Untitled Quiz

Systems Pharmacology and Chemotherapeutics

• Course: SCPCB3-B44
• Institution: Eduvos
• Eduvos (Pty) Ltd is registered with the Department of Higher Education and Training as a private higher education institution.
• Registration Certificate number: 2001/HE07/008

Antivirals

• Lesson 1
• Focuses on antiviral drugs

Viral host ranges

• Bacteriophage and Influenza are shown
• Diagrams of virus components are provided (protein coat, nucleic acid, DNA, RNA, tail, fibres, membrane envelope)

Mammalian viruses

• Diagram of a mammalian virus, along with examples of pathogens
• Includes parts of a virus (envelope protein, viral genome, nucleocapsid, viral tegument)

Life cycle of a generic DNA virus

• The virus binds to cellular receptors for entry into a cell
• Viral DNA and mRNA transcripts are released and translated.
• Viral and cellular expressed proteins are replicated.
• Viral and cellular proteins are packaged into the virion.
• The virion is released from the cell.

General principles: Viral diseases

• DNA-based viruses: herpes simplex types 1 & 2, varicella zoster, herpes zoster, Human papillomavirus, Epstein-Barr virus, Poxvirus
• Resultant diseases: herpes, encephalitis, chickenpox, shingles, warts, cancer, mononucleosis, Burkitt's lymphoma, nasopharyngeal carcinoma, smallpox, chickenpox
• RNA-based viruses: HIV-1, HIV-2, Rhinovirus, Hepatitis A, B, C viruses, Influenza A, B, C viruses
• Resultant diseases: HIV, AIDS, respiratory/GI infections, common cold, hepatitis, influenza

Antiviral drugs

• Categorized by infection type (respiratory, hepatic, herpes/CMV)
• Lists specific antiviral drugs for each category. (e.g., Amantadine, Oseltamivir, Ribavirin, Acyclovir, Cidofovir, Famciclovir, Fomiversin, Foscarnet, Ganciclovir, Penciclovir, Valacyclovir, Valganciclovir, Vidarabin, Adefovir, Entecavir, Interferon, Lamivudine, Telbivudine, Tenofovir)

Respiratory virus infections

• Influenza type A & B, Respiratory syncytial virus (RSV)
• Vaccination is a preferred treatment.
• Also mentions influenza C viruses

Neuraminidase inhibitors (NAI)

• Oseltamivir, zanamivir
• Orthomyxoviruses have neuraminidase
• Catalyzes hydrolysis of terminal sialic acid residues
• Effective against all influenza types A & B
• Administered prophylactically or within initial 24-48 hours of onset to reduce symptom intensity and duration.

Tamiflu

• Oseltamivir, is a frontline drug for influenza.
• Reduced death risk in the 2009-2010 pandemic.

PK & PD of different types of antiviral drugs

• Details of Oseltamivir, Zanamivir (oral/inhaled)
• Resistance issues due to neuraminidase mutations
• Adverse effects for both types (GI issues often for Oseltamivir, respiratory distress for Zanamivir).

Adamantine Antivirals

• Amantadine and rimantadine
• Interfere with viral M2 proteins and viral particle release
• Effective against influenza A infections and used in early stages to treat and prevent.
• Significant resistance and used in combination with interferon.
• Interferes with viral protein expression.

Adverse effects of Amantadine

• Mild: insomnia, dizziness, ataxia
• Severe: hallucinations, seizures
• Rimantadine had fewer CNS side-effects

Ribavirin

• Guanosine analog
• Used for RSV infections in infants/children and in Hepatitis C & Lassa fever (with interferon)
• Mechanism involves conversion to ribavirin-triphosphate, inhibition of GTP formation, blocking RNA-dependent RNA polymerase, and subsequent blocking of RNA synthesis.

Adverse effects of Ribavirin:

• Dose-dependent transient anemia
• Elevated bilirubin levels
• Respiratory deterioration

Hepatic viral infections

• Hepatitis B & C
• Cause: cirrhosis, Hepatocellular carcinoma, destruction of hepatocytes
• Hepatitis B: Peginterferon-α-2a or lamivudine (combination therapy no more effective than lamivudine monotherapy)
• Hepatitis C: Combination of interferon α and ribavirin

Interferon

• Used for various conditions (chronic hepatitis, genital warts, leukemia)
• Interferes with viral protein expression and early stages of viral infection.
• Methods of administation: intra -lesionally, subcutaneously, intravenously
• Drug interactions: Interferons interfere with hepatic drug metabolism (leading to increased toxicity of theophylline)
• Interferons may potentiate the myelosuppression effects of other drugs.
• Adverse effects: flu-like symptoms (fever, chills, generalized muscle pain, gastrointestinal disturbances). Rare, but serious, include: acute hypersensitivity reactions and hepatic failure. Other serious side effects include various dose-limiting toxicities, such as severe fatigue, weight loss, autoimmune disorders, thyroiditis, cardiovascular problems, cardiac failure, bone marrow suppression, granulocytopenia, neurotoxicity (somnolence & behavioral disturbances).

Cytosine analogue: Lamivudine

• Inhibits HBV DNA polymerase and HIV reverse transcriptase.
• Phosphorylation by host enzymes activates it.
• Primarily effects viral DNA polymerase
• Intracellular t_1/2 > plasma t_1/2
• Widely distributed.
• Renal insufficiency requires dosage adjustments.
• Adverse effects: headache & dizziness

Nucleotide analogues: Adefovir, Entecavir, Telbivudine, Tenofovir

• Adefovir: phosphorylated to adefovir diphosphate, incorporated into viral DNA, terminates chain elongation
• Entecavir: guanosine analog, intracellular phosphorylation to triphosphate, competes with natural substrate for viral reverse transcriptase
• Telbivudine: thymidine analog
• Tenofovir: acyclic nucleoside phosphonate analog

Hepatitis C virus NS3/4A serine protease inhibitors: Boceprevir and telaprevir

• Oral administration
• Direct-acting; used in combination.
• Reversibly bind NS3 protease active site
• Strong inhibitors of CYP3A4/5

Herpes Virus Infections

• HSV-1: orofacial
• HSV-2: genital herpes
• Dormancy periods
• Infectious (outbreaks) not fatal, but incurable
• Treatment options: Acyclovir (purine mimic), Cidofovir (pyrimidine mimic), Foscarnet (pyrophosphate), Ganciclovir (purine mimic)

Acyclovir (Ganciclovir)

• Primarily for herpes infections (HSV-1 & HSV-2) • Structurally similar to 2'-deoxyguanosine, lacks 3' hydroxyl group. • Administered: topical, intravenous, oral • Prophylaxis: seropositive patients, before transplants.

Acyclovir MOA

• Acyclovir is phosphorylated to its active form.
• Analog causes chain termination by incorporation into DNA.

Acyclovir PK & PD

• Drug crosses the blood-brain barrier
• Drug and metabolites appear in the urine
• Accumulation with renal failure is a common effect
• Resistance (altered or deficient thymidine kinase or DNA polymerase) is more common in immunocompromised patients
• Other side effects include local irritation, headache, diarrhea, nausea & vomiting, transient renal dysfunction, and GIT problems.

Cidofovir

• CMV-induced retinits in AIDS patients.
• Less prevalent since HAART.
• Nucleotide analog of cytosine
• Phosphorylation not dependent on viral enzymes
• Inhibits viral DNA synthesis
• Intravenous, topical, and intravitreal administration
• Slow elimination leads to extended dosage intervals
• Adverse effects include nephrotoxicity (contraindicated in pre-existing renal impairment).

Foscarnet

• Rx for: CMV retinitis, acyclovir-resistant HSV, herpes zoster infection
• Reversibly inhibits viral DNA & RNA polymerase by terminating chain elongation.
• Poorly orally absorbed; needs frequent dosing intervals; good distribution.
• Nephrotoxicity, anaemia, nausea, and fever are common adverse effects.
• Chelation with divalent cations (hypocalcaemia, hypomagnesemia, hypokalaemia) can occur as well as arrhythmias.

Penciclovir

• Guanosine nucleoside derivative for HSV-1, HSV-2 and VZV
• Topical administration.
• Monophosphorylated by viral thymidine kinase
• Inhibits HSV DNA polymerase

Famciclovir

• Analog of 2'-deoxyguanosine.
• Prodrug; activated to active penciclovir.
• Common adverse effects include headache and nausea.
• In experimental animals, increased incidence of mammary adenocarcinomas & testicular toxicity has been reported.

Nucleotide vs nucleoside

• Nucleotides have a phosphate group and nucleosides only have sugar & a base.

Purine Nucleosides

• Structures of different types (ribavirin, famciclovir, etc)
• Drugs associated with these include Adefovir, Entecavir, Telbivudine, Tenofovir, Ganciclovir, Ribavirin, Famciclovir.

Pyrimidine Nucleosides

• Structures of different types (thymidine, telbivudine, etc)
• Drugs associated with these include, Telbivudine

HIV/AIDS Antiretrovirals

• List of drugs used to treat HIV infections (e.g. Abacavir, Didanosine, Emtricitabine, Enfurvitide, Efavirenz, Indinavir, Lamivudine, Lopinavir, Nevirapine, Ritonavir, Saquinavir, Stavudine, Tenofovir, Zalcitabine, Zidovudine)
• Global prevalence map (2010-2017).
• Symptoms (brief flu-like illness, swollen lymph nodes, diarrhoea, weight loss, fever, cough & shortness of breath).
• Opportunistic infection symptoms are also mentioned.
• HIV life cycle diagram is shown also.

Treatment options: ARTs antiretrovirals

• No vaccination
• Serodiscordant couples
• Condoms and serotyping
• PrEP (pre-exposure prophylaxis) a pill a day, PO
• Fixed dose combinations (FDC)

Treatment options: ARTs antiretrovirals (continued)

• HIV testing before, and every three months during, the treatment period.
• PEP (post-exposure prophylaxis), given within 3 days of a possible exposure
• Daily for 28 days after a potential HIV exposure.
• Use triple ARV regimens.
• Nevirapine not recommended for PEP due to side effects.

HAART

• Combination therapy of: Nucleoside/-tide reverse transcriptase inhibitors, Nonnucleoside reverse transcriptase inhibitors, Protease inhibitors, Entry inhibitors, Integrase inhibitors.

NRTI's

• Analogs of ribosides or nucleosides containing a ribose, but lacking a 3' hydroxyl group, which prevent chain elongation.
• List of drugs: Zidovudine (AZT), Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Tenofovir, Emtricitabine

Zidovudine (AZT)

• Indications: prevention of prenatal infection and prophylaxis for exposed individuals; children and adults.
• MOA: Converted to active triphosphate and inhibits phosphorylation (dTMP to dTDP), which is required for DNA synthesis.
• PK: Penetrates BBB; Food decreases peak drug levels; Metabolized to glucuronide.
• Resistance: Mutations at codons and cross-resistance with other NRTIs
• Adverse effects: Bone marrow toxicity, headaches, seizures, and interactions with other glucuronylated drugs.

Didanosine

• MOA: missing both 2' and 3' -OH
• PK: Acid labile; food-induced protein binding
• AE: pancreatitis, dose-dependent peripheral neuropathy, rash, stomatitis, and increased renal excretion
• Resistance: Reverse transcription mutations (substitutions in NRTI binding sites), cross-resistance with other NRTIs.

Zalcitabine, Stavudine

• Similar MOA to AZT, but specific toxicities differing from AZT.

Lamivudine, Abacavir, Tenofovir, Emtricitabine

• Similar MOA (NRTIs) with specific pharmacokinetics, side effects, and resistance patterns.

NNRTIs (Non-nucleoside reverse transcriptase inhibitors)

• Highly selective, non-competitive inhibitors of HIV-1 reverse transcriptase.

List of NNRTIs:

• Nevirapine, Delavirdine, Efavirenz, Etravirine

Nevirapine

• Indications: HIV-1 treatment and prevention of mother-to-child transmission in adults and children.
• Resistance develops rapidly with monotherapy, should be used in combination with other ARVs.
• PK: Well absorbed orally; not affected by food or antacids; good distribution to the CNS; excretion is primarily urine metabolites.
• AE: Rash, fever, headache; elevated serum transaminases; serious dermatological conditions (Stevens-Johnson syndrome, toxic epidermal necrolysis) and hepatotoxocity
• Drug interactions: Induces CYP3A4 (results in the decrease in PI levels) and no dosage adjustments are required with the use of NRTIs.
• Dosage adjustments may be necessary if the patient is concurrently taking drugs which are CYP3A4 substrates such as oral contraceptives etc.

Delavirdine, Efavirenz

• Similar indications and general actions as described for Nevirapine
• Have some notable side effects and drug interactions

Protease Inhibitors (PI's)

• List of drugs: Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir, Atazanavir, Darunavir, Fosamprenavir, Tipranavir
• Used in combination with other ARVs.
• Mechanism of action : block HIV protease (necessary for viral maturation) preventing the production of infectious viral particles.

PI Considerations

• Poor oral bioavailability.
• High-fat meals affect bioavailability (more problematic in some PIs than in others)
• Requires dosage reduction in renal failure; but not in most cases of hepatic dysfunction
• Drug interactions with other CYP450 inhibitors/inducers will often impact efficacy or increase toxicity
• Common side effects include disturbances in fat and glucose metabolism

Viral Entry Inhibitors

• Enfuvirtide: Prevents HIV from entering the host cell by interfering with the conformational change of gp41 when the HIV binds to the host cell surface.
• Maraviroc: Inhibits the CCR5 co-receptor.

Integrase Inhibitors

• Raltegravir: Inhibits HIV DNA integration in host cells.

Adverse effects of Raltegravir

• Less serious: Nausea, headache, diarrhoea, Elevated creatine kinase, Muscle pain, Rhabdomyolysis
• Severe: Depression, Suicidal ideation.

Prevention of mother-to-child transmission (PMTCT)

• Key aspects of PMTCT are: HIV counselling and testing, provision of ARVs to the newborn, avoidance of breastfeeding.
• There are different stages of PMTCT, including antepartum (before birth), in the period around birth (intrapartum), and postpartum (after birth).

Cancer Chemotherapy

• Approaches to cancer treatment and some associated challenges.
• Key hallmarks and principles of cancer chemotherapy described:
• Chemotherapy can arrest a tumour's progression
• Targets metabolic sites essential to cell replication including cell-cycle-specific sites.
• Important to note that chemotherapy may affect cancerous and healthy cells impacting some individuals by impacting specific normal cells more or less than cancerous cells
• Resistance, including melanoma resistance
• Multidrug resistance (P-glycoprotein ATP dependence, expression in various organs)
• Toxicity (narrow therapeutic index and treatment-induced tumors) including drug-induced specific issues such as pulmonary toxicity or neurotoxicity.

Other Alkylating agents

• Chlorambucil, Busulfan • Used for chronic conditions (leukemias, lymphomas)

Vinca Alkaloids

• Examples: vincristine, vinblastine, vinorelbine
• Mechanism of action: Cell-cycle and phase-specific: metaphase, binds to microtubular protein: tubulin, blocks the ability of tubulin to polymerise, prevents chromosomal segregation & cell proliferation
• Resistance: Enhanced efflux, Alterations in tubulin structure
• Adverse effects: Various side-effects

Taxanes: paclitaxel & docetaxel

• Indications: Ovarian cancer, Metastatic breast cancer, Paclitaxel & cisplatin: lung cancer, fewer side-effects.
• Pharmacokinetics: Large volume of distribution; does not cross BBB; Requires dosage reduction in hepatic dysfunction.
• Resistance: Amplified (increased levels of) P-glycoprotein expression, Mutation in tubulin structure
• AE: Dose-limiting toxicity (neutropaenia); peripheral neuropathy; transient ischemic bradycardia, fluid retention, hyperuricaemia, alopecia.

Steroid hormones and antagonists

• Hormone-responsive tumours are often treated with hormones, or antagonists thereof

Prednisone

• Indications: Treating lymphoma
• MOA: Reduced to active prednisolone by 11-β-hydroxysteroid dehydrogenase, steroid binds to receptor, triggers protein production
• Resistance: Absence/mutation of receptors
• PK: Oral administration, highly plasma-protein bound, prednisolone is glucuronidated by the liver and excreted.
• AE: Immunosuppressant, predisposes to infection, hyperglycaemia, cataracts, glaucoma, osteoporosis, behavioural changes (euphoria, psychosis).

Tamoxifen

• Indications: Oestrogen receptor-positive breast cancer
• MOA: Binds to oestrogen receptor, non-productive complex, competes with oestrogen, lowers oestrogen levels;administered with leuprolide
• Resistance: Decreased affinity for receptor, dysfunctional receptors
• AE: Hot flashes, nausea, vomiting, skin rashes, vaginal bleeding/discharge, similar to natural oestrogen effects.
• Potential to cause endometrial cancer, hypercalcaemia, thromboembolism, affects vision.

Aromatase Inhibitors

• Examples: Aminoglutethimide, Anastrozole & Letrozole, Exemestane
• MOA: Decrease oestrogen production.
• Indications: Metastatic breast cancer treatment.
• Uses in combination with chemotherapy or other medications

Progestins

• Example: megestrol acetate
• Indications: Metastatic hormone-responsive breast and endometrial cancer.

Leuprolide & goserelin

• Indications: Testicular cancer, advanced breast cancer, prostate cancer
• MOA: Desensitises GnRH receptors, causing decreased release of LH & FSH; resulting in less androgen & oestrogen secretion.
• Administration: Leuprolide= sustained-release preparation, SC and depot intramuscular injection, Goserelin by IM administration
• AE: Impotence, tumor flare.

Oestrogens

• Examples: diethylstilbestrol, ethinyl estradiol
• Indications: Prostate cancer
• MOA: Inhibit growth of prostatic tissue by blocking LH production and decreasing androgen synthesis.
• AE: Thromboemboli, Myocardial infarction, Hypercalcaemia, Gynecomastia, Impotence

Monoclonal antibodies

• Directed against specific targets, resulting in fewer adverse effects.
• Ex: Rituximab, Tositumomab, Alemtuzumab, Trastuzumab, Gemtuzumab ozogamicin, Bevacizumab, Cetuximab

Trastuzumab

• Overexpression of transmembrane human epidermal growth factor-receptor protein 2 (HER2) causing cell growth and division.
• MOA: Down-regulation of HER2 and decrease in angiogenesis
• Pharmacokinetics: IV, does not cross the blood-brain barrier
• AE: CHF, infusion-related (fever, chills, headache, nausea), vomiting, abdominal pain, hypersensitivity reactions.

Rituximab

• Monoclonal antibody against CD20 antigen on normal & malignant B cells.
• Indications: Non-Hodgkin lymphoma, CLL
• Pharmacokinetics: IV
• MOA: Binds to CD20 on B lymphocytes, recruits immune effector functions, and causes rapid depletion of B lymphocytes
• AE: Hypotension, bronchospasm, angioedema, chills, fever, release of TNFalpha.

Bevacizumab

• Anti-angiogenesis agent
• Indication: metastatic colorectal cancer (combined with 5-FU).
• MOA: Attaches to and stops VEGF (Vascular Endothelial Growth Factor) from forming new blood vessels. This can inhibit the tumour’s ability to receive necessary nutrients and oxygen.
• Adverse effects; commonly hypertension, stomatitis and diarrhoea. Other effects are; intestinal bleeding, proteinuria, hepatic failure, and rare cases of bowel perforation.

Cetuximab

• Indication: colorectal cancer (IV)
• MOA: Targets the epidermal growth factor receptor (EGFR) on the surface of cancer cells, interfering with their growth.
• Adverse effects: Difficulty breathing, hypotension, pulmonary toxicity and other common side effects such as rash, fever, constipation and abdominal pain

Tyrosine Kinase Inhibitors

• List of drugs: Imatinib, Dasatinib, Nilotinib, Erlotinib, Sunitinib
• MOA: block tyrosine kinases or serine/threonine & tyrosine kinases.
• Indications based on specific kinases involved: Imatinib indications are CML, GI stromal tumors and other indications are also mentioned
• Adverse effects include fluid retention/oedema, QT prolongation, hepatotoxicity, thrombocytopenia & neutropenia, nausea & vomiting.

Cisplatin, Carboplatin, Oxaliplatin

• Platinum coordination complexes
• Indication: Solid tumors. Specific indications like various types of carcinomas, leukemias, and other conditions are mentioned.
• Mechanism of action: Similar to alkylating agents, loss of chloride ions, binds to guanine in DNA, intra- & inter-strand cross-links, inhibition of DNA & RNA synthesis; cells are most vulnerable in G1 and S phases.
• Pharmacokinetics: Poor penetration into the CNS; IV, IA, intraperitoneal, primarily excreted in the urine.
• Resistance: Increased glutathione levels, reduced cellular uptake
• Adverse effects: Severe persistent vomiting,Dose-limiting toxicity: nephrotoxicity

Topoisomerase inhibitors: Irinotecan & topotecan

• Topoisomerases relieve torsional strain in DNA
• Indication: Resistant metastatic ovarian cancer, small cell lung cancer, colon or rectal cancer (often in combination with other drugs)
• MOA: Inhibit topoisomerase I which prevents re-annealing of single-strand breaks. This leads to DNA damage and cell death.
• Pharmacokinetics: IV administration, renal dysfunction requires dosage adjustments.
• Resistance: Increased efflux, decreased ability to convert irinotecan to active metabolite, downregulation/mutation of topoisomerase I
• AE: Dose-limiting toxicity: myelosuppression.

Etoposide

• Indication: Lung cancer, testicular carcinoma, used in combination with bleomycin & cisplatin
• MOA: Blocks cells in S/G2 phase, Leads to double strand DNA breaks.
• Resistance: P-glycoprotein, mutation of topoisomerase II.

Procarbazine

• MOA: undergoes a series of oxidative reactions; on DNA, RNA & protein synthesis
• AE: Bone marrow supression, nausea, vomiting, diarrhea, and neurotoxicity
• Monoamine oxidase inhibitor; mutagenic & teratogenic.

L-asparaginase

• MOA: Hydrolyses asparagine to aspartic acid and ammonia, decreases protein synthesis
• Indication: ALL, combination with vincristine & prednisone.
• Resistance: Increased capacity of tumour cells to synthesize asparagine.
• Adverse effects: Hypersensitivity reactions, decrease in clotting factors, liver abnormalities, pancreatitis, seizures & coma.

Interferons: α-2b

• MOA: Secreted by producing cells, interact with surface receptors on other cells, leading to enzyme synthesis, suppression of cell proliferation, macrophage activation, and increased cytotoxicity of lymphocytes.
• Pharmacokinetics: IM or SC

Gastrointestinal Drugs

• This section focuses on drugs used for peptic ulcers, nausea & vomiting, diarrhoea, and constipation. It includes a wide variety of categories of anti-ulcer agents