloroquine-resistant infections. This drug is approved for
treatment, not prevention, of malaria
HELMINTIC INFECTION
•
•
•
Helminths consist of various species of parasitic worms,
which have more complex anatomy, physiology, and life
cycles than the protozoans.
Diseases due to these pathogens affect more than 2
billion people worldwide and are com mon in areas
lacking high standards of sanitation.
Helmin \thic infections in the United States and Canada
are neither common nor fatal, although drug therapy may
be indicated.
PHARMACOTHERAPY OF HELMINTIC INFECTION
•
•
•
•
•
Helminths are classified as roundworms (nematodes),
flukes (trematodes), or tapeworms (cestodes)
The most common helminth disease worldwide is
ascariasis, which is caused by the roundworm Ascaris
lumbricoides.
Pharmacotherapy of enterobiasis includes a single dose
of mebendazole, albendazole (Albenza) or pyrantel
(Antiminth, Ascarel, Pin-X, Pinworm Caplets).
When the infestation is severe or complications occur,
pharmacotherapy is initiated. Complications caused by
extensive infestations may include physical obstruction in
the intestine, malabsorption, increased risk for secondary
bacterial infections, and severe fatigue.
Pharmacotherapy is targeted at killing the parasites
locally in the intestine and systemically in the tissues and
organs they have invaded.
SELECTED DRUGS FOR HELMINTIC
INFECTIONS
Topical forms of
metronidazole
(MetroGel,
MetroCream,
MetroLotion)
KEY POINTS
•
•
•
•
•
•
are used to treat rosacea, a disease
characterized by skin reddening and
hyperplasia of the sebaceous glands,
particularly around the nose and face
SELECTED DRUGS FOR HELMINTIC INFECTIONS
SELECTED DRUGS FOR HELMINTIC INFECTIONS
MEBENDAZOLE (VERMOX)
Therapeutic Class: Anti-infective, antiprotozoan
Pharmacologic Class: Drug that disrupts nucleic acid
synthesis
Actions and Uses:
•
It is used in the treatment of a wide range of helminth
infections, including those caused by roundworm
•
It is effective against both the intestinal and hepatic stages
of the disease
SELECTED DRUGS FOR HELMINTIC INFECTIONS
METRONIDAZOLE
Therapeutic Class: Anti-infective, antiprotozoan
Pharmacologic Class: Drug that disrupts nucleic acid
synthesis
Actions and Uses:
•
Metronidazole is the prototype drug for most forms of
amebiasis, being effective against both the intestinal and
hepatic stages of the disease.
•
It preferred drug for giardiasis and trichomoniasis.
•
Metronidazole is unique among antiprotozoan drugs in
that it also has antibiotic activity against anaerobic bacteria
and thus is used to treat a number of respiratory, bone,
skin, and CNS infections
•
Helidac is a combination drug containing metronidazole,
bismuth, and tetracycline that is used to eradicate H. pylori
infection associated with peptic ulcer disease.
•
Fungi have more complex physiology than bacteria and
are unaffected by most antibiotics. Most serious fungal
infections occur in patients with suppressed immune
defenses.
Antifungal medications act by disrupting aspects of
growth or metabolism that are unique to these organisms.
Systemic mycoses affect internal organs and may require
prolonged and aggressive drug therapy. Amphotericin B
(Fungizone) is the traditional drug of choice for serious
fungal infections.
The azole class of antifungal drugs has become widely
used in the pharmacotherapy of both systemic and
superficial mycoses owing to a
Malaria is the most common protozoan disease and re
quires multidrug therapy owing to the complicated life
cycle of the parasite. Drugs may be administered for pro
phylaxis and therapy for acute attacks and prevention of
relapses.
Treatment of non-Plasmodium protozoan disease re
quires a different set of medications from those used for
malaria. Other protozoan diseases that may be in
dications for pharmacotherapy include amebiasis, toxo
plasmosis, giardiasis, cryptosporidiosis, trichomoniasis,
trypanosomiasis, and leishmaniasis.
Helminths are parasitic worms that cause significant dis
ease in certain regions of the world. The goals of
pharmacotherapy are to kill the parasites locally and to
disrupt their life cycle
NCM 106: PHARMACOLOGY
DRUGS FOR VIRAL INFECTIONS
SOURCE: REPORTER’S PPT
TRANSCRIBERS: SHANE VERSOZA
CHECKER: AZI GONZALES & JEWEL SHTONE
TOPIC OUTLINE
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
What is virus?
Characteristics of viruses
Three basic strategies used for antiviral pharmacotherapy
Replication of HIV
General principles of HIV pharmacotherapy
Two laboratory tests used to monitor the progress of
pharmacotherapy
The therapeutic goals for the pharmacotherapy of HIV
AIDS
Classification of drugs for HIV-AIDS
Treatment failures commonly occur during antiretroviral
therapy
Regimen choices for initial therapy of HIV infection
Progress for HIV that has been made on its prevention
Pharmacotherapy with reverse transcriptase inhibitors
Pharmacotherapy with entry inhibitors and integrase
inhibitors
Prevention of transmission of HIV
Postexposure prophylaxis of HIV infection following
occupational exposure
Pharmacotherapy of herpesvirus
Pharmacotherapy of influenza
Pharmacotherapy of viral hepatitis
SECOND YEAR
FIRST SEM
•
•
Antiretroviral drugs slow the growth of the causative agent for
AIDS, the human immunodeficiency virus (HIV), by several
mechanisms.
Resistance to these drugs is a major clinical problem, and a
pharmacologic cure for HIV-AIDS is not yet achievable.
REPLICATION OF HIV
•
•
•
Infection with HIV occurs by exposure to contaminated body
fluids, most commonly blood or semen.
Transmission may occur through
→ sexual activity (oral, anal, or vaginal) or
→ through contact of infected fluids with broken skin,
mucous membranes, or needlesticks
Newborns can receive the virus during birth or from breastfeeding.
VIRUSES
•
•
•
Viruses are tiny infectious agents capable of causing
disease in humans and other organisms.
After infecting an organism, viruses use host enzymes and
cellular structures to replicate.
Antivirals remain the least effective of all the anti-infective
drug classes.
1.
2.
CHARACTERISTICS OF VIRUSES
1.
2.
3.
4.
5.
Viruses are nonliving agents that infect bacteria, plants, and
animals
Surrounded by a protective protein coat, or capsid
Viruses are intracellular parasites: They must be inside a host
cell to cause infection
The host organism and cell are often very specific; it may be
a single species of plant, bacteria, or animal, or even a single
type of cell within that species
Most often viruses only one species
3.
ANTIVIRAL PHARMACOTHERAPY
•
•
Can be extremely challenging because of the rapid mutation
rate of viruses.
Antiviral drugs have narrow spectrums of activity, usually
limited to one specific virus.
4.
THREE BASIC STRATEGIES USED FOR
ANTIVIRAL PHARMACOTHERAPY
•
•
•
Prevent viral infections through the administration of vaccines
Treat active infections with drugs such as acyclovir (Zovirax)
that interrupt an aspect of the virus’s replication cycle.
For prophylaxis, use drugs that boost the patient’s immune
response (immunostimulants) so that the virus remains in
latency with the patient symptom free.
GENERAL PRINCIPLES OF HIV
PHARMACOTHERAPY
•
HIV - AIDS
•
Acquired immune deficiency syndrome (AIDS)
Acquired immune deficiency syndrome (AIDS) is
characterized by profound immunosuppression that leads to
opportunistic infections and malignancies not commonly
found in patients with healthy immune defenses.
The virus attaches to its preferred target—the CD4 receptor
on T4 (helper) lymphocytes. During this early stage, structural
proteins on the surface of HIV fuse with the CD4 receptor.
Coreceptors known as CCR5 and CXCR4 have been
discovered that assist HIV in binding to the T4 lymphocyte
The virus uncoats and the genetic material of HIV, singlestranded RNA, enters the host cell. HIV converts its RNA
strands to double-stranded DNA, using the viral enzyme
reverse transcriptase. The viral DNA eventually enters the
nucleus of the T4 lymphocyte where it becomes incorporated
into the host’s chromosomes. This action is performed by HIV
integrase, another enzyme unique to HIV
The virus uncoats and the genetic material of HIV, singlestranded RNA, enters the host cell. HIV converts its RNA
strands to double-stranded DNA, using the viral enzyme
reverse transcriptase. The viral DNA eventually enters the
nucleus of the T4 lymphocyte where it becomes incorporated
into the host’s chromosomes. This action is performed by HIV
integrase, another enzyme unique to HIV. It may remain in
the host DNA for many years before it becomes activated to
begin producing more viral particles
The new virions eventually bud from the host cell and enter
the bloodstream. The new virions, however, are not yet
infectious. As a final step, the viral enzyme protease cleaves
some of the proteins associated with the HIV DNA, enabling
the virion to infect other T4 lymphocytes. Once budding
occurs, the immune system recognizes that the cell is
infected and kills the T4 lymphocyte
•
•
HIV-AIDS is unlike any other infectious disease because it is
most often sexually transmitted, is uniformly fatal, and
demands a continuous supply of new drugs for patient survival
The challenges of HIV-AIDS have resulted in the development
of over 20 new antiretroviral drugs
Unfortunately, the initial hopes of curing HIV-AIDS through
antiretroviral therapy or vaccines have not been realized; none
of these drugs produces a cure for this disease
•
Although pharmacotherapy for HIV-AIDS has not produced a
cure, it has resulted in a number of therapeutic successes
→ For example, many patients with HIV infection are able to
live symptom free with the disease for a longer time
because of medications. Furthermore, the transmission of
the virus from a mother who is infected with HIV to her
newborn has been reduced dramatically
Along with better patient education and prevention, successes
in pharmacotherapy have produced a 70% decline in the death
rate due to HIV-AIDS in the United States but not in African
countries because antiviral drugs are not as readily available,
largely because of their high cost
During a chronic latent phase of HIV where HIV incorporates
its viral DNA into the nucleus of the T4 lymphocyte, it may
remain dormant for several months to many years, patients are
asymptomatic and may not even realize they are infected.
The advantage of beginning during the asymptomatic stage is
that the viral load or burden can be reduced
Early therapy is especially critical for infants younger than 12
months
•
•
•
•
NEGATIVE CONSEQUENCES
1. Drugs for HIV-AIDS are expensive
2. These drugs produce a number of uncomfortable and
potentially serious adverse effect
3. Therapy over many years promotes viral resistance
SYMPTOTIC
The decision to begin therapy during the symptomatic phase is
much easier because the severe symptoms of AIDS can rapidly
lead to death
TWO LABORATORY TESTS
USED TO MONITOR THE PROGRESS OF
PHARMACOTHERAPY OF HIV
ABSOLUTE CD4 T-CELL COUNT
predicts the likelihood of opportunistic disease; however, it does
not indicate how rapidly HIV is replicating.
Viral load is determined by measuring the amount of HIV RNA
in the blood
MEASUREMENT OF HIV RNA IN THE PLASMA
the HIV RNA level is an estimate of how rapidly the virus is
replicating and is considered a more accurate predictor of clinical
outcome than CD4 cell counts
NOTE:
1. These tests are performed every 3 to 6 months
2. The goal of antiretroviral therapy is to reduce plasma HIV
RNA to less than 75 copies/mL.
3. For most patients, 12 to 24 weeks of HIV pharmacotherapy
is required to achieve this level
The therapeutic goals for the pharmacotherapy
of HIV AIDS
1.
2.
3.
4.
5.
Reduce HIV-related morbidity and prolong survival
Improve the quality of life
Restore and preserve immunologic function
Promote maximum suppression of viral load
Prevent the transmission from mother to child in pregnant
patients who are infected with HIV
THE ROUTINE USE OF STRUCTURED TREATMENT
INTERRUPTIONS (STIS):
•
This technique was believed to reduce adverse effects
•
increase the patient’s quality of life, and diminish the
potential for resistant HIV strains
•
Research studies, however, have questioned the
effectiveness of STIs; in-deed, some data suggest that this
strategy actually promotes drug resistance and hastens
disease progression
*In all cases, viral load increases when drug therapy is
discontinued
CLASSIFICATION OF DRUGS FOR HIV-AIDS
→ Antiretroviral drugs target specific phases of the HIV
replication cycle.
→ The standard pharmacotherapy for HIV-AIDS includes
aggressive treatment with multiple drugs concurrently, a
regimen called highly active antiretroviral therapy (HAART).
→ The goal of HAART is to reduce the plasma HIV RNA to its
lowest possible level.
→ The simultaneous use of drugs from several classes
reduces the probability that HIV will become resistant to
treatment.
→ Antiretroviral therapy must be continued for the lifetime of
the patient.
HIV-AIDS antiretrovirals are classified into the following groups,
based on their
(NRTIs/
NtRTIs)
(PIs)
Entry
inhibitors
(NNRTIs)
Integrase
inhibitors
MECHANISMS OF ACTION
Nucleoside/nucleotide reverse transcriptase
inhibitors
Protease inhibitors (PIs)
Entry inhibitors (includes fusion inhibitors and
CCR5 antagonists)
Nonnucleoside reverse transcriptase inhibitors
(NNRTIs)
Integrase inhibitors
REGIMENS
often different for patients who are receiving these drugs for the
first time (treatment naïve) versus patients who have been
taking antiretrovirals for months or years (treatment experienced)
TREATMENT FAILURES COMMONLY OCCUR
DURING ANTIRETROVIRAL THERAPY
•
•
•
•
The primary factors responsible for treatment failure are
inability to tolerate the adverse effects of the medications
Nonadherence to the complex drug therapy regimen
Emergence of resistant HIV strains, and
Genetic variability among patients
Drug manufacturers have responded to the need for simpler treatment
regimens by combining several medica-tions into a
SINGLE CAPSULE OR TABLET
Atripla
(efavirenz + emtricitabine + tenofovir)
Combivir
(lamivudine + zidovudine)
Complera (emtricitabine +rilpivirene+tenofovir),
Epzicom
(abacavir + Lamivudine)
trizivir
(abacavir + lamivudine + zidovudine)
ruvada
(emtricitabine + tenofovir).
* These once- or twice-daily tablets lower the pill burden and
likely improve patient compliance with complicated regimens
THE MOST SUCCESSFUL REGIMEN CHOICES
FOR THE INITIAL THERAPY OF HIV INFECTION
NNRTIbased
regimen:
PI-based
regimens:
Integrase
inhibitorbased
regimen:
efavirenz + tenofovir + emtricitabine.
-
atazanavir (ritonavir-boosted) + tenofovir +
emtricitabine
darunavir (ritonavir-boosted) + tenofovir +
emtricitabine
raltegravir + tenofovir + emtricitabine
ALTHOUGH NO DRUG OR DRUG COMBINATION
HAS YET BEEN FOUND TO CURE HIV-AIDS,
SOME PROGRESS HAS BEEN MADE ON ITS
PREVENTION
Truvada
has been found to reduce the risk of acquiring
(emtricitabine HIV infection and may be recommended for
+ tenofovir)
people at very high risk for the disease
This drug is not 100% effective and that it should not replace
established methods for HIV prevention such as abstinence,
condoms, or other safe sex measures.
PHARMACOTHERAPY WITH REVERSE
TRANSCRIPTASE INHIBITORS
REVERSE TRANSCRIPTASE INHIBITORS (NRTIS, NNRTIS,
AND NTRTIS)
• HIV virions come “prepack-aged” with reverse transcriptase;
the enzyme necessary to convert the retroviral RNA genome
into double-stranded DNA. This viral DNA then migrates to the
nucleus and becomes integrated into the host genome.
• Because reverse transcriptase is a viral enzyme not found in
human cells, it has been possible to design drugs capable of
selectively inhibiting viral replication
• Viral DNA synthesis requires building blocks called
nucleosides
• Drugs in the nucleoside and nucleotide reverse transcriptase
inhibitor classes (NRTIs and NtRTIs) chemically resemble the
natural building blocks of DNA. In essence, reverse
transcriptase is fooled by these drugs and inserts them into the
proviral DNA strand. As the “false” nucleosides and
nucleotides are used to build DNA, however, the proviral DNA
chain is prevented from lengthening
• A second mechanism for inhibiting reverse transcriptase
targets the enzyme’s function.
• Although there are differences in their pharmacokinetic and
toxicity profiles, no single NRTI or NNRTI offers a clear
therapeutic advantage over any other
• Choice of drugs depends on patient response and the
experience of the clinician
Zidovudine (Retrovir, AZT)
have been used consistently for more than 25 years, the
potential for resistance must be considered when selecting the
specific agent. There is a high degree of cross-resistance among
the NRTIs. The NRTIs and NNRTIs are nearly always used in
multidrug combinations in HAART.
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBTOR
(NRTI)
As a class, the NRTIs are well tolerated, although nausea,
vomiting, diarrhea, headache, and fatigue are common
during the first few weeks of therapy. After prolonged therapy
with NRTIs, inhibition of mitochondrial function can cause
various organ abnormalities, blood disorders, lactic acidosis,
and lipodystrophy. Areas such as the face, arms, and legs
tend to lose fat, whereas the abdomen, breasts, and base of
the neck (buffalo hump) accumulate excessive fat deposits.
*Tesamorelin (Egrifta) was approved in 2010 as an option
to reduce excessive abdominal fat caused by NRTI-induced
lipodystrophy.
Efavirenz (Sustiva)
exhibits a high incidence of CNS effects such as dizziness,
sleep disorders, and fatigue, but these symptoms are rare in
patients taking nevirapine (Viramune). Unlike some other
antiretrovirals that negatively affect lipid metabolism,
nevirapine actually improves the lipid profiles of many
patients by increasing HDL levels
NONNUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBTOR (NNRTI)
The NNRTIs are also generally well tolerated and exhibit
few serious adverse effects. The adverse effects from these
drugs, however, are different from those of the NRTIs. Rash
is common, and liver toxicity is possible, increasing the risk
of drug–drug interactions
PHARMACOTHERAPY WITH PROTEASE
INHIBITORS
PROTEASE INHIBTORS
Drugs in the protease inhibitor class block the viral enzyme
protease, which is responsible for the final assembly of the
HIV virions. They have become key drugs in the
pharmacotherapy of HIV infection.
•
•
•
•
•
•
•
•
•
•
•
HIV protease cuts up large precursor proteins into smaller
proteins. These smaller proteins combine with HIV's
genetic material to form a new HIV virus
The protease inhibitors (PIs) attach to the active site of
HIV protease, thus preventing the final maturation of the
virions
The virions are noninfectious without this final step
When combined with other antiretroviral drug classes, the
PIs are capable of lowering plasma levels of HIV RNA to
an undetectable range.
Since their development in 1995, the PIs have become
essential drugs in the treatment of HIV-AIDS.
They are well tolerated, with gastrointestinal (GI)
complaints being the most common side effects
All PIs have equivalent effectiveness and exhibit a simi-lar
range of adverse effects
Atazanavir and darunavir (both combined with ritonavir)
are preferred drugs for the initial treatment of HIV.
The initial choice of protease inhibitor usually includes low
doses of ritonavir
Addition of small amounts of ritonavir allows less frequent
dosing intervals and increases the plasma concentration
of the primary protease inhibitor.
This is known as ritonavir boosting
PHARMACOTHERAPY WITH ENTRY
INHIBITORS AND INTEGRASE INHIBITORS
ENTRY INHIBTORS AND INTEGRASE INHIBITORS
Because HIV develops resistance to most of the frequently
prescribed antiretrovirals, scientists have been looking
intensively for unique mechanisms of drug action. In recent
years, entry inhibitors and integrase inhibitors have been
discovered
Entry inhibitors prevent the entry of the viral nucleic acid into the
T4 lymphocyte. The two drugs in this class block the entry of
HIV by different mechanisms.
Enfuvirtide (Fuzeon)
blocks the fusion of the viral membrane with the bilipid layer of
the host’s plasma membrane, a step required for entry of the
virus. Because this mechanism is so different from other
antiretrovirals, many patients who are resistant to other drug
classes are still sensitive to the effects of enfuvirtide. Its current
use is for treating HIV infections in treatment-experienced
patients with strains resistant to other antiretrovirals
Maraviroc (Selzentry)
was developed after scientists discovered that HIV needs
coreceptors (in addition to the CD4 receptor) to enter into
human cells. CCR5 is the name of one of the coreceptors
required for entry. Maraviroc blocks CCR5 and has the ability to
significantly reduce viral load and increase T-cell production.
Maraviroc is approved for combination therapy with other
antiretrovirals in treatment-naïve patients
Raltegravir (Isentress)
the first integrase inhibitor.
Raltegravir is indicated for combination therapy with other
antiretroviral agents for the treatment of HIV infection in adult
patients
PREVENTION OF PERINATAL
TRANSMISSION OF HIV
therapy more than 48 hours after birth is ineffective in
preventing the infection.
POSTEXPOSURE PROPHYLAXIS OF HIV
INFECTION FOLLOWING OCCUPATIONAL
EXPOSURE
Since the start of the AIDS epidemic, nurses and other health
care workers have been concerned about acquiring the
infection from their patients with HIV-AIDS. Fortunately, if
proper precautions are observed, the disease is rarely
transmitted from patient to caregiver. Accidents have occurred,
however, in which health care workers have acquired the
infection by exposure to the blood or body fluids of a patient
infected with HIV.
The success of postexposure prophylaxis (PEP) therapy
following HIV exposure is difficult to assess because of the lack
of controlled studies and the small number of cases. Enough
data have been accumulated, however, to demonstrate that
PEP is successful in certain circumstances
If the HIV status of the patient is unknown, PEP is decided case
by case, based on the type of exposure and the likelihood that
the blood or body fluid contained HIV
The basic PEP treatment includes one of the following
regimens, conducted over a 4-week period
1. Tenofovir and emtricitabine
2. Lamivudine and tenofovir
3. Zidovudine and emtricitabin
4. Zidovudine and lamivudine
•
If the accidental HIV exposure was particularly severe, and
the source is a symptomatic HIV-infected person with a
high viral load, a third drug may be added to the regimen
(lopinavir boosted with ritonavir). Adding a third drug
increases the risk for adverse effects and has not been
proved to be more successful than a two-drug regimen
PHARMACOTHERAPY OF HERPRESVIRUS
HERPESVIRUSES
Herpes simplex viruses (HSVs) are a family of DNA viruses that
cause repeated blister-like lesions on the skin, genitals, and
other mucosal surfaces.
Antiviral drugs can lower the frequency of acute herpes
episodes and diminish the intensity of acute disease
Herpesviruses are usually acquired through direct physical
contact with an infected person but they may also be
transmitted from infected mothers to their newborns sometimes
resulting in severe CNS disease.
One of the most tragic aspects of the AIDS epidemic is
transmission of the virus from a mother to her child during
pregnancy, delivery, or breast-feeding. Newborns with HIV
may succumb to the infection within weeks, or symptoms may
be delayed for months or years. The prognosis for these
children is generally poor; thus, the best approach to dealing
with HIV infections in neonates is prevention.
The risk of transmission may be reduced approximately
70% using the following regimen:
•
Oral administration of zidovudine to the mother,
beginning at week 14 of gestation and continuing to
week 34 of gestation
•
Intravenous administration of zidovudine to the mother
during labor
•
Oral administration of zidovudine to the newborn for 6
weeks following delivery. (HIV infection is established in
infants by age 1 to 2 weeks; starting antiretroviral
The herpesvirus family includes the following:
1. HSV-1. Primarily infections of the eye, mouth, and lips,
although the incidence of genital infections is increasing
2. HSV-2 Primarily genital infections
3. Cytomegalovirus (CMV). Affects multiple body systems in
immunosuppressed patients
4. Varicella-zoster virus (VZV). Shingles (zoster) and
chickenpox (varicella)
5. Epstein–Barr virus (EBV). Infectious mononucleosis and a
form of cancer called Burkitt’s lymphoma
6. Herpesvirus-type 6. Roseola in children and hepatitis or
encephalitis in immunosuppressed patients
PHARMACOTHERAPY OF HERPESVIRUS
INFECTIONS
In immunocompromised patients, IV acyclovir may be indicated.
Ocular herpes is treated with local application of drops or
ointment. Trifluridine (Viroptic) and idoxuridine (Dendrid,
Herplex) are available in ophthalmic formulations. Oral acyclovir
is used when topical drops or ointments are contraindicated.
Uncomplicated ocular herpes usually resolves after 1 to 2
weeks of pharmacotherapy
Initial HSV-1 and HSV-2 infections are usually treated with oral
antiviral therapy for 5 to 10 days. The most commonly
prescribed antivirals for HSV and VZV include acyclovir
(Zovirax), famciclovir (Famvir), and valacyclovir (Valtrex).
Topical forms of several antivirals are available for application
to herpes lesions, although they are not as effective as the oral
forms.
PHARMACOTHERAPY OF INFLUENZA
It is important to understand that these antivirals are not
effective against the common cold virus. About 200 different
viruses, including rhinoviruses, cause symptoms identified with
the common cold. Despite considerable attempts to develop
drugs to prevent this annoying infection, success has not yet
been achieved.
PHARMACOTHERAPY OF VIRAL HEPATITIS
HEPATITIS A VIRUS (HAV)
•
•
•
•
Spread by the oral-fecal route and causes epidemics in
regions of the world having poor sanitation
The most common cause of acute hepatitis in the United
States
Normally considered as an acute disease since most
recover without pharmacotherapy and develop lifelong
immunity to the virus. Only a small number of patients
develop severe liver failure.
The best treatment is prevention.
HAV VACCINE (HAVRIX, VAQTA)
•
•
PHARMACOTHERAPY OF INFLUENZA
INFLUENZA
a viral infection characterized by acute symptoms that include
sore throat, sneezing, coughing, fever, and chills. The infectious
viral particles are easily spread via airborne droplets. In
immunosuppressed patients, an influenza infection may be
fatal. In 1918– 1919, a worldwide outbreak of influenza killed an
estimated 20 million people. Influenza viruses are designated
with the letters A, B, or C. Type A has been responsible for
several serious pandemics throughout history. The
RNAcontaining influenza viruses should not be confused with
Haemophilus influenzae, which is a bacterium that causes
respiratory disease.
The best approach to influenza infection is prevention through
annual vaccination.
Antivirals may be used to prevent influenza or decrease the
severity of acute symptoms. Amantadine has been available to
prevent
and
treat
influenza
for
many
years.
Chemoprophylaxis with amantadine or rimantadine
(flumadine) is indicated for unvaccinated type A. therapy with
these antiviral offers protection during the 2 weeks before
therapeutic antibody titers are achieved from the vaccine.
Because of the expense and possible adverse effects of these
drugs, they are generally reserved for patients who are greatest
risk for the severe complications of influenza.
•
HEPATITIS A IMMUNOGLOBULINS (HAIg)
•
•
•
Concentrated solution of antibodies
Administered as prophylaxis for patients traveling to
endemic areas and to close personal contacts of infected
patients to prevent transmission of the virus.
A single IM dose can provide passive protection and
prophylaxis for about 3 months. Its estimated that the
immunoglobulins are 85% effective at preventing HAV in
patients exposed to the virus.
HEPATITIS B VIRUS (HBV)
•
•
•
•
•
•
ACTIVE INFLUENZA INFECTION
The neuroaminidase inhibitors were introduced in 1999 to treat
active influenza infections. If given within 48 hours of the onset
of symptoms, oseltamivir (Tamiflu) and zanamivir (Relenza)
are reported to shorten the normal 7-days duration of influenza
symptoms to 5 days. Oseltamivir is given orally, whereas
zanamivir is inhaled. Because these agents are expensive and
produce only modest results, prevention through vaccination
remain the best alternative.
Has been available since 1995
Indicated for all children ages 2 to 18, travelers to
countries with high HAV infection rates, people treated
with clotting factor concentrates, men who have sex with
men, and illegal drug users.
The average length of protection is approximately 5 to 8
years, although protection may last 20 years or longer in
some patients.
Transmitted primarily through exposure to contaminated
blood and body fluids
Major risk factors: injected drug abuse, sex with an HBVinfected partner, and sex between men.
The primary mode of transmission of HBV is by thee
perinatal route and from child to child.
Treatment of acute HBV infection is. Symptomatic,
because no specific. Therapy is available.
HBV may develop as long as 10 years following
exposure.
HBV has a much greater probability of progression to
chronic hepatitis and a greater mortality rate than does
HAV
HBV VACCINE (ENGERIX-B, RECOMBIVAX
HB)
•
•
•
Best treatment of HBV is prevented through
immunization
Universal vaccination of all children is now
recommended, with three dose starting at birth to 28
months of ages.
A combination vaccine is available that provides
immunity to both HAV and HBV – Twinrix
1.
2.
TWO BASIC STRATEGIES FOR ELIMINATING HBV
Give antivirals that stop replication.
To administer immunomodulators that boost body
defenses.
APPROVED THERAPIES FOR CHRONIC
HBV PHARMACOTHERAPY
1.
2.
3.
4.
5.
Interferon alfa or PEG interferon
Lamivudine (Epivir)
Adefovir (Hepsera)
Entecavir (Baraclude)
Tenofovir (Viread)
HEPATITIS C AND OTHER HEPATITIS
VIRUSES
•
•
•
•
•
•
Hepatitis C, D, E, and G viruses are sometimes
referred to as A-non B viruses.
Hepatitis C Virus (HCV) is more common than HBV;
transmitted primarily through exposure to infected
blood or body fluids.
There is no available vaccine for HCV. Post Exposure
to prophylaxis of HAC with immunoglobulins is not
recommended because its effectiveness has not
been demonstrated.
Current pharmacotherapy for chronic HCV infection
includes several types of interferon and the antiviral
ribavirin.
Pegylation: process that attaches polyethylene
glycol PEG) to an interferon to extend its duration of
action, thus allowing it to be administered less
frequently.
In 2022, two new antivirals were approved for chronic
hepatitis C Infection. Bocepprevir (virelis) and
telaprevir (Incivek) are approved only in combination
therapy with ribavirin and PE interferon alfa.
NCM 106: PHARMACOLOGY
CHAPTER #: DRUGS FOR NEOPLASIA
SOURCE: GROUP 2 PPT
TRANSCRIBERS: SOFIA ELLAINE F. FANOGA
CHECKER: AZI GONZALES & JEWEL SHTONE
SECOND YEAR
FIRST SEM
TOPIC OUTLINE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Cancer
Characteristics of Cancer
Tumor
Metastasis
Classification and Naming of Tumors
Causes of Cancer
Cancer Prevention
Selenium’s Role in Cancer Prevention
Chemotherapy
Cell Cycle
Alkylating Agents
Pharmacotherapy of Alkylating Agents
Cyclophosphamide (Cytoxan)
Antimetabolites
Pharmacotherapy with Antimetabolites
Methotrexate (Rheumatrex, Trexall)
Antitumor Antibiotics
Pharmacotherapy with Antitumor Antibiotics
Doxorubicin (Adriamycin)
Pharmacotherapy with Natural Products
Vincristine (Oncovin)
Pharmacotherapy with Hormones and Hormone
Antagonists
Tamoxifen
Pharmacotherapy with Biologic Response Modifiers
and Targeted Therapies
Miscellaneous Antineoplastics
CANCER
•
•
•
•
•
•
one of the most feared diseases in society
often silent, producing no symptoms until it reaches an
advanced stage
sometimes requires painful and disfiguring treatments
may strike at an early age, even during childhood, to
deprive people of a normal life span
The medical treatment of cancer often cannot offer a
cure, and progression to death is sometimes slow, painful,
and psychologically difficult for patients and their loved
ones.
Despite its feared status, many successes have been
made in the diagnosis, understanding, and treatment of
cancer. Modern treatment methods result in a cure for
nearly two of every three people and the 5-year survival
rate has steadily increased for many types of cancer.
METASTASIS
•
CLASSIFICATION OF NAMING OF TUMORS
CAUSES OF CANCER
Carcinogens
•
•
•
Cancer, or carcinoma, is a disease characterized by
abnormal, uncontrolled cell division. Cancer is thought
to result from damage to the genes controlling cell growth.
Once damaged, the cell is no longer responsive
Cancer is thought to result from damage to the genes
controlling cell growth. Once damaged, the cell is no
longer responsive to normal chemical signals checking its
growth. The cancer cells lose their normal functions,
divide rapidly, and invade surrounding cells.
TUMOR
•
•
•
•
•
Tumor defined as a swelling, abnormal enlargement, or
mass.
often used interchangeably with the word neoplasm
may be solid masses, such as lung or breast cancer, or
they
may be widely disseminated in the blood, such as
leukemia
named according to their tissue of origin, generally with
the suffix -oma.
factors that have been found to cause cancer or to be
associated with a higher risk for acquiring the disease
Historically, the antifungal drugs used for superficial
infections where clearly distinct from those prescribed for
systemic infections. In recent years, some of the newer
antifungal medications may be used for either superficial
or systemic infections. Some superficial infections may be
treated with oral, rather than topical drugs.
Chemical Carcinogens
•
•
•
•
chemicals in tobacco smoke
Alcohol ingestion - linked to certain cancers, including
esophageal, oral, breast, and liver cancers.
Asbestos and benzene - associated with a higher
incidence of cancer in the workplace.
In some cases, the site of the cancer may be distant from
the entry location, as with bladder cancer caused by the
inhalation of certain industrial chemicals.
Physical Factors
•
exposure to large amounts of x-rays - associated with a
higher risk of leukemia.
•
Ultraviolet (UV) light from the sun is a known cause of skin
cancer.
It is estimated that viruses are associated with about 15% of all
human cancers.
•
herpes simplex types I and II
•
Epstein Barr
•
human papillomavirus (HPV)
•
cytomegalovirus
•
human T-lymphotrophic viruses
CHARACTERISTICS OF CANCER
•
process wherein the abnormal cells often travel to distant
sites where they populate new tumors.
Factors that Suppress the Immune System
•
HIV or drugs given after transplant surgery - may
encourage the growth of cancer cells
•
•
genes may predispose close relatives to the condition
abnormal genes interact with chemical, physical, and
biologic agents to promote cancer formation
•
•
•
may inhibit the formation of tumors
if damaged, cancer may result
damage to the suppressor gene p53 is associated with
cancers of the breast, lung, brain, colon, and bone
•
Eliminate tobacco use and exposure to secondhand
smoke.
Limit or eliminate alcoholic beverage use.
Maintain a healthy diet low in fat and high in fresh
vegetables and fruit.
Genetic Component
Tumor Suppressor Genes
CANCER PREVENTION
•
•
•
•
•
•
Choose most foods from plant sources; increase fiber in
the diet.
Exercise regularly and maintain body weight within
recommended guidelines.
Self-examine your body monthly for abnormal lumps and
skin lesions.
Avoid chronic or prolonged exposure to direct sunlight
and/or wear protective clothing or sunscreen.
•
purpose is to rid the body of any cancerous cells that
could not be removed during surgery or to treat any
microscopic metastases that may be developing
•
chemoprophylaxis - prevent cancer from occurring in
patients at high risk for developing tumors.
*For example, some patients who have had a primary breast
cancer removed may receive tamoxifen, even if there is no
evidence of metastases, because there is a high likelihood that
the disease will recur.
SELENIUM’S ROLE IN CANCER PREVENTION
•
•
•
•
•
CHEMOTHERAPY
PHARMACOTHERAPY OF CANCER /
CHEMOTHERAPY
general goals: cure, control, and palliation.
CURE:
•
permanent removal of all cancer cells from the body
•
possibility for cure is much greater if a cancer is
identified and treated in its early stages, when the
tumor is small and localized to a well-defined region
•
Hodgkin’s lymphoma, certain leukemias, and
choriocarcinoma.
Control
•
cancer is managed as a chronic disease, such as
hypertension or diabetes
•
Chemotherapy drugs are administered to reduce the size
of the tumor, easing the severity of pain and other tumor
symptoms
advanced cancers for which palliation is frequently used
include: osteosarcoma, pancreatic cancer, and
Kaposi’s sarcoma.
Chemotherapy may be used alone or in combination with
other treatment modalities such as surgery or radiation
therapy.
Palliation
•
•
Surgery
•
•
•
useful for removing solid tumors that are localized
lowers the number of cancer cells in the body so that
radiation therapy and pharmacotherapy can be more
successful
not an option for tumors of blood cells or when it would
not be expected to extend a patient’s life span or to
improve the quality of life
Radiation therapy
•
•
•
•
most successful and produces the fewest adverse effects
for cancers that are localized, when high doses of ionizing
radiation can be aimed directly at the tumor and be
confined to a small area.
frequently prescribed postoperatively to kill cancer cells
that may remain following an operation
sometimes given as palliation for inoperable cancers to
shrink the size of a tumor that may be pressing on vital
organs, and to relieve pain, difficulty breathing, or difficulty
swallowing
Adjuvant chemotherapy
•
CELL CYCLE
Selenium is an essential trace element that is necessary
to maintain healthy immune function.
It is a vital antioxidant, especially when combined with
vitamin E.
It protects the immune system by preventing the formation
of free radicals, which can damage the body.
Selenium can be found in meat and grains, Brazil nuts,
brewer’s yeast, broccoli, brown rice, dairy products, garlic,
molasses, andonions.
Low dietary intake of selenium is associated with
increased incidence of several cancers, including lung,
colorectal, skin, and prostate.
administration of antineoplastic drugs after surgery or
radiation therapy
•
Both normal and cancerous cells go through a sequence
of events known as the cell cycle. Cells spend most of
their lifetime in the Go phase. Although sometimes called
the resting stage, the Go is the phase during which cells
conduct their everyday activities such as metabolism,
impulse conduction, contraction, or secretion.
•
If the cell receives a signal to divide, it leaves Go and
enters the G1 phase, during which it synthesizes the RNA,
proteins, and other components needed to duplicate its
DNA during the S phase.
•
Following duplication of its DNA, the cell enters the
premitotic phase, or G2. Following mitosis in the M phase,
the cell re-enters its resting Go phase, where it may
remain for extended periods, depending on the specific
tissue and surrounding cellular signals.
•
The actions of many of the antineoplastic drugs are
specific to certain phases of the cell cycle, whereas others
are mostly independent of the cell cycle.
•
For example, mitotic inhibitors such as vincristine
(Oncovin) affect the M phase, which includes prophase,
metaphase, anaphase, and telophase. Antimetabolites
such as fluorouracil (5-FU, Adrucil, Carac, Efudex) are
most effective during the S phase.
•
The
effects
of
alkylating
agents
such
as
cyclophosphamide (Cytoxan) are generally independent of
the phases of the cell cycle.
The actions of many of the antineoplastic drugs are specific to
certain phases of the cell cycle, whereas others are mostly
independent of the cell cycle.
Mitotic inhibitors: vincristine (Oncovin)
•
M phase (prophase, metaphase,
telophase)
anaphase,
and
Antimetabolites: fluorouracil (5-FU, Adrucil, Carac, Efudex)
•
S phase
Alkylating agents: cyclophosphamide (Cytoxan)
•
independent of the phases of the cell cycle
ALKYLATING AGENTS
Nitrogen Mustards
•
•
•
first alkylating agents
developed in secrecy as chemical warfare agents during
World War II. nitrogen mustards
Although the drugs in this class have different chemical
structures, all share the common characteristics of forming
bonds or linkages with DNA, a process called alkylation.
ALKYLATING AGENTS
ADVERSE EFFECTS
•
•
•
•
•
•
•
Bone marrow suppression - occurs during days 9–14 of
therapy
severe infection and sepsis
Thrombocytopenia
Nausea, vomiting, anorexia, and diarrhea
reversible alopecia
hemorrhagic cystitis
permanent sterility in some patients
ANTIMETABOLITES
•
PHARMACOTHERAPY WITH ALKYLATING AGENTS
•
•
•
•
Alkylation changes the shape of the DNA double helix and
prevents the nucleic acid from completing normal cell
division.
Alkylating agents have the effect of inducing cell death, or at
least slowing the replication of tumor cells.
Although the process of alkylation occurs independently of
the cell cycle, the killing action does not occur until the
affected cell attempts to divide.
The alkylating agents have a broad spectrum and are used
against many types of malignancies.
Bone marrow suppression
•
•
blood cells are particularly sensitive to alkylating agents
Within days after administration, the numbers of
erythrocytes, leukocytes, and platelets begin to decline,
reaching a nadir at 6 to 10 days.
Epithelial cells lining the GI tract are Damaged
•
results to nausea, vomiting, and diarrhea.
•
the nitrosoureas and mechlorethamine are strong vesicants.
Alopecia
Acute Nonlymphocytic Leukemia
•
approximately 5% of the patients treated with alkylating
agents develop acute nonlymphocytic leukemia 4 years or
more after chemotherapy has been completed.
CYCLOPHOSPHAMIDE (CYTOXAN)
•
•
•
•
•
•
a commonly prescribed nitrogen mustard
used alone, or in combination with other drugs, against a
wide variety of cancers, including Hodgkin’s disease,
lymphoma, multiple myeloma, breast cancer, and ovarian
cancer
acts by attaching to DNA and disrupting replication,
particularly in rapidly dividing cells
one of only a few anticancer drugs that are well absorbed
when given orally
powerful immunosuppressant
used to intentionally cause immunosuppression for the
prophylaxis of organ transplant rejection and to treat severe
rheumatoid arthritis and systemic lupus erythematosus
(SLE)
ADMINISTRATION ALERTS
•
•
•
•
PHARMACOTHERAPY WITH ANTIMETABOLITES
•
•
•
•
Dilute prior to IV administration.
Monitor platelet count prior to IM administration; if low, hold
dose.
To avoid GI upset, take with meals or divide doses.
Pregnancy category C.
When cancer cells attempt to synthesize proteins, RNA, or
DNA using the antimetabolites, metabolic pathways are
disrupted and the cancer cells die or their growth is slowed.
folic acid analogs, purine ana-logs, and pyrimidine
analogs
adverse effect: Bone marrow toxicity, GI toxicity-ulcerations
of the mucosa
Mercaptopurine and thioguanine - cause hepatotoxicity,
including cholestatic jaundice
Folic Acid Analogs
•
•
•
•
•
Folate
Vitamin B9
essential for the growth and maintenance of cells
lack of this vitamin during pregnancy can cause neural tube
defects in the fetus
given at high doses, which can be toxic to normal cells as
well as cancer cells
Methotrexate
•
•
•
Therapeutic Class: Antineoplastic
Pharmacologic Class: Alkylating agent; nitrogen mustard
ACTIONS AND USES
•
•
•
antineoplastic drugs that chemically resemble essential
building blocks of cells
interfere with aspects of the nutrient or nucleic acid
metabolism of rapidly growing tumor cells
oldest folic acid analogs are used as antineoplastic drugs
prescribed for several autoimmune disorders in addition to
cancer
Pemetrexed (Alimta) and pralatrexate (Folotyn) - have very
limited therapeutic applications.
Leucovorin or Folinic Acid
•
•
•
administered following chemotherapy with methotrexate to
“rescue” normal cells
a reduced form of folic acid that is able to enter normal cells
but not cancer cells.
when used with fluorouracil (5-FU) in the treatment of
colorectal cancer, it has been found to enhance cell killing.
Purine and Pyrimidine Analogs
•
•
•
•
bases used in the biosynthesis of DNA and RNA
drugs structurally similar to their naturally occurring
counterparts
can inhibit the synthesis of purine or pyrimidine bases, thus
limiting the precursors needed for DNA and RNA
biosynthesis
can become incorporated into the structures of DNA and
RNA, resulting in a disruption of nucleic acid function
ANTIMETABOLITES
ANTITUMOR ANTIBIOTICS
DOXORUBICIN (ADRIAMYCIN)
•
•
Therapeutic Class: Antineoplastic
Pharmacologic Class: Antitumor antibiotic
METHOTREXATE (RHEUMATREX, TREXALL)
•
•
•
Therapeutic Class: Antineoplastic
Pharmacologic Class: Antimetabolite, folic acid analog
•
•
•
•
available by the oral, parenteral, and intrathecal routes
inhibits replication, particularly in rapidly dividing cells by
blocking the synthesis of folic acid (vitamin B9)
prescribed alone or in combination with other drugs for
choriocarcinoma, osteogenic sarcoma, leukemias, head
and neck cancers, breast carcinoma, and lung carcinoma
antineoplastic agent - combination therapy to maintain
induced remissions in those persons who have had
surgical resection or amputation for a primary tumor
antimetabolite - powerful immunosuppressants that can
be used to treat severe rheumatoid arthritis, ulcerative
colitis, lupus, and psoriasis that are unresponsive to
safer medications.
attaches to DNA, distorting its double helical structure
and preventing normal DNA and RNA synthesis
it is administered only by IV infusion
a broad-spectrum cytotoxic antibiotic, prescribed for solid
tumors of the lung, breast, ovary, and bladder, and for
various leukemias and lymphomas
structurally similar to daunorubicin.
Doxorubicin is one of the most effective single agents
against solid tumors
ACTIONS AND USES
ACTIONS AND USES
•
•
•
ADMINISTRATION ALERTS
•
•
•
•
Avoid skin exposure to drug.
Avoid inhaling drug particles.
Dilute prior to intravenous (IV) administration.
Pregnancy category X.
•
Nausea and vomiting are severe at high doses.
•
drugs obtained from bacteria that have the ability to kill
cancer cells
Although not widely used, they are very effective against
certain tumors
•
•
ADMINISTRATION ALERTS
•
•
•
•
•
Extravasation can cause severe pain and extensive
tissue damage.
Skin contact or extravasation should be treated
immediately with local ice packs to reduce absorption of
the drug.
For infants and children, verify concentration and rate of
IV infusion with the health care provider.
Avoid skin contact with the drug. If exposure occurs,
wash thoroughly with soap and water.
Pregnancy category D.
ADVERSE EFFECTS
•
ADVERSE EFFECTS
The most serious dose-limiting adverse effect of
doxorubicin is cardiotoxicity. Like many anticancer
drugs, doxorubicin may profoundly lower blood cell
counts. Acute nausea and vomiting are common and
often require antiemetic therapy. Complete, though
reversible, hair loss occurs in most patients.
ANTITUMOR ANTIBIOTICS
•
PHARMACOTHERAPY WITH NATURAL
PRODUCTS
•
PHARMACOTHERAPY WITH ANTITUMOR
ANTIBIOTICS
•
•
•
•
•
antitumor antibiotics must be administered intravenously
or through direct instillation via a catheter into a body
cavity
can cause major damage to the skin, subcutaneous
tissue, and nerves should extravasation occur
adverse effect: bone marrow suppression
Doxorubicin, daunorubicin, epirubicin, and idarubicin cardiac toxicity
Cardiotoxicity
may occur within minutes of
administration, or be delayed for months or years after
chemotherapy has been completed.
Plants have been a valuable source for antineoplastic
drugs. These natural products act by preventing the
division of cancer cells. Agents with antineoplastic
activity have been isolated from a number of plants,
including the common periwinkle (Vinca rosea), Pacific
yew (Taxus baccata), mandrake (May apple), and the
shrub Camptotheca acuminata. Although structurally
very different, medications in this class have the common
ability to affect cell division; thus, some of them are
called mitotic inhibitors.
VINCRISTINE (ONCOVIN)
•
•
Therapeutic Class: Antineoplastic
Pharmacologic Class: Vinca alkaloid, mitotic inhibitor,
natural product
ACTIONS AND USES
•
•
•
specific for the M-phase of the cell cycle where it kills
cancer cells by preventing their ability to complete mitosis.
It exerts this action by inhibiting microtubule formation in
the mitotic spindle. Although vincristine must be given
intravenously, its major advantage is that it causes
minimal immunosuppression.
It has a wider spectrum of clinical activity than vinblastine
and is usually prescribed in combination with other
antineoplastics for the treatment of Hodgkin’s and nonHodgkin’s lymphomas, leukemias, Kaposi’s sarcoma,
Wilms’ tumor, bladder carcinoma, and breast carcinoma.
ADMINISTRATION ALERTS
•
•
•
•
Extravasation may result in serious tissue damage.
Stop injection immediately if extravasation occurs and
apply local heat and inject hyaluronidase as ordered.
Observe the site for sloughing.
Avoid eye contact, which can cause severe irritation and
corneal changes.
Pregnancy category D.
TAMOXIFEN
•
•
Therapeutic Class: Antineoplastic
Pharmacologic Class: Estrogen receptor blocker
•
is an oral antiestrogen that is a preferred drug for treating
metastatic breast cancer.
It is effective against breast tumor cells that require
estrogen for their growth (ER-positive cells).
It blocks estrogen receptors on breast cancer cells, but
tamoxifen actually activates estrogen receptors in other
parts of the body, resulting in typical estrogen-like effects
such as reduced low density lipoprotein (LDL) levels and
increased mineral density of bone.
ACTIONS AND USES
•
•
ADMINISTRATION ALERTS
•
•
•
•
ADVERSE EFFECTS
•
ADVERSE EFFECTS
•
The most serious dose-limiting adverse effects of
vincristine relate to nervous system toxicity. Children
are particularly susceptible. Symptoms include numbness
and tingling in the limbs, muscular weakness, loss of
neural reflexes, and pain. Severe constipation is common
and paralytic ileus may occur in young children.
Reversible alopecia occurs in most patients.
•
PHARMACOTHERAPY WITH HORMONES AND
HORMONE ANTAGONISTS
A number of hormones are used in cancer
chemotherapy, including corticosteroids, progestins,
estrogens, and androgens. In addition, several hormone
antagonists have been found to exhibit antitumor activity.
The mechanism of hormone antineoplastic activity is
largely unknown. It is likely, however, that these antitumor
properties are independent of their normal hormone
mechanisms because the doses used in cancer
chemotherapy are magnitudes larger than the amount
normally present in the body.
The hormones and hormone antagonists are believed to act
by blocking substances essential for tumor growth. These
agents may be classified into four general groups:
•
•
•
•
Corticosteroids- the primary corticosteroids used in
chemotherapy are dexamethasone (Decadron) and
prednisone (Deltasone). Because of the natural ability of
corticosteroids to suppress cell division in lymphocytes,
the principal value of these hormones is in the treatment
of lymphomas, Hodgkin's disease, and leukemias.
Gonadal hormones- Gonadal hormones are used to treat
tumor cells that possess specific hormone receptors.
Estrogen antagonists- the estrogen antagonists or
antiestrogens are used to treat ER-positive tumors.
Androgen antagonists- the androgen antagonists
prevent testosterone and other androgens from reaching
their receptors on cancer cells, thus depriving the cells of
an important growth promoter.
Nausea and vomiting are common adverse effects of
tamoxifen. Hot flashes, fluid retention, and vaginal
discharges are relatively common. Tamoxifen causes
initial “tumor flare,” an idiosyncratic increase in tumor size,
but this is an expected therapeutic event. Hypertension
and edema occur in about 10% of patients taking the
drug.
PHARMACOTHERAPY WITH BIOLOGIC
RESPONSE MODIFIERS AND TARGETED
THERAPIES
•
•
Give with food or fluids to decrease GI irritation.
Do not crush or chew drug.
Avoid antacids for 1–2 h following PO dosage of
tamoxifen.
Pregnancy category D.
•
Biologic response modifiers are drugs that are used to
enhance the ability of body defenses to destroy cancer
cells. BRMs include interferons, interleukins, and certain
other cytokines. Some drugs in this class are
immunostimulants.
A targeted therapy is an antineoplastic drug that has
been specially engineered to attack these cancer
antigens. Unlike interferons and interleukins, which are
considered general immunostimulants, targeted therapies
are engineered to attack only one specific type of tumor
cell.
Monoclonal antibodies (MABS) are BRMs that are type
of targeted therapy. Once the MAB binds to its target cell,
the cancer cell dies, or is marked for destruction by other
cells of the immune response.
MISCELLANEOUS ANTINEOPLASTICS
•
Certain anticancer drugs act through mechanisms other
than those previously described. For example,
asparaginase (Elspar) deprives cancer cells of
asparagine, an essential amino acid. It is used to treat
acute lymphocytic leukemia. Mitotane (Lysodren), similar
to the insecticide DDT, poisons cancer cells by forming
links to proteins and is used for advanced andrenocortical
cancer.
MISCELLANEOUS ANTINEOPLASTICS