PHM350 - Exam 3 (Final exam)

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Forms of Treatment for Cancer

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Forms of Treatment for Cancer

"DNA targeting"

Surgery = primary treatment for most major forms Radiation = damages cells so they cant reproduce; often used with chemotherapy Chemotherapy = drugs, chemicals (non-operable cancers, disseminated tumors, blood and lymph)

Classified as:

Cell cycle specific = drugs act during S phase to inhibit DNA synthesis, or during M phase to inhibit cell division phase of mitosis Cell cycle non-specific: drugs are generally cytotoxic at any stage of the cell cycle

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Potential Adverse Effects/Adverse Reactions to Drugs used in Cancer Treatment

many drugs affect DNA synthesis or affect chromosomal separation in mitotic cell division

effects:

Hair loss GI tract: Nausea, vomiting, diarrhea Susceptibility to infection, hemorrhage, anemia (suppress bone marrow function) Liver or Kidney damage

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Alkylating Agents

  • "DNA targeting" drugs

  • Non Cell Cycle Specific

  • Highly reactive agents that transfer alkyl groups to cellular constituents especially DNA

  • some of these drugs also crosslink the paired DNA strands

  • Guanine is the target

  • Cell replication & function compromised

  • Induction of apoptosis

  • Alkylated DNA must be repaired to be functional

  • preferential action on rapidly proliferating cells - Dealkylation does occur but it is a relatively slow process (if not reversible, the drugs would be fatal)

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"Nitrogen Mustards"

Drug group originally derived from First World War chemical warfare agents know as "sulfur mustards"

  • Alkylate DNA

  • Inhibit DNA replication

  • Slow cell replication

  • Reduce protein production

Very toxic agents

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"Nitrogen Mustards" drugs

Cyclophosphamide (CYTOXAN) - Must be metabolically activated in the liver

Mechlorethamine (MUSTARGEN) - Shortest duration of action with respect to potential to alkylate DNA (rapidly eliminated) - Only used by intravenous injection

Chlorambucil (LEUKERAN) - Least toxic agent of this group

Carmustine (BCNU) & Lomustine (CCNU) - Alkylate RNA (as well as DNA) - Lipid-soluble - crosses blood-brain barrier and exerts effect on brain tumors

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"Nitrogen Mustards" drugs

Mitomycin (MUTAMYCIN) Doxorubicin (ADRIAMYCIN) Idarubicin (IDAMYCIN)

  • Antibiotic used primarily as cancer chemotherapeutic agents

  • Alkylates DNA (but is not alkyl donor) and causes DNA strand breakage OR crosslinks DNA and inhibits DNA replication

  • Inhibits DNA synthesis and inhibits protein synthesis and cell replication

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Platins

Alkylating agents

  • Do not technically alkylate DNA; bind to and cross link DNA in the same way the Alkylating agents affect DNA

  • Inhibits DNA synthesis and inhibits protein synthesis and cell replication

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Platins (drugs)

Cisplatin (PLATINOL): major dose-limiting adverse effect is the renal toxicity, which can be reduced by proper hydration

Carboplatin (PARAPLATIN): is effective and safer

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Uses of Alkylating Agents

Hodgkin's disease Lymphoma Leukemia Ovarian/Breast/Testicular cancers Head/Neck/Lung cancers Neuroblastomas/Brain Tumors

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Adverse Affects of Alkylating Agents

Largely the result of inhibition of cell replication in populations of normal cells which are relatively rapidly replicating (GI tract lining, skin, bone marrow)

  • Nausea

  • Hair loss

  • Bone marrow suppression: - tiredness, increased bleeding time, increased susceptibility to infections

  • Renal toxicity - Hemorrhagic cystitis

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Antimetabolites

  • "DNA targeting" drugs

  • Analogs of "growth factors"

  • Cell Cycle Specific

Synthesis of DNA during the S phase of the cell cycle, it is critical to normal cell replication

Can act in one of two ways:

  • Substitute for A, G, C and T bases in DNA

  • Substitute for the bases themselves

As substitute molecules, these drugs must be chemical analogs of the normal bases, they are processed by nucleotide-synthesizing enzymes so that abnormal nucleotide and abnormal DNA is formed

Alternatively, the drugs bind and block the activity of these nucleotide synthesizing enzymes so that the DNA can not be synthesized

Cell replication is slowed and cell viability is reduced

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Adverse Effects of Antimetabolites

Largely the result of inhibition of cell replication in populations of normal cells which are relatively rapidly replicating (GI tract lining, skin, bone marrow)

  • Nausea

  • Hair loss

  • Bone marrow suppression: tiredness, increased bleeding time, increased susceptibility to infections

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Antimetabolites - Purine Analogs

"Purine Antagonists" Adenine and Guanine are purine bases

6-Mercaptopurine (A) (PURINETHOL; 6-MP) Thioguanine (TABLOID)

Inhibit enzymes for synthesis of adenine containing deoxyadenosine (6-mercaptopurine) and of guanine containing deoxyaguanine (thioguanine)

Production of abnormal DNA; failure of DNA synthesis

failure of cell replication

Failure of (normal) protein production.. cell death

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Antimetabolites - Pyrimidine Analogs

"Pyrimidine Antagonists" Cytosine (C) and Thymidine (T) are pyrimidine bases

5-Fluorouracil (5-FU; ADRUCIL): - Substitutes for uracil which is the precursor for Thymidine - Failure of DNA synthesis - Failure of cell replication...cell death - Failure of (normal) protein production...cell death Cytosine Arabinoside [cytarabine] (CYTOSAR-U): - Substitute for cytosine - Incorporated into DNA (instead of cytosine) - Production of abnormal DNA - Failure of cell replication...cell death - Failure of (normal) protein production...cell death

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Antimetabolites - Folic Acid Analogs

"Folate Antagonists"

Methotrexate (MTX; FOLEX; MEXATE): - Inhibitor of dihydrofolate reductase (necessary for production of thymidine) - Inhibits production of thymidine from folate - Reduced production of DNA - Failure of cell replication - Failure of (normal) protein production...cell death - (also used as immunesuppressant in autoimmune- inflammatory disorders as Crohn's Disease, Rheumatoid Arthritis, and Lupus)

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Uses of Antimetabolites

  • Breast/Colorectal (and other solid tumor) cancers

  • Osteosarcoma

  • Leukemias/Non-Hodgkin's Lymphoma

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Adverse Effects of Antimetabolites

Largely the result of inhibition of cell replication in populations of normal cells which are relatively rapidly replication (GI tract lining, skin, bone marrow)

  • Nausea

  • Hair loss

  • Bone marrow suppression: - Tiredness - Increased bleeding time - Increased susceptibility to infections

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Mitotic Inhibitors

"DNA targeting" drugs Mitosis (Chromosomal division) Cell Cycle Specific

Their prime biological action is to prevent mitosis and cell division Also called "Cell Motor Inhibitors" because their prime cellular effect is to cause tubulin (a major "cell motor") dysfunction

  • Vinblastine (VELBAN)

  • Vincristine (VINSCAR)

  • Paclitaxel (TAXOL)

Binds to tubulin and prevents normal cycle of polymerization and depolymerization which tubulin undergoes when operating normally - This cycle is required so that tubulin can fulfill its Normal cellular function: - To move large molecules and organelles within the cell Tubulin dysfunction disrupts chromosome separation in mitosis as cell division is starting

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Mitotic Inhibitors - Uses

  • Hematologic cancers (Leukemias)

  • Breast cancer and other solid tumors

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Adverse Effects of AntiMitotic Agents

Largely the result of inhibition of cell replication in populations of normal cells which are relatively rapidly replication (GI tract lining, skin, bone marrow)

  • Nausea

  • Hair loss

  • Bone marrow suppression: - Tiredness - Increased bleeding time - Increased susceptibility to infections

  • Neuropathy (particularly sensory: loss of sensation in hands and feet)

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DNA Topoisomerase Inhibitors

"DNA targeting" drugs Cell Cycle Specific

Inhibit action of DNA topoisomerase which has critical function in maintenance (i.e., function) and replication of DNA Inhibitors of the enzyme cause DNA strand breakage

  • Etoposide (VEPISID)

  • Teniposide (VUMON)

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DNA Topoisomerase Inhibitors - Uses & Adverse Effects

Uses:

  • Ovarian

  • Colorectal

  • Testicular

  • Lung cancer

Adverse Effects:

  • Largely the result of inhibition of cell replication in populations of normal cells which are relatively rapidly replicating (GI tract lining, skin, bone marrow)

  • Nausea

  • Hair loss -Bone marrow suppression:

    • Tiredness

    • Increased bleeding time

    • Increased susceptibility to infections

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Hormone Receptor Agonists & Antagonists

Some tumor cells express receptors for steroid hormones including estrogens (estradiol), androgens (testosterone) and glucocorticoids (cortisol)

These steroid receptors may be expressed by the normal cells from which the tumor cells are derived but are expressed in greater number by the tumor cells.

One of the functions of the receptors in the normal cells (from which the tumor cells are derived) and in the tumor cells derived from these normal cells may be control of replication rate.

Alternatively, tumor cells may express a type of steroid hormone receptor which is not usually expressed by the normal cells from which the tumor cells are derived. One of the functions of these receptors may be to control replication rate of the tumor cells.

In either situation, activation of these steroid receptors can either increase or decrease dependent on the cell type and the linkage of those receptors to cell replication.

Steroid hormone receptor agonists or antagonists (dependent on the situation) may be effective in slowing rate of proliferation of cells in a tumor. However these drugs do not generally cause tumor regression (as other cancer chemotherapeutic drugs can).

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Steroid Hormone Receptor Agonists - Estrogens

Estradiol

  • Agonist at estrogen receptors

  • Competes with endogenous testosterone to bind androgen receptors

  • Reduces anterior pituitary secretion of FSH and thus secretion of testicular testosterone

Uses:

  • Testicular Cancer

  • Prostate Cancer

Adverse Effects:

  • Feminization

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Steroid Hormone Receptor Agonists - Androgens

  • Testosterone Propionate

  • Fluoxymesterone (HALOTESTIN) - Agonists at testosteron (androgen) receptors

Uses:

  • Carcinoma of breast when these cells express testosterone receptors

Adverse Effects:

  • Virilization

  • Edema

  • Hypercalcemia

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Steroid Hormone Receptor Agonists - Corticosteroids

Prednisone (DELTASONE):

  • Lympholytic effects; suppressed lymphocyte mitosis

Uses:

  • Acute leukemia in children

  • Malignant lymphoma in adults

Adverse effects:

  • GI ulcers

  • Osteoporosis

  • Mental confusion

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Steroid Hormone Receptor Agonists - Progestins

Medroxyprogesterone Hydroxyprogesterone Megestrol (MEGACE): - Agonists at progestin receptors

Uses:

  • Metastatic estrogen dependent breast cancer

  • Renal carcinoma

  • Endometrial carcinoma

Adverse Effects:

  • As P used as contraceptives in women

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Steroid Hormone Receptor Antagonists - Anti-Estrogens

Tamoxifen (NOLVADEX): - Estrogen receptor antagonist - Prevent normal and pathological cell growth effects of estrogen in breast - Effective in 60% breast cancer cases

Uses:

  • Ongoing breast cancer

  • Prophylactic against breast cancer recurrence

Adverse Effects:

  • Not a steroid - less toxic

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Steroid Hormone Receptor Antagonists - Anti-Androgens

Flutamide (EULEXIN): - Androgen receptor antagonist - Testicular and prostate cancer growth promoted by testosterone

Uses:

  • Metastatic prostate cancer

  • Testicular cancer

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Steroid Hormone Receptor Antagonists - Aromatase Inhibitors

In women aromatase converts testosterone (from adrenal medulla) to estradiol - Prime source of estradiol in postmenopausal women

Anastrozome (ARIMIDEX) Letrozole (FEMARA)

Uses:

  • Estrogen dependent breast cancer in postmenopausal women

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Tyrosine Kinase Inhibitors

Non "DNA targeting" drugs Not cell cycle specific

New group of drugs for cancer treatment - Target tyrosine kinase Important enzyme in normal and tumor cells in multiple signal transduction pathways Still in early use:

  • Uses and adverse effects still under study

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Tyrosine Kinase Inhibitors - Drugs/Uses/Adverse Effects

Family of enzymes: differential expression in different cell types

Mutations and normal forms of enzyme may be important in cancer

Erlotinib (TARCEVA) Gefitinib (IRESSA) - Inhibits EGF effects including cell replication and population growth Imatinib (GLEEVEC) Nilotinib (TASIGNA) - Inhibitor of cytoplasmic EGF receptor mutant - Does not target normal form of this enzyme

Adverse Effects Include:

  • Uticaria (skin rash)

  • Fatigue

  • Diarrhea

  • Nausea

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Monoclonal Antibodies

Non "DNA targeting" drugs Non cell cycle specific

New group of drugs for cancer treatment

Highly specific mechanism to target tumors and cancer cells through several different mechanisms including:

  • Stimulant of immune system

  • "Carrier" of radioisotopes of metals which emit cell killing, but short spreading, β particles

  • "Carrier" of cell killing toxins

  • Inhibitors of angiogenesis

  • Inhibitors of EGF - receptor cell proliferation

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Monoclonal Antibodies - Drugs

Bevacizumab (AVASTIN)

  • Antibody binds VEGF (vascular endothelial growth factor)

  • VEGF binds and activates vascular VEGF receptor

  • Activation of VEGF receptor induces blood vessel formation

  • Activation of VEGF receptor also important in maintaining normal structure/function of blood vessels and in repair of blood vessels after injury

  • Antibody prevents VEGF induced angiogenesis (new blood vessel formation)

  • Reduces blood vessel-dependent oxygen delivery to cells in tumor

  • Causes tumor cells to be hypoxic, reduces proliferation of tumor cells

Uses:

Colon cancer Lung cancers Renal cell cancer Glioblastoma

Adverse Effects:

Hypertension Blood vessel degradation (“injury”; spontaneous bruising) Gastrointestinal bleeding and perforation

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Monoclonal Antibodies - Drugs

Brentuximab vedotin (ADCETRIS)

Antibody - toxic drug complex: brentuximab attached to cytotoxic monoethyl auristatin E (MMAE)

  • Antibody targets CD30 protein highly expressed on surface of malignant lymphocyte cells in Hodgkin’s lymphoma (HL) and some other cancer cells - but also present on other, non- cancerous cell types (e.g. cells of blood cell forming tissue)

  • After binding lymphocyte CD30, the antibody-cytotoxin is internalized and cleaved by intracellular protease to release toxic MMAE.

  • MMAE causes microtubule disruption and endoplasmic reticulum stress with subsequent arrest of cell cycle and apoptosis (“programmed cell death” or “cell suicide”), and makes cells recognizable as foreign by immune system

  • MMAE is toxic to “all” cell types if it enters the cell but this approach allows delivery of MMAE only to those cells expressing the CD30 protein and especially those cancerous cells expressing CD30 at high level

Uses:

  • Hodgkin’s lymphoma and anaplastic large cell lymphoma (Lymphoma is a cancer associated with lymphocytes, a type of white blood cell).

Adverse Effects:

  • Peripheral neuropathy (a sign of microtubule dysfunction)

  • Neutropenia, anemia, and thrombocytopenia

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Monoclonal Antibodies - Drugs

Cetuximab (ERBUTIX) Panitumumab (VECTIBIX)

Antibody binds to but does not activate EGF receptor - effectively EGF receptor anatgonist Prevents binding and effects of EGF Reduces cell proliferation Effective in cancers over-expressing EGF receptors

Uses:

Cancer of head and neck (cetuximab) Metastatic colorectal cancer (cetuximab and panitumumab)

Adverse Effects:

Cetuximab: Cardiac arrest and other signs of severe allergic reaction (antihistamine may be administered prior or antibody infusion); Acne rash

Panitumumab: Skin rash, Fatigue, Fever, Diarrhea

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Monoclonal Antibodies - Drugs

Ibritumomab tiuxetan (ZEVALIN)

  • Antibody - chemical complex: tiuxetan will chelate radioisotopic Yttrium (Y90) or Indium (In111) Mechanism of Action

  • Antibody targets CD20 protein highly expressed on surface of Hodgkin’s lymphoma (HL) malignant B lymphocyte cells and some other cancer cells - but also present on other, non- cancerous cell types (e.g. cells of blood cell forming tissue)

  • Antibody-chemical-radioisotope complex is internalized. Radiation from radiosotope - principally β particles - emitted; short distance emission in tissue Emitted β particles damage DNA in surrounding tissues and cause cell death - prevent cell replication and proliferation; death of malignant cells

  • Efficient mechanism to deliver radioisotope directly to tumor or cancerous tissue

  • Some effects also due to direct (radiation independent) effects of ibritumomab binding to malignant B lymphocyte cells

Uses:

Hodgkin’s lymphoma and anaplastic large cell lymphoma (Lymphoma is a cancer associated with lymphocytes, a type of white blood cell)

Adverse Effects:

Peripheral neuropathy (a sign of microtubule dysfunction) Neutropenia, anemia, and thrombocytopenia

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Monoclonal Antibodies - Drugs

Ocrelizumab (OCREVUS) Ritumimab (RITUXAN)

  • Antibody binds to CD20 protein

  • CD20 is cell surface protein expressed overexpressed by malignant B lymphocytes

  • Antibody binding CD20 causes B lymphocyte cell death

  • Antibody binding to lymphocyte makes lymphocytes more vulnerable to effects of so called immune natural killer (NK) cells to induce lymphocyte cytoxicity and apoptosis

  • Antibody reduces B lymphocyte number and function including immune response of these cells; antibody effectively immune suppressant

Use: Ocrelizumab

Some autoimmune diseases including; rheumatoid arthritis and Lupus, Multiple Sclerosis, Non-Hodgkins lymphoma (characterized by excessive B lymphocyte presence and activity) Various cancers

Use: Rituximab

Some autoimmune diseases including; rheumatoid arthritis, Lupus, and multiple sclerosis, Some cancers

Adverse Effects:

Rituxumab: Cardiac arrest; Pulmonary issues Ocrelizumab: Skin rash; Headache; Cardiac palpitations

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Monoclonal Antibodies - Drugs

Pembrolizumab (KEYTRUDA)

  • So called “Checkpoint inhibitor” - stimulates anti-cancer immune system role

  • Antibody binds to PD-1 “cell death” receptor on lymphocytes

  • Endogenous ligand for this receptor is PD-L1, a membrane embedded (outward facing) protein expressed by some cell types

  • PD-L1 binding to PD-1 turns off lymphocyte and prevents lymphocyte destruction of PD-L1 expressing cell

  • PD-L1 over expressed in some cancers - effectively protects cancer cell from lymphocyte action - PD-L1 expressing cell is essentially invisible to lymphocyte

  • Antibody binds to PD-1 so that PD-L1 on cancer cell binding to lymphocyte PD-1 is inhibited - cancer cell may now be recognized by lymphocyte as being foreign and destroyed by immune system

  • Antibody effectively makes cancer cells initially “invisible” to immune system to become “visible” to immune system

Uses:

  • Multiple cancers

Adverse Effects:

  • Colitis

  • Hepatitis

  • Lung inflammation

  • Endocrine disruption

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Monoclonal Antibodies - Drugs

Trastuzumab (HERCEPTIN)

  • Binds HER2, Human Epithelial Growth Factor Receptor-2 - HER2 receptor activated by endogenous human EGF

  • Activation of HER2 receptor induces cell replication

  • HER2 is 100x overexpressed in some breast cancers

  • EGF more effective with HER2 overexpression

  • Cell replication (proliferation) uncontrolled

  • Antibody reduces cell proliferation in breast tumor

  • Also some effects to reduce angiogenesis (blood vessel formation) in breast tumor (lack of vascularization of tumor leads to hypoxia in tumor and thus slower tumor growth)

  • Also some effects to make breast cancer cells “visible” and vulnerable to immune system activity

  • Antibody only useful in breast cancers overexpressing this receptor

  • HER2 overexpression determined prior to starting antibody use

Uses:

Metastatic breast cancer

Side effects: Heart failure

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Monoclonal Antibodies - Drugs

Trastuzumab emtansine (KADCYLA)

  • Antibody trastuzumab covalently linked to emantasnine (aka DM1)

  • Antibody binds HER2, Human Epithelial Growth Factor Receptor-2

  • HER2 is 100x overexpressed in some breast cancers

  • Antibody-drug complex internalized by HER2 expressing cells

  • Complex metabolized in these cells to release tubulin disrupting cytotoxic agent DM1

  • Tubulin disruption disrupts mitosis (chromosome pair separation) process

  • Prevents cell replication & proliferation, causes cell death

  • Active even in cancer which has become resistant to effects of trastuzumab in native state

  • Antibody-drug complex most useful in breast cancers overexpressing this

  • HER-2 receptor HER2 overexpression determined prior to starting antibody use

Uses:

Metastatic breast cancer

Side effects: Cardiac damage & heart failure

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Classification of Antibacterial Drugs: Narrow Spectrum Antibacterial

Gram +ve

Penicillin G Cephalosporins (1st & 2nd Generations) Vancomycin Clindamycin Linezolid

Gram -ve

Aminoglycosides

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Classification of Antibacterial Drugs: Broad Spectrum Antibacterial

Methicillin Erythromycin Cephalosporins (3rd, 4th, & 5th generations) Tetracylines Trimethoprim Sulfonamides Quinolones

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Mechanism of Action of Antibacterial Drugs

  • Competitively block bacterial intermediary metabolism (sulfonamides, trimethoprim)

  • Cell wall disruption, inhibition of cell wall synthesis (penicillins, cephalosporins, vancomycin)

  • Bacteriostatic Inhibition of protein synthesis (erythromycin, clindamycin)

  • Bactericidal Inhibition of protein synthesis (tetracyclines, aminoglycosides)

  • Inhibition of DNA/RNA synthesis (quinolones)

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Anti-Folate Antibacterials

Targeting Bacterial Intermediary Metabolism

  • Sulfonamides

  • Trimethoprim

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Sulfonamides: Mechanism of Action

Sulfonamide antibacterial drugs are structural analogs of para-aminobenzoic acid (PABA).

Sulfonamides are therefore competitive substrates for dihydropteroate synthase the enzyme for which PABA is normal substrate.

Bacterial PABA metabolism, folic acid synthesis and thus thymidine synthesis, and DNA synthesis are reduced by these drugs considered bacteriostatic except at high concentrations

Prodrug

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Sulfonamides: Antibacterial Spectrum

Broad Spectrum

Gram +ve and Grame -ve bacteria

Bacteriostatic except in high doses

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Sulfonamides: Uses

Restricted due to bacterial resistance & availability of less toxic drugs

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Sulfonamides: Adverse effects

Toxicity: Crystalluria

  • crystals of the drug form in the kidney tubules and urinary tract producing renal and urinary tract injury

  • Nausea and vomiting

  • hemolytic anemia, aplastic anemia, agranulocytosis

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Sulfonamides: Subgroups

  • Rapidly absorbed across GI tract, rapidly excreted

  • Short acting

  • Systemic infections, respiratory tract, CNS, Urinary tract

Sulfisoxazole (GANSTRIN)

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Sulfonamides: Subgroups

  • Slowly absorbed across GI tract

  • Long acting

  • GI tract infections

Sulfamethoxazole (GANTANOL)

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Sulfonamides: Subgroups

  • Topically applied, not systemically applied

Sulfacetamide (ISOPTO-DETAMIDE)

  • Ophthalmic infections

Mafenide (SULFAMYLON)

  • Prevention of infection on burned skin

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Trimethoprim (PROLOPRIM)

Mechanism of Action:

  • suppression of (dihydro)folate reductase

  • Used in combination with sulfonamides

Spectrum of Action:

  • Broad spectrum

  • Tendency for Gram-positive bacteria to be more sensitive than gram-negative bacteria

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Targeting the Bacterial Cell Wall

  • A group of antibacterial drugs affects the integrity of the bacterial cell wall after binding to penicillin binding proteins (PBPs) within the cell wall. These proteins are important enzymes necessary for maintenance and synthesis of the bacterial cell wall.

  • These antibacterial drugs either cause disruption of the cell wall, and subsequent rupture of the plasma membrane and cell death - are bactericidal - or prevent cell wall synthesis are bacteriostatic except for dividing bacteria where the drugs are bactericidal.

  • Most drugs in this group have a chemical structure which has a beta-lactam ring as a core component

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Cell wall Disrupters: Penicillins [Mechanism of Action]

  • Destruction of bacterial cell wall by binding to PBPs with subsequent failure of cross-linking of peptidoglycan strands and consequent dysfunction of cell wall and rupture of plasma membrane.

  • Mammalian cells do not have cell wall or PBPs and are therefore “unaffected” these drugs.

  • Bactericidal

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Cell wall Disrupters: Penicillins (PENTIDS) [Spectrum of Action]

Relatively narrow spectrum:

  • Activity against Gram+ve bacteria such as Streptococci and some Staphylococci. Recall that the penicillinase content of the cell wall of Gram+ve bacteria is low and thus these bacteria are susceptible to these drugs.

  • Gram-ve bacteria which have higher penicillinase content in the cell wall (and the outer wall “shell” to prevent drug diffusion) are relatively resistant to penicillin and penicillin-like drugs. However, penicillin is effective against some Gram-ve organisms such as Neisseria gonorrheae (causes gonorrhea) and the spirochete Treponema pallidum (causes syphilis).

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Cell wall Disrupters: Penicillins [Problems/Adverse Effects]

Toxicity/Hypersensitivity:

  • Intrinsic toxicity very low

  • Significant incidence of hypersensitivity reactions

  • Anaphylactic shock

  • Broncho-constriction & severe hypotension

  • Dermatitis

  • GI upset potential for colitis

Resistance:

  • Resistant organisms have ability to destroy drug with penicillinase in their cell wall - obviously Gram -ve bacteria are resistant to penicillin and penicillin-derived drugs

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Cell wall Disrupters: Penicillin Derivatives:

Methicillin (STAPHCILLIN) Oxacillin (PROSTAPHLIN) Ampicillin (POLYCILLIN) Amoxicillin (AMOXIL) Ticaricillin (TICAR

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Cell wall Disrupters: Penicillin Derivatives:

A number of antibacterials based on penicillin have been synthesized.

The objective in synthesis of these compounds is to produce drugs which are less rapidly metabolized by penicillinase and are more stable in the gastrointestinal tract.

Slower metabolism by penicillinase will effectively make the spectrum of action of the penicillin-derivative greater than that of penicillin.

Increased stability within the gastrointestinal tract makes it more likely that the penicillin-derivative (compared to penicillin) will achieve therapeutic benefit with oral administration of a low dose of the drug

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Cell wall Disrupters: Penicillin Inhibitors/Additives:

Penicillin Inhibitors:

  • Clavulanate (AUGMENTIN)

  • Sulbactam (UNISYN)

Penicillin Additives:

  • Amoxicillin + clavulanate (AUGMENTIN)

  • Ampicillin + sulbactam (UNISYN)

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Cell wall Disrupters: Penicillin Inhibitors/Additives:

Clavulanate and Sulbactam are not active antibacterial compounds

Use of penicillinase inhibitors, such as clavulanate or sulbactam which can be coadministered (in the same tablet/caplet/solution) with penicillin or the penicillin- derived antibacterial drug.

Such co-administration effectively increases the spectrum of action and the duration of action of penicillin or the penicillin-derivative.

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Cell wall Disrupters: Cephalosporins

Contain beta-lactam ring (as penicillin)

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Cell wall Disrupters: Cephalosporins [Mechanism of Action]

Same as penicillin

Bind PBPs with subsequent failure of cross-linking of peptidoglycan strands and consequent dysfunction of cell wall and rupture of plasma membrane

Bactericidal

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Cell wall Disrupters: Cephalosporins [Spectrum of Action]

Older: Narrow:

  • Gram +ve bacteria sensitive

Newer:

  • Gram +ve and -ve bacteria sensitive

  • Have been over-used as broad-spectrum antibiotic

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Cell wall Disrupters: Cephalosporins [Problems/Adverse Effects]

  • Poorly absorbed across GI tract

  • Often injected rather than oral

  • Development of resistance

  • Allergic adverse effects include rashes and anaphylactic shock

  • Adverse effects include bone marrow suppression

  • Diarrhea - potential for colitis

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Cell wall Disrupters: Five Generations of Cephalosporins

  • Each generation has seen new drugs developed to increase resistance to metabolism by bacterial penicillinase and thus increase activity against Gram -ve bacteria, and to increase entry to central nervous system

  • Increase resistance to beta-lactamase

  • Increase GI absorption

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Cell wall Disrupters: Five Generations of Cephalosporins [ 1st & 2nd]

1st:

  • Gram+ve activity and minimal Gram -ve activity

  • sensitive to penicillinase

    Cefazolin (ANCEF) Cephalexin (KEFLEX)

2nd:

  • Increased resistance to penicillinase

  • Increased Gram-ve effectiveness

  • Increased entry to CNS

    Cefoxitin (MEFOXIN)

Uses:

  • 1st and 2nd generation drugs not used for active infections (cheaper, more effective drugs available) except in some cases of penicillin allergy

  • used as anti-bacterial prophylactic prior to surgery

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Cell wall Disrupters: Five Generations of Cephalosporins [3rd & 4th]

3rd:

  • Increased gram+ve and gram-ve effectiveness

  • Increased spectrum of action

  • Increased resistance to penicillinase

  • Increased entry to CNS

    Cefotaxime (CLAFORAN)

4th:

  • Increased gram+ve and gram-ve effectiveness

  • Increased spectrum of action

  • Increased resistance to penicillinase

  • Increased entry into CNS

    Cefepime (MAXIPIME)

Uses:

  • 3rd and 4th generation drugs used for meningitis resulting from gram -ve bacilli, gonorrhea (N. gonorrhoeae), influenza (Hemophilus influenzae), Salmonella and some nosocomial infections

  • Used in "most difficult to treat" infections

  • (CNS, Bone, Joint, Nosocomial)

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Cell wall Disrupters: Five Generations of Cephalosporins [5th]

5th:

  • Increased gram+ve and gram-ve effectiveness

  • Increased spectrum of action

  • Increased resistance to penicillinase

  • Effective against methicillin-resistant Gram +ve bacteria

    Ceftaroline (TEFLARO) Ceftobiprole (ZEFTERA)

Uses:

  • To treat Methicillin-resistant Gram +ve bacteria; Methicillin resistant Staphylococcus aureus (MRSA)

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Cell wall Disrupters: Vancomycin (VANCOCIN)

Relatively new, synthetic drug Glycopeptide without beta-lactam core component

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Cell wall Disrupters: Vancomycin (VANCOCIN) [Mechanism of Action]

Inhibits cell wall synthesis by inhibiting peptidoglycan synthesis

causes osmotic disruption

Bactericidal only for dividing bacteria; otherwise bacteriostatic

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Cell wall Disrupters: Vancomycin (VANCOCIN) [Spectrum of Action]

Particularly useful against gram+ve bacteria Surprisingly weak activity against gram-ve bacteria (considering lack of sensitivity to penicillinase)

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Cell wall Disrupters: Vancomycin (VANCOCIN) [Uses/Adverse Effects]

Uses:

  • Poorly absorbed from GI tract

  • Does not cross blood brain barrier

  • For systemic use, must be infused intravenously

  • Used in severe infections where Gram +ve bacteria is resistant to methicillin or in patients allergic to penicillin and cephalosporins; particularly useful against Staphylococcal infections

Adverse Effects:

  • Skin rashes

  • Anaphylactic shock

  • Ototoxicity (deafness, problems with balance)

  • Nephrotoxicity (renal dysfunction)

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Protein Synthesis: Ribosome Inhibitors

Translation of mRNA is a critical step in production of proteins and is dependent on the action of ribosomes.

Humans and other mammals have ribosomes with a so called 40S subunit and a so called 60S subunit - both subunits being present in the ribosome and both subunits necessary for protein synthesis.

Bacteria have ribosomes with a so called 30S subunit and a so called 50S subunit - both subunits being present in the ribosome and both subunits necessary for protein synthesis.

Some antibacterial drugs bind to and inhibit the activity of bacterial ribosomes and inhibit bacterial protein synthesis - without similar effects on human cells

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Protein Synthesis: 50S Ribosome Inhibitors

Erythromycin (E-MYCIN) Azithromycin (ZITHROMAX)

  • Erythromycin first isolated from Streptococcus arythreus

  • Azithromycin modern synthetic drug

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Protein Synthesis: 50S Ribosome Inhibitors [Mechanism of Action]

  • Bind and inhibit 50S ribosome to inhibit protein synthesis

-Bacteriostatic against Gram+ve and some Gram-ve bacteria

  • Bacteriostatic/Bactericidal

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Protein Synthesis: 50S Ribosome Inhibitors [Spectrum of Action]

Considered a broad-spectrum antibiotic: any selectivity is mostly on relative ability of drug to enter bacterial cytoplasm (slower in Gram-ve bacteria with outer wall structure)

  • Gram +ve bacteria more sensitive

  • Some gram -ve bacteria sensitive

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Protein Synthesis: 50S Ribosome Inhibitors [Problems/Adverse Effects/Uses]

Problems:

  • Oral administration only after protection (encapsulation) against gastric acid and enzymes.

  • Also available for IV injection and for topical application

  • It is excreted primarily by the liver into bile

Adverse Effects:

  • GI disturbances

  • Erythromycin: Liver injury - cholestatic hepatitis. (Serious, perhaps fatal, liver inflammation resulting from drug-induced inhibition of bile secretion (into the intestine) and back up of bile into the liver (where bile is produced).

Uses:

  • Similar to penicillin especially when bacterium is penicillin resistant or patient is sensitive to penicillin

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Protein Synthesis: 50S Ribosome Inhibitors (Clindamycin {CLEOCIN}) [Mechanism/Spectrum of Action]

Mechanism of Action:

  • Bind and inhibit 50S ribosome to inhibit protein synthesis -Bacteriostatic against Gram+ve and some Gram-ve bacteria.

  • Cross-resistance with erythromycin

Spectrum of Action:

  • Gram +ve bacteria more sensitive

  • Some gram -ve bacteria sensitive

  • Considered broad spectrum

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Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines

Tetracycline (PANMYCIN) Demechlorcycline (DECLOMYCIN) Doxycycline (VIBRAMYCIN) Minocycline (MINOCIN)

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Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines [Mechanism of Action]

  • Inhibits 30S ribosome subunit function

  • Blocks bacterial protein synthesis

  • Bacteriostatic

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Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines [Spectrum of Action]

Considered a broad-spectrum antibiotic: any selectivity is mostly on relative ability of drug to enter bacterial cytoplasm (slower in Gram-ve bacteria with outer wall structure).

Gram +ve and Gram -ve bacteria

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Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines [Problems]

Usually given orally - 75% crosses GI tract

Food or antacids in stomach containing calcium, magnesium or aluminum reduce absorption because drug binds to calcium.

Alteration of normal gastrointestinal bacteria by unabsorbed tetracycline can lead to suprainfections of the tract

Wide distribution (except CSF) and cell penetration

Tendency to chelate with calcium of developing teeth and bones.

Short duration of action:

  • Tetracycline (PANMYCIN)

Medium duration of action:

  • Demechlorcycline (DECLOMYCIN)

Long duration of action:

  • Doxycycline (VIBRAMYCIN) & Minocycline (MINOCIN)

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Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines [Uses/Adverse Effects]

Uses:

  • Extensive use in the past.

  • Now less used because of better/cheaper drugs and because of bacterial resistance.

Adverse Effects:

  • GI upset due to direct irritation (nausea, vomiting, diarrhea) -liver damage with large doses and prolonged use

  • induction of suprainfections

  • teeth discoloration (binding of drug to tooth calcium during tooth growth)

  • renal damage

  • ototoxicity (balance problems)

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Protein Synthesis: 30S Ribosome Inhibitors: Aminoglycosides

Streptomycin (STREPTOMYCIN) Neomycin (MYCIFRADIN) Kanamycin (KANTREX) Gentamicin (GARAMYCIN) Tobramycin (NEBCIN

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Protein Synthesis: 30S Ribosome Inhibitors: Aminoglycosides [Mechanism/Spectrum of Action]

Mechanism of Action:

  • Inhibit 30S ribosome subunit function

  • Blocks bacterial protein synthesis

  • Bactericidal

Spectrum of Action:

  • Considered a broad-spectrum antibiotic: actually Gram-ve bacteria may be more sensitive than Gram +ve bacteria.

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Protein Synthesis: 30S Ribosome Inhibitors: Aminoglycosides [Problems/Uses]

Problems:

  • Not well absorbed from the gastrointestinal tract.

  • Can be administered intravenously

  • Some topical use for infections of eyes, skin & nose

  • Do not penetrate CSF fluid except in meningitis

Uses:

  • Multiple especially against Gram -ve bacteria: E. coli and other enteric bacteria

  • Pseudomonas

  • Also has been used against the tubercle bacillus Usually reserved for use in serious infections because of their potential for toxicity and development of resistance

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Protein Synthesis: 30S Ribosome Inhibitors: Aminoglycosides [Adverse Effects]

  • Damage to the eighth cranial nerve causes some hearing loss and vestibular disturbances -placental crossing leads to irreversible hearing loss in fetus.

  • Dose of drug used and duration of treatment is a factor.

Renal toxicity: drugs accumulate in and are toxic to cells of renal tubules.Dysfunction of skeletal neuromuscular junction which causes muscle weakness

Resistance: Resistance can develop rapidly - mutation so that bacteriametabolize drug

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Protein Synthesis: 30S Ribosome Inhibitors: Linezolid (ZYVOX)

Developed in response to increased resistance of (Gram+ve) bacteria to many antibiotics Including:

  • Vancomycin resistant enterococci

  • Methicillin resistant Staphylococcus aureus

  • Penicillin/cephalosporin resistant Streptococcus pneumoniae

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Protein Synthesis: 30S Ribosome Inhibitors: Linezolid (ZYVOX) [Mechanism/Spectrum of Action & Adverse Effects]

Mechanism of Action:

  • Inhibits 30S ribosome subunit function

  • Blocks bacterial protein synthesis

  • Bactericidal

Spectrum of Action:

  • Considered broad spectrum

  • Reserved for use against Gram +ve bacteria with resistance to penicillin and cephalosporins

Adverse Effects:

  • Relatively undocumented (new drug)

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DNA Maintenance Inhibition: Quinolones

Nalidixic acid (NEVIGRAMON) Cinoxacin (CINOBAC) Norfloxacin (NOROXIN) Ciprofloxacin (CIPRO)

A relatively newer group of anti bacterials, the quinolones, inhibit bacterial DNA topoisomerase and thus inhibit DNA maintenance and replication.

Quinolone antibiotics - the “floxacin”s

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DNA Maintenance Inhibition: Quinolones [Mechanism/Spectrum of Action]

Mechanism of Action:

  • Inhibit bacterial DNA synthesis by targeting bacterial DNA topoisomerase

  • Bacteriostatic/Bactericidal

Spectrum of Action:

  • Broad spectrum (Gram +ve and Gram -ve) activity only restricted by ability to enter cytoplasm of Gram -ve bacteria.

  • Used when cheaper drugs are ineffective due to resistance

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DNA Maintenance Inhibition: Quinolones [Absorption/Distribution & Uses]

Absorption & Distribution:

  • Fair to good oral absorption

  • No substantial first-pass effect

  • Wide distribution throughout the body but CSF concentrations are only

  • about 10% of peak serum concentrations.

Uses:

  • Urinary tract infections

  • Bacterial diarrhea

  • Infections of bone, joints & soft tissue

  • Anthrax

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DNA Maintenance Inhibition: Quinolones [Adverse Effects]

  • In neonate and fetus, quinolone exposure can lead to improper cartilage/bone development (Not used in children or pregnant women)

  • Breakdown of tendons

  • Nephrotoxicity (crystalluria)

  • CNS effects (dizziness, light headedness, headache, confusion),

  • gastrointestinal tract (nausea, vomiting, diarrhea, abdominal pain)

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Non Selective Reuptake Inhibitors: Tricyclic Antidepressants (TCA’s)

Drugs of choice for endogenous unipolar depression First used in the 1950's All have structure based on three hydrocarbon rings

Imipramine (TOFRANIL) Desimipramine (NORPRAMIN) Amytriptyline (ELAVIL) Nortriptyline (AVENTYL) Clomipramine (ANAFRANIL) Doxepin (SILENOR)

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TCAs [Mechanism of Action]

  • Decreased NE and 5HT re-uptake into axon terminals in CNS

  • May bind to NE/5HT binding site to reduce NE/5HT binding or reduce NE/5HT binding by negative allosteric mechanism

  • Increased NE and 5HT concentration and effect in synaptic gap in CNS

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TCAs [Approved/Off label Uses]

Approved uses:

  • Unipolar depression (ongoing or prophylactic)

  • Bipolar disorder (depressive phases)

  • Enuresis (nighttime bedwetting)

  • Eating disorders

  • Chronic pain

  • Phobias & Panic attacks

  • Obsessive compulsive disorders

"Off Label" uses:

  • ADD

  • Migraine

  • PTSD

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TCAs [Adverse Effects]

PNS:

  • Dry Mouth

  • Constipation

SNS:

  • Vasodilation (paradoxical effect)

  • Orthostatic Hypotension

  • Tachycardia: Direct & reflex effects

CNS-based:

  • Weight Gain

  • Sexual dysfunction

  • Sedation

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Non-tricyclic Non Selective Reuptake Inhibitors

Duloxetine (CYMBALTA) Venlafaxine (EFFEXOR)

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Non-tricyclic Non Selective Reuptake Inhibitors

Most recent group of drugs for depression

  • Non tricyclic in chemical structure although similar (therapeutic and adverse) effects

  • Inhibit NE and 5HT reuptake (as TCAs)

  • Adverse effects largely uncharacterized...likely not too dissimilar to TCAs

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