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
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
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)
"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
"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
"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
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
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
Uses of Alkylating Agents
Hodgkin's disease Lymphoma Leukemia Ovarian/Breast/Testicular cancers Head/Neck/Lung cancers Neuroblastomas/Brain Tumors
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
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
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
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
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
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)
Uses of Antimetabolites
Breast/Colorectal (and other solid tumor) cancers
Osteosarcoma
Leukemias/Non-Hodgkin's Lymphoma
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
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
Mitotic Inhibitors - Uses
Hematologic cancers (Leukemias)
Breast cancer and other solid tumors
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)
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)
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
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).
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Classification of Antibacterial Drugs: Narrow Spectrum Antibacterial
Gram +ve
Penicillin G Cephalosporins (1st & 2nd Generations) Vancomycin Clindamycin Linezolid
Gram -ve
Aminoglycosides
Classification of Antibacterial Drugs: Broad Spectrum Antibacterial
Methicillin Erythromycin Cephalosporins (3rd, 4th, & 5th generations) Tetracylines Trimethoprim Sulfonamides Quinolones
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)
Anti-Folate Antibacterials
Targeting Bacterial Intermediary Metabolism
Sulfonamides
Trimethoprim
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
Sulfonamides: Antibacterial Spectrum
Broad Spectrum
Gram +ve and Grame -ve bacteria
Bacteriostatic except in high doses
Sulfonamides: Uses
Restricted due to bacterial resistance & availability of less toxic drugs
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
Sulfonamides: Subgroups
Rapidly absorbed across GI tract, rapidly excreted
Short acting
Systemic infections, respiratory tract, CNS, Urinary tract
Sulfisoxazole (GANSTRIN)
Sulfonamides: Subgroups
Slowly absorbed across GI tract
Long acting
GI tract infections
Sulfamethoxazole (GANTANOL)
Sulfonamides: Subgroups
Topically applied, not systemically applied
Sulfacetamide (ISOPTO-DETAMIDE)
Ophthalmic infections
Mafenide (SULFAMYLON)
Prevention of infection on burned skin
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
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
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
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).
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
Cell wall Disrupters: Penicillin Derivatives:
Methicillin (STAPHCILLIN) Oxacillin (PROSTAPHLIN) Ampicillin (POLYCILLIN) Amoxicillin (AMOXIL) Ticaricillin (TICAR
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
Cell wall Disrupters: Penicillin Inhibitors/Additives:
Penicillin Inhibitors:
Clavulanate (AUGMENTIN)
Sulbactam (UNISYN)
Penicillin Additives:
Amoxicillin + clavulanate (AUGMENTIN)
Ampicillin + sulbactam (UNISYN)
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.
Cell wall Disrupters: Cephalosporins
Contain beta-lactam ring (as penicillin)
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
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
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
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
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
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)
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)
Cell wall Disrupters: Vancomycin (VANCOCIN)
Relatively new, synthetic drug Glycopeptide without beta-lactam core component
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
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)
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)
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
Protein Synthesis: 50S Ribosome Inhibitors
Erythromycin (E-MYCIN) Azithromycin (ZITHROMAX)
Erythromycin first isolated from Streptococcus arythreus
Azithromycin modern synthetic drug
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
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
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
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
Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines
Tetracycline (PANMYCIN) Demechlorcycline (DECLOMYCIN) Doxycycline (VIBRAMYCIN) Minocycline (MINOCIN)
Protein Synthesis: 30S Ribosome Inhibitors: Tetracyclines [Mechanism of Action]
Inhibits 30S ribosome subunit function
Blocks bacterial protein synthesis
Bacteriostatic
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
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)
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)
Protein Synthesis: 30S Ribosome Inhibitors: Aminoglycosides
Streptomycin (STREPTOMYCIN) Neomycin (MYCIFRADIN) Kanamycin (KANTREX) Gentamicin (GARAMYCIN) Tobramycin (NEBCIN
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.
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
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
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
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)
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
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
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
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)
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)
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
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
TCAs [Adverse Effects]
PNS:
Dry Mouth
Constipation
SNS:
Vasodilation (paradoxical effect)
Orthostatic Hypotension
Tachycardia: Direct & reflex effects
CNS-based:
Weight Gain
Sexual dysfunction
Sedation
Non-tricyclic Non Selective Reuptake Inhibitors
Duloxetine (CYMBALTA) Venlafaxine (EFFEXOR)
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