Final Exam Flashcards
5 main classes of antifungal drugs
- Polyenes
- Azoles
- Pneumocandins & echinocandins
- Pyrimidines
- Drugs used to treat dermatophytosis
Polyenes
- ex. amphotericin B
- broad spectrum; fungicidal
- high systemic toxicity
MOA: binds ergosterol and enters fungal membrane —> several molecules form a pore; fungal cell lyses
binds cholesterol = toxicity to host cells
PK: long half-life; > 100 h — excretion continues weeks after therapy discontinuation
AE: most toxic of its type in clinical use; dose-dependent nephrotoxicity; IV admin. may cause thrombosis = must be slow (4-6 hrs.); preparations containing bile salts add to toxicity
**lipid-complex formulations = safer; more effective = much less toxic (can be infused at higher dosages over 1-2 hrs.)
CA: mainly admin. IV for life-threatening systemic mycoses (esp. immunocompromised patients = fungicidal nature); often given once prior to longer follow-up therapy w/ an azole
Azoles
- broad spectrum; fungistatic
- very low toxicity
MOA: inhibit fungal P450 enzymes involved in ergosterol formation = inhibit fungal membrane synthesis
AE: teratogenic; inhibit mammalian hepatic P450 enzymes (inhibit metabolism of concurrently admin. drugs)
2 main classes:
- Imidazoles (ex. clotrimazole, miconazole - topical) toxicity preludes systemic use
- AE: inhibit fungal and mammalian sterol synthesis (cortisol, testosterone = endocrine) - Triazoles (ex. itraconazole - oral, non-life-threatening systemic mycosis, sometimes replaces or used after amphotericin B (life-threatening)) longer half-lives
- AE: interferes less w/ sterol synthesis of host’s enzymes than imidazoles; systemic endocrine AEs = uncommon
Pneumocandins & echinocandins
- ex. caspofungin, micafungin, anidulafungin
- fungicidal; low toxicity; resistance uncommon for E
- newest antifungal drugs; replacing polyenes for systemic therapy
- drawbacks: narrower SOA; expensive
in humans, all agents well-tolerated w/ similar AE profiles and few drug-drug interactions
MOA: inhibit an enzyme necessary for cell wall synthesis of several fungi
Pyrimidines
- ex. flucytosine
- penetrate BBB well
An example of a drug used to treat dermatophytosis (ringworm)…
Terbinafine
MOA: inhibit ergosterol synthesis in virtually all dermatophytosis; toxicity metabolites accumulate — fungicidal
- distributes to skin, hair, nails, fat; enters newly forming keratin (skin - 3 months; nails - >12 months)
- given orally = serious infection
- more effective than itraconazole
AE: uncommon, generally safe
What is inflammation?
- active, complex, local response of tissues to injury
- can be either protective & beneficial OR exaggerated & harmful
- involves immune responses, coagulation cascade, and regeneration & repair processes
Inflammation: Function is to protect the body following injury, which involves…
- removal of injurious stimuli/ insult (bacteria, chemical irritants, etc.)
- removal of necrotic cells
- containment of damage (abscess)
- stimulation of repair & regeneration
Four major changes that occur during acute inflammation
- Blood vessels dilate (warmth & redness)
- Blood vessels become leaky (fluid & proteins enter tissue —> edema)
- WBCs enter inflamed tissue
- Nociceptors become sensitized (pain)
Cardinal signs of inflammation
- Heat
- Redness
- Swelling
- Pain
- Loss of function
Chronic inflammation
- stimulates fibrosis (scarring)
- depending on site — may impair vision, mobility, oxygenation, etc. OR cause seizures, arrhythmias, intestinal strictures, etc.
anti-inflammatory therapy may be necessary if stimulus cannot be identified or eliminated
Inflammatory mediators (synthesis & redundancy)
Synthesis: produced in advance and released at time (histamine) OR synthesized at site in response (PGs)
Redundancy: several mediators trigger same inflammatory process = inhibitors of one class of mediator may lessen BUT NOT abolish inflammation
Major classes of pro-inflammatory mediators
- Eicosanoids (PGs, TXA2, PGI2)
- Leukotrienes the most effective anti-inflammatory drugs inhibit many or all of these
Therapeutic options for inflammation
Non-pharmacological: rest, heat/cold, weight reduction, surgery
Pharmacological: NSAIDs, glucocorticoids, misc.
Main beneficial effects of NSAIDs
Anti-inflammatory, antipyretic, analgesic
Eicosanoids (mainly PGs)
Normal physiological roles — required for normal homeostasis in all tissues; synthesized from arachidonic acid by COX enzymes (COX1 & COX2)
Roles in inflammation — COX2 up-regulated; locally responds to plasma membrane damage OR inflammatory mediator release —> excessive vasodilation occurs, promoting inflammation
NSAIDs (MOA)
MOA: inhibit COX enzymes
- reduces synthesis of PGs, including those that promote vasodilation
- reduces blood flow to site
- reduces sensitization of nociceptors
- alleviates inflammation
NSAIDs (MOA of AEs in gastric mucosa)
Normal protective effects of PGs in stomach inhibited = decreased blood flow, bicarbonate and mucus secretion; increased acid secretion
gastric bleeding +/ ulceration (most common AE)
NSAIDs (MOA of AEs in platelets)
Only COX1 is present —NSAIDs inhibit conversion of AA to TXA2 in platelets = slightly increases general tendency to bleed
excessive doses = more pronounced bleeding
NSAIDs (MOA of AEs in kidney)
Excessive COX inhibition = renal medullary hypoxia & papillary necrosis
COX2
NSAIDs (shared general properties)
PK: weak acids, highly protein-bound, hepatic metabolism (phase 2 conjugation), variable elimination
Contraindications: patients w/ GI ulcers, renal disease, hepatic disorders, hypoproteinemia, dehydration or cardiac disease
Clinical uses: for relief of musculoskeletal & inflammatory pain, including post-operative
NSAIDs (shared AEs)
- GI ulceration*
- inhibition of platelet aggregation (bleeding)*, uterine motility, PG-mediated renal perfusion
- renal papillary necrosis (dehydrated patients)
*PG synthesis in other tissues inhibited — excessive inhibition:
- in GI epithelium: decreases PGI2 (decreased blood flow & bicarbonate secretion, increased acid secretion = gastric ulcers); decreases PGE2, decreases gastric mucus = gastric ulcers)
- in the kidney: decreases PGE2, decreases blood flow = hypoxia; renal papillary necrosis
Aspirin (ASA)
- oldest of the NSAIDs
- prolonged effects even at low doses; shorter duration of action
- anti-inflammatory, antipyretic, analgesic
- effective for musculoskeletal/cutaneous pain BUT poor for visceral pain
- most commonly used anti-platelet drug; prevents thrombus formation and re-thrombosis (does not lyse existing thrombus) — MI, stroke, peripheral vascular diseases
MOA: irreversibly inhibits COX1 —> inhibits PG synthesis —> prevents TXA2 production (reduces platelet aggregation)
AEs: bleeding tendencies (inhibits platelet function); dose-dependent gastric ulceration; renal damage (dehydrated patients)
Contraindications: patients w/ bleeding disorders; those prone to GI ulcers (receiving glucocorticoids)
Ibuprofen
- anti-inflammatory, antipyretic, analgesic
- indicated for arthritis & musculoskeletal pain
- preferred for some chronic uses (osteoarthritis)
MI risk may be elevated when used ‘chronically in high doses’ BUT appears to be less risky than selective COX inhibitors
MOA: inhibits both COX1 & COX 2
AE (main): gastric ulceration but less intense than w/ aspirin
Celecoxib
- almost 100% selective for COX2 ‘in vivo’
- approved for osteoarthritis
- poor to negligible analgesia
- no effect on platelets/bleeding
- far less likely to cause GI ulceration & bleeding than non-selective NSAIDs, if gastric lesions are not already present — COX2 products involved in healing gastric ulcers
Concerns:
- reduced blood flow to kidneys = reduced renal function; intravascular clotting = increased risk of stroke & MI
- w/ chronic use in osteoarthritis and rheumatoid arthritis, not with acute or intermittent use
How do coxibs increase the risk of stroke & heart attack?
- regular non-selective NSAIDs inhibits synthesis of all COX1 & COX2 products = inhibition of TXA2 has a greater effect than inhibition of PGI2 — in favour of bleeding
- coxibs inhibit only COX2 = less PGI2 produced — in favour of intravascular coagulation (hence, stroke & MI)
effects are only observed after prolonged use (>18 months)
Acetaminophen
- antipyretic, analgesic
- little peripheral activity = negligible anti-inflammatory effect & no effect on blood clotting
no longer considered an NSAID
MOA: centrally inhibits PG synthesis
Glucocorticoids (mechanism)
Two mechanisms:
1. Nuclear pathway promotes protein production, inhibiting EGFR
2. Cytoplasmic pathway activates proteins, inhibiting EGFR
plasma membrane receptors = rapid effects
MOA: indirectly inhibit PA2 —> inhibits synthesis of AA —> inhibits synthesis of PGs & leukotrienes —> inhibits inflammation & essentially all WBC functions
more profound effect than NSAIDs
To elevate blood glucose, glucocorticoids…
- stimulate hepatic glucose syn. from amino acids & lipids
- inhibit glucose uptake by muscle & adipose
- stimulate fat breakdown in adipose
- mobilize amino acids from non-hepatic tissues
Glucocorticoids inhibit _____ absorption, bone _____________, __________ healing, ____________ function, etc.
Ca2+, formation, wound, immune
_________________ is a common AE of chronic glucocorticoid administration.
Osteoporosis
Glucocorticoids (PK)
Absorption: oral; IM / SQ; intra-articular; topical
Distribution: carried in blood via albumin & transcortin
Metabolism: hepatic ADRs possible
~ some activated in liver:
- cortisol —> hydrocortisone
- prednisone —> prednisolone
Excretion: urine / feces
Glucocorticoids (AEs)
Serious AEs — usually only seen after ~2 weeks of continuous, dose-dependent therapy
risk of AEs related to duration AND dose
Numerous, possibly severe if not used properly:
• Increased appetite, thirst, & urination
• Impaired wound healing/thinning of skin
• Hypertension (mineralocorticoid activity, RAS activation, etc.)
• Edema
• Negative calcium balance (osteoporosis)
• Gastric ulcers
• Psychoses / euphoria
• Infection
• ‘Centripetal’ fat distribution & hair loss
Glucocorticoids (therapeutic principles)
- Empirical use, except for replacement therapy
→ alleviation of a patient’s symptoms until initial insult has been resolved (if possible) - Consider risks / benefits in that patient
— goal = toleration of condition, not complete relief - Dose very dependent on disease/patient → trial & error
— use smallest possible dose - Re-evaluate periodically
— gradually reduce dose to minimum acceptable - Generally, even large single doses are harmless
— crisis situation - < 1 week unlikely to be harmful
- Time & dose related to toxicity (> 1 week)
- With chronic use, abrupt cessation
→ adrenal insufficiency
MUST wean patient off drug GRADUALLY
Hypoadrenocorticism secondary to abrupt glucocorticoid cessation
~ may or may not be as severe as Addison’s disease, depending on the drug
~ drugs such as cortisone, prednisone, and prednisolone, which have some mineralocorticoid activity, will suppress the patient’s aldosterone levels during therapy
~ aldosterone levels may be inadequate following abrupt cessation of the glucocorticoid, resulting in:
— Na+ and water loss → low BP
— K+ retention → arrhythmias
these effects may be fatal
Arthritis (clinical use of GCs)
- provide early to minimize damage from inflammation; patient should exercise affected joints moderately = slow disease progress
- caution regarding “masking” of pain; patients may overuse & injure inflamed joints (ex. athletes)
- hypersensitivities for oral / inhaler; use injectable drug for anaphylaxis
What is the goal of normal homeostasis?
To prevent prolonged hemorrhage & spontaneous thrombosis; remain localized
involves temporally overlapping stages
Prothrombogenic factors
- platelet activators
- procoagulants
- vasoconstriction
- fibrinolytic inhibitors
Antithrombogenic activators
- platelet inhibitors
- anticoagulants
- vasodilators
- fibrinolytic activators
What are the stages of hemostasis?
- Vasospasm (vasoconstriction)
- Platelet response
- Coagulation phase
- Clot dissolution (fibrinolysis)
Vasospasm
- damaged vessel immediately constricts, reducing blood flow = limits blood loss
- response occurs as a result of sympathetics & local factors (e.g. TXA2, endothelin) = initiates myogenic properties in vessel wall
smooth muscle contraction
Platelet response
- platelets adhere to exposed collagen of damaged endothelium and to each other = platelet plug releases chemical mediators (e.g. TXA2, ADP)
recruits more platelets, promotes vasoconstriction, initiates coagulation cascade
Coagulation phase
- involves sequential conversion of inactive proteins into catalytically active proteases; divided into intrinsic (in vitro) & extrinsic (in vivo) pathways (converge at factor X activation — common pathway)
- extrinsic pathway: coagulation cascade initiated at site of injury by expression of TF complexing with factor VIIa = conversion of fibrinogen to fibrin by thrombin — protein matrix reinforces clot
Clot dissolution (fibrinolysis)
- involves proteolytic actions of plasmin bound to clot
needed for wound healing & vessel flow restoration
Excessive bleeding may be caused by…
- platelet deficiency (thrombocytopenia; von Willebrand’s)
- clotting factor deficiency (single factor (hemophilia - VIII, IX); multiple factors (vitamin K deficiency))
- fibrinolytic hyperactivity
Drugs/treatments used in hemorrhagic diseases…
- vitamin K
- antifibrinolytic agents
- blood products (replacement factors)
- others*
Vitamin K
2 natural form exist: vitamin K1 (phytonadione — foods); vitamin K2 (menaquinone — intestinal bacteria)
- available for oral & parenteral use; IV route (give slow; anaphylaxis); SC injection (preferred route)
- considered very safe; fat-soluble (requires bile salts for intestinal absorption)
MOA: confers biological activity to factors II, VII, IX, X via post-translational modification
- requires ~6-12 hours for new factors & clinical effects
Uses: anticoagulant toxicity; vitamin K deficiency; prevent hemorrhagic disease (newborns)
Antifibrinolytics/fibrinolytic inhibitors
Plasmin lyses fibrin and fibrinogen by attaching to lysine binding sites
Aminocaproic acid (Amicar)
- synthetic agent similar to lysine
- MOA: blocks lysine binding site; competitively inhibits plasmin action on fibrin
incomplete lysis can lead to thrombi formation
- Uses: bleeding from fibrinolytic therapy; adjunct therapy-hemophiliacs
Plasma fractions
Deficiencies in plasma coagulation factors can cause bleeding; spontaneous when key factors < 5-10% of normal levels
- examples: factor VIII deficiency (hemophilia A/classic hemophilia); factor IX deficiency (hemophilia B/Christmas disease) — treatment? concentrated plasma factors!
Desmopressin acetate (DDAVP)
- transiently increases factor VIII activity in mild hemophilia or von Willebrand’s disease
- available as tablets, injectable or nasal spray (high doses)
Protamine sulfate
- low MW, strongly basic (cationic) protein produced by recombinant technology
- used to treat heparin overdoses by binding & neutralizing its coagulant effects
more effective against large MW heparin molecules in unfractionated heparins vs. low MW heparins - give IV slowly to avoid AEs (includes collapse)
- monitor patient — high doses can produce anticoagulant effects
Drugs/treatments used in anemias…
- essential nutrients
- growth factors
What is the aim of anemia therapy?
- to provide components for RBCs and hemoglobin
- to stimulate bone marrow formations of RBCs
Iron
- forms complex w/ oxygen in hemoglobin & myoglobin (transport)
- used in treatment or prevention of disorders associated w/ deficiency (chronic blood loss in adults; prevention of newborn iron deficiency; anemia from chronic renal failure; inadequate iron absorption from GI tract)
- oral (ferrous salts) or parenteral (iron dextrans via injection) administration
Vitamins (anemia)
- essential for DNA synthesis
- examples: folic acid; vitamin B12 (cyanocobalamin) administered alone or in multivitamin preparations; oral or injected
Erythropoietin (Epogen, Procrit) - growth factor -
- glycoprotein hormone produced by kidney in response to hypoxia
primarily used in cases of chronic anemia due to reduced EPO in CRF; has been used in anemia of other causes (AIDs, cancers, elective surgeries)
iron supplementation advised in combination
MOA: stimulates proliferation & differentiation of red cell progenitors & release of reticulocytes
- following treatment: increase in hematocrit & hemoglobin in 2-6 weeks
AEs: hypertension, thrombosis
Filgastrim (Neupogen)
- granulocyte colony stimulating factor
MOA: stimulates proliferation & differentiation of myeloid progenitor cells (neutrophil lineage)
- activates polymorphic neutrophils (increases their life in circulation)
- mobilizes hematopoietic stem cells in circulation important source of cells for transplantations following high dose chemotherapy; improves stem cell engraftment & recovery
Uses: indicated for chemotherapy-induced neutropenia — ameliorates myelosuppression of neutrophils (no improvement in survival noted)
Oprelvekin (Neumega)
MOA: stimulates myeloid, lymphoid & megakaryocyte progenitor cells in conjunction w/ growth factors
- used to treat thrombocytopenia
Red thrombus
Fibrin-rich; contains large # of RBCs; occurring in veins
White thrombus
Platelet-rich; occurring in arteries
Pathogenesis of thrombosis requires ______________________.
Prothrombic factors
Prothrombic factors can be released due to…
- endothelial injury (local vessel)
- circulatory stasis
- altered blood coagulability (hyperactivity of hemostatic mechanisms; hypoactivity of fibrinolytic mechanisms)
Drug classes for thromboembolic disease
- systemic anticoagulants
- antithrombotic drugs
- fibrinolytic drugs
An ideal systemic anticoagulant…
- prevents pathologic thrombosis
- limits reperfusion injury & bleeding
- allows normal response to vascular injury
Heparin
- mixture of sulfated mucopolysaccharides; highly negatively charged
MOA: enhances (accelerates 100-fold) action of antithrombin III (forms heparin-ATIII complex); AT-III inhibits activated clotting factors, especially thrombin IIa and Xa — “suicide substrate”
Uses: primarily used in initial treatment of thrombosis and thromboembolic disease; prevents thrombi from enlarging & new thrombus formation (does not lyse existing thrombus)
rapid onset of action = acute anticoagulant (oral - concurrently)
used in venous thrombosis, pulmonary embolism, unstable angina, atrial fibrillation, acute MI & various cardiovascular surgeries
AEs: bleeding tendencies & possible thrombocytopenia
monitor aPTT - 1.8-2.5 X normal mean; protamine sulfate can neutralize heparin overdose
Enoxaparin (Lovenox)
- low MW heparin
- inactivate factor Xa well, but not thrombin (IIa)
- used more commonly due to advantages (less bleeding tendencies possible, protamine sulfate less active against LMW heparins (reversible), less risk of thrombocytopenia, improved pharmacokinetics (can give SC; longer half-life))
Warfarin (Coumadin)
- oral / injectable anticoagulant
- used as chronic preventative anticoagulant therapy; dosing usually begun w/ heparin administration
- monitor using INR (PT/mean PT) — increase to 2.0-3.0
MOA: antagonizes vitamin K actions, reducing clotting factors (II, VII*, IX and X) — clotting not affected until existing factors used
*6 hrs half-life
Toxicities: bleeding tendencies (can treat w/ vitamin K1); serious bleeding (requires fresh blood/plasma); crosses placenta (heparin does not cross)
An example of a selective factor Xa inhibitor
Rivaroxaban (Xarelto)
MOA: inactivates factor Xa directly; does not interact w/ ATIII and no thrombin activity
- prevention of stroke secondary to atrial fibrillation
- prevention & treatment of deep venous thrombosis & pulmonary embolism
Direct thrombin inhibitors & examples
- more specific inhibition of thrombin w/ negligible effects at factor Xa
Bivalirudin (Angiomax)
- derived originally from lepirudin (medicinal leeches); now prepared synthetically; given by IV injection
MOA: binds and inhibits thrombin via its active site & exosite
Dabigatran (Pradaxa)
- given orally; prodrug
MOA: binds and inhibits thrombin via its active site
Antithrombotic drugs therapeutically target _________________________ via agents…
Platelet activators
- outside platelet acting on its membrane (collagen, thrombin)
- produced within granules that act on platelet membrane once released (ADP, 5-HT, TXA2)
- produced in platelet and act within it (cyclooxygenase, cAMP, cGM and Ca2+)
Examples of ADP inhibitors
Clopidogrel* (Plavix), Prasugrel* (Efient), Ticagrelor (Brilinta)**
*irreversible inhibitors; prodrug (must be activated by liver P450 metabolism)
**competitive inhibitor of P2Y12 receptor
- indicated to reduce and prevent recurrence of stroke and MI in affected individuals; agents are fairly safe
MOA: reduces aggregation by inhibiting ADP pathways
- acts as P2Y12 receptor antagonists (prevent binding of ADP to receptors); may be synergistic w/ aspirin (different MOAs)
Glycoprotein IIb/IIIa inhibitors & examples
Glycoprotein IIb/IIIa (platelet surface integrin receptor for fibrinogen) — receptor expression activated by thrombin, collagen, ADP, epinephrine & TXA2; once activated, binds & anchors platelets to each other
Abciximab (REOPRO)
MOA: Fab fragment of humanized monoclonal antibody directed against IIb/IIIa platelet receptor; irreversibly inhibits platelet aggregation
- indicated in percutaneous angioplasty associated w/ coronary thrombosis
- major toxicity: possible bleeding tendencies
Eptifibatide (Integrillin)
MOA: synthetic peptide reversibly inhibits IIb/IIIa receptor & platelet aggregation
- similar uses & AEs to abciximab
Fibrinolytic drugs & examples
MOA: rapidly lyse thrombi by activating plasmin from clot-bound plasminogen (ideally local fibrinolysis only)
Tissue plasminogen activator; t-PA or alteplase (Activase)
- serine protease that binds fibrin (produce by endothelial cells)
- preferentially activates clot-bound plasminogen; limits activation of systemic plasmin
- fairly short half-life = constant infusion
- uses: treatment of coronary thrombosis in acute MI; deep venous thrombosis; acute ischemic stroke; pulmonary embolism
- toxicities: bleeding tendencies
Tenecteplase (TNKase)
- engineered variant of t-PA w/ similar efficacy & possibly less bleeding
- longer half-life = single bolus injection
Atherosclerosis is due to…
Cholesterol/lipid plaques in coronary arteries from many lipid disorders
Atherosclerotic risk associated w/ _______ in LDL, IDL, and VLDL and _________ HDL levels. _______ plasma lipoproteins (mainly LDL) ______ atherosclerosis.
Increase; decrease; decrease; decrease
______________ are the bulk lipid transport of the body.
Lipoproteins
___________________, _______________, and _______________________ are sequelaes to atherosclerosis.
Coronary artery disease; stroke; peripheral artery disease
Inhibitors of cholesterol synthesis (statins) & examples
- these compounds are structural analogs of HMG-CoA (enzyme that mediates early steps of hepatic sterol synthesis)
Lovastatin, Rosuvastatin (Crestor)
- most effective & best tolerated drugs for therapy of hyperlipidemias; used as monotherapy (high efficacy); may be used w/ other drug classes
Pleiotropic effects: may contribute to reduction in cardiovascular morbidity & mortality (decreased inflammation (reduction in C-reactive protein); reversal of endothelial dysfunction (improved vasodilation to NO); decreased thrombosis; increase atherosclerotic plaque stability)
MOA: partially inhibit HMG-CoA reductase (decreases hepatic cholesterol levels)
- have high hepatic first-pass effect
- induce an increase in high affinity LDL receptors (principally in the liver) — increases LDL clearance; decreases plasma LDLs
Toxicities: possible increase in liver enzymes & risk of teratogenic effects (contraindicated in pregnancy); drug interactions possible = altered CYP450’s
Niacin
- one of the oldest drugs used to treat hyperlipidemias
- rapid-release & slow-release tablets
- acts as a vitamin B3 when converted to NAD
unconverted niacin produces lipid lowering effects
MOA: inhibits VLDL production & secretion = decreases LDL levels via liver effects; decreases adipose lipoprotein lipase activity = decrease hepatic production of VLDL’s
- best agent for raising HDL’s
Toxicities: cutaneous flushing & pruritus can occur (mediated by PG release (can be alleviated w/ aspirin or another NSAID)); GI distress & ulcers possible
Inhibitors of bile acid absorption (resins) & examples
Cholestryamine, Colestipol (Colestid)
- one of the oldest & safest drugs used to treat hyperlipidemias
- very large highly positively charged (cationic) resins
- usually used as second agents if statins alone are ineffective
- available as granule packets or tabs (oral); taken w/ meals (bile secretion is highest); insoluble in water (not absorbed by GI tract)
MOA: bind negatively charged bile acids in GI tract lumen (prevents re-uptake in jejunum/ileum; increased bile acid synthesis = decreased liver cholesterol concentration = increased hepatic LDL receptors & increased LDL uptake & clearance from plasma
Toxicities: constipation & bloating (common); drug interactions possible = positive charges on resins
Fibrates (PPAR activators)
Gemfibrozil (Lopid)
MOA: unclear — acts as ligand for nuclear transcription receptor PPAR-alpha*
*found largely in liver, skeletal muscle; increases lipoprotein lipase levels in muscle = decrease in VLDL (and its secretion); modest decrease in LDL’s & moderate increase in HDL’s occur
- considered safe & can be used in combination w/ other lipid lowering agents
AEs: GI discomfort (most common); increases risk of cholesterol gallstones
Inhibitors of cholesterol absorption
Ezetimibe (Zetia)
MOA: inhibits intestinal absorption of phytosterols & cholesterol (targets transport protein in jejunal enterocytes used to uptake cholesterol present in micelles); decreases LDL levels (hepatic LDL receptors increase as LDL’s removed from plasma) — both dietary & biliary cholesterol affected
- excreted in bile following absorption & metabolism
- used primarily as an adjunct w/ statins
- appears very safe
- inhibitors of bile acid absorption may inhibit ezetimibe absorption
Most common treatments for cancer…
Surgery, radiation, chemotherapy
Carcinomas
Cancers of epithelial cells lining the surface of organs
Sarcomas
Cancers of muscle, bone, cartilage, fat, connective tissue
Leukemia
Group of blood cancers, usually originate in bone marrow resulting in underdeveloped blood cells
Lymphoma
Group of cancers that develop from lymphocytes
Blastoma
Cancers that develop from precursor cells or embryonic tissue
80 - 90 % of cancers are of which type?
Carcinomas
- epithelial cells = site of extensive cell proliferation & frequent exposure to chemical/physical damage
Most cancers originate from…
A single aberrant cell = genetic mutation or epigenetic mutation
Tumour progression depends on:
- mutation/epigenetic alteration rate
- selective advantage
- proliferation rate
- invasiveness
Critical cancer genes play a role in…
- DNA proofreading/repair genes
- genes maintaining chromosomal integrity
- oncogenes
- tumour suppressor genes
Oncogene
- gain of function
- mutation in gene regulating cell growth = increase mitosis
- examples: hormones/growth factors, receptors, cell signalling molecules, transcription factors
Tumour suppressor
- loss of function
- mutation in gene that normally suppresses mitosis & cell growth, induces apoptosis or DNA repair
- examples: transcription factors/repressors
Angiogenesis
- larger tumours require oxygen & nutrients
- tumours secrete growth factors to induce blood vessel growth
Metastasis
least understood & most feared aspect of cancer
- detachment of cells from parent tumour
- entry into blood vessel
- exit circulation
- survival & proliferation in new environment
Knowledge of cell cycle & tumour growth kinetics important for…
- design of effective treatments
- understanding lack of drug response
Many drugs are most cytotoxic during which phase of the cell cycle?
S-phase
some effective during M-phase
Most drugs are ineffective in which phase of the cell cycle?
G₀ phase
Growth fraction equals…
% dividing cells sensitive to chemotherapy
________________ tumours stimulate proliferation
Debulking
_________________________ have high growth fraction
Early metastases
____________________ cancers are more responsive
Fast-growing
Several treatment cycles are necessary to ___________________ cells
Synchronize
Chemotherapy kills cancer via _______________ kinetics
First-order (constant %)
10⁹ to 10⁵ = 4 log kill (difference of 10000 times)
Chemotherapy principles
- Cure requires death of ALL tumour cells
- Drugs kill constant proportion of tumour cells
- Tumours detected later = prolonged treatment
- Drugs have narrow therapeutic index
- Drug combinations = increase effectiveness & decrease AEs
- Intermittent high-dose therapy = more effective
- Adjuvant therapy may decrease metastases and/or AEs
Factors influencing patient survival (cancer)
- nature of cancer (type, stage at diagnosis, cell-cycling phase, growth rate, heterogeneity)
- pharmacology (time of initiation & timing of treatment, drug combination)
- patient (general health, tumour blood supply, immune status)
- failure of anticancer drugs (lack of specificity (side effects, dosage limitations), cancer exhibits/develops resistance)
Major sites of toxicity (cancer)
- bone marrow (myelosuppression)
- GI tract (vomiting, nausea, diarrhea)
- hair follicle (alopecia)
- reproductive tract (decreased sperm, menopause, teratogenicity)
- secondary carcinogenicity
Cancer resistance
- natural (some neoplasm cells inherently resistant)
- acquired (mutation —> resistance development)
- multidrug resistance (cells express resistance mechanism that affects multiple drugs (e.g. p-glycoprotein pumps drug out of cell)
Treatment regimen (cancer)
- most often given in combination (synergistic, different MOAs & resistance)
- drugs should be given as frequently & as close to the maximal effective dose as possible
Dosage (cancer)
- generally based on body surface area
- PKs, drug interactions & impact on liver, kidney & immune system taken into account
Patient (cancer)
- type/stage of cancer
- health of patient (renal/hepatic function, bone marrow reserve, concurrent medical problems)
- desire to undergo difficult/dangerous treatment
- ability to cope w/ side effects
- pre-treatment screening
Considerations (cancer)
- long-term gain vs. risk
- probability of successful treatment vs. quality of life
DNA alkylating agents
MOA: transfer alkyl group to cellular constituents; major site of action in DNA — attaches to N7 and/or O6 of guanine
- agents can be monofunctional (alkylate single DNA strand) or bifunctional (alkylate at two locations; cross-link)
proliferating cells are more sensitive
Major classes of DNA alkylating agents
Alkylsulfonates
Methyl/ethylenimines
Nitrogen mustards (cyclophosphamide)
Nitrosoureas
Platinum compounds* (cisplatin)
Triazenes
*technically not alkylating agents, but also bind N7 & cross-link DNA
Cyclophosphamide
- most commonly used alkylating agent
- administered IV or orally; lipid soluble
- prodrug; activated by cytochrome P450
- broad spectrum: used alone or in combo w/ other drugs to treat neuroblastomas, lymphomas, leukemias & colon, breast, ovarian, small cell lung & testicular cancers
less toxic than some alkylating agents due to cellular metabolism of aldophosphamide by ALDH
AEs: dose-dependent GI disturbances, bone marrow suppression, immunosuppression, hair loss, hemorrhagic cystitis (acrolein accumulation); increased risk of sterility, menopause, cancer
Resistance occurs due to…
- reaction w/ other cellular constituents
- increase in metabolism (ALDH, GST)
- increase in DNA repair (e.g. cancer cells w/ high levels of MGMT less susceptible)
Cisplatin
- inorganic metal: covalently binds N7 & O6 of guanine; interacts with cytosine and adenine
- administered IV
- particularly effective for testicular, bladder, ovarian cancer; used to treat lymphomas, sarcomas, and lung carcinomas
AEs: bone marrow suppression, anemia, GI distress (one of most emetogenic chemotherapies), nephrotoxicity, electrolyte imbalances, neurotoxicity (hearing loss, peripheral neuropathy)
Resistance occurs due to…
- decreased access to DNA
- increased DNA repair
Non-covalent DNA binding agents
- antibiotics extracted from soil microbe (streptomyces) — has anti-tumour activity
MOA: form tight drug-DNA interactions (DNA intercalation); free radical DNA damage = DNA unwinding, impaired synthesis, single & double strand breaks — interfering w/ cell proliferation
Bleomycin
- administered through variety of routes (IV, IM, SC), typically in combo with other drugs to treat lymphomas & cervical, ovarian & testicular cancer
MOA: forms DNA-bleomycin-Fe(II) complex that interacts w/ oxygen (oxidation = free radicals; DNA strand breakage & damage of other cellular constituents)
AEs: pulmonary fibrosis, anaphylaxis, GI disturbances, alopecia
Resistance occurs due to…
- increased DNA repair
- increased drug efflux
- increased expression of antioxidants or bleomycin hydrolase
Commonly used regimen of breast cancer chemotherapy that combines which three anti-cancer agents?
Cyclophosphamide, methotrexate, fluorouracil (CMF)
refer to image
Antimetabolites (MOA)
- affect cell proliferation by interfering with DNA & RNA synthesis (interfere with the availability of purines & pyrimidines)
most effective in S-phase of cell cycle
Major classes of antimetabolites
Folate antagonists (methotrexate)
Pyrimidine analogues (5-fluorouracil)
Purine analogues
Sugar-modified analogues
Methotrexate
- usually used in combo with other drugs for a variety of carcinomas, leukemias & lymphomas
- administered orally or via injection (IV, IM, SC, IT)
MOA: enter cells via active transport (folic acid inhibitor: structurally similar to folate & binds to DHF reductase); reduces purine & pyrimidine synthesis = affects RNA, DNA, and protein synthesis
methotrexate-polyglutamate metabolites retained in cells to further inhibit RNA or DNA synthesis
AEs: bone marrow suppression, GI distress, alopecia, liver damage (long-term treatment), renal damage (high dose)
Resistance occurs due to…
- decreased cellular uptake
- increased DHF reductase expression
- decreased binding to DHF reductase
- increased efflux
Drug interactions:
- aminoglycosides decrease methotrexate absorption
- NSAIDS, penicillins, cephalosporins, cisplatin, probenecid decrease methotrexate elimination
5-fluorouracil
- primarily used to treat carcinomas of breast, skin, & GI tract (esophageal, gastric, rectal, anal)
- administered IV or topically
MOA: carrier-mediated transport into the cell; converted to ribosyl & deoxyribosyl nucleotide metabolites & incorporated into RNA & DNA; inhibits TS = decreased thymidine synthesis = decreased DNA synthesis
AEs: bone marrow suppression, GI disturbances, (nausea, vomiting, diarrhea, ulceration), alopecia, cardiotoxicity (angina, arrhythmias), skin irritation
Resistance occurs due to…
- decreased cell uptake
- increased 5-fluorouracil metabolism
- decreased conversion to nucleotide metabolite
- increased TS activity
- prolonged DNA synthesis time (DNA repair)
Dosing concerns:
- under & overdosing
- minimum effective dose & maximum tolerated dose = very close
- monitoring of serum levels being investigated to maximize efficacy & minimize AEs
Chromatin modulators (examples)
Topoisomerase inhibitors
topoisomerase II = transient ATP hydrolysis-dependent double-strand break (re-ligation of DNA); assists w/ DNA replication & transcription
- camptothecins
- anthracyclines (doxorubicin)
- epipodophyllotoxins
- amsacrine
Microtubule inhibitors
plant or synthetic alkaloids; tubulin polymerizes to form mitotic spindles; microtubule half-life decreases = spindle dissolves = cell divides
- vinca alkaloids (vincristine)
- taxanes (paclitaxel)
Doxorubicin
- administered IV & used for leukemias & lymphomas, bladder, breast, stomach, lung, ovarian and thyroid carcinoma, tissue sarcomas & multiple myeloma
MOA: intercalates w/ DNA; binds to & stabilizes topoisomerase II DNA complex to prevent re-ligation of DNA breaks; generates free radicals that damage DNA; inhibits DNA replication & transcription
AEs: cardiomyopathy/heart failure, bone marrow suppression, GI disturbances, alopecia, rash/swelling of hands & feet
Resistance occurs due to…
- increased efflux via P-glycoprotein in cell membrane
- overexpression or mutation of topoisomerase II
Vincristine
- administered IV in combo w/ other drugs to treat some carcinomas (small cell lung, breast), leukemias, lymphomas & neuroblastomas
- kills cells in M-stage of cell cycle
MOA: inhibits tubulin polymerization = dysfunctional spindle
AEs: peripheral neuropathy, nausea, vomiting, alopecia, constipation
Resistance occurs due to…
- altered tubulin structure (mutations)
- altered expression of tubulin isotypes
- increased efflux via P-glycoprotein in cell membrane
Interactions (metabolized by CYP3A4)
- metabolism accelerated by some anti-convulsants & some HIV medications (nevirapine)
- metabolism slowed down by some antifungals (azoles), HIV medications & grapefruit juice
Paclitaxel
- kills cells in M-stage of cell cycle
- primarily used to treat breast, ovarian & non-small cell carcinomas & AIDS-related Kaposi’s sarcoma
MOA: inhibits tubulin depolymerization = overly stable microtubules = cell cannot divide
AEs: hypersensitivity, peripheral neuropathy, bone marrow suppression, alopecia, GI distress, anorexia
Resistance occurs due to…
- altered tubulin structure (mutations)
- altered expression of tubulin isotypes
- increased efflux via P-glycoprotein in cell membrane
Interactions (metabolized by CYP3A4)
- metabolism accelerated by some anti-convulsants & some HIV medications (nevirapine)
- metabolism slowed down by some antifungals (azoles), HIV medications & grapefruit juice
Steroid hormones & antagonists
- useful for cancers w/ steroid hormone-sensitive cells
- must have steroid receptors; hormone-responsive & hormone-dependent
- steroids regulate expression of genes involved in cell growth & proliferation
Prednisone
- used for immune & inflammatory suppression in variety of disorders (oral, inhalation, injection)
MOA: converted to active form (prednisolone) in liver; binds irreversibly to glucocorticoid receptors; can induce apoptosis of leukemic & lymphoid cells
AEs: immunosuppression, hypertension, hyperglycaemia, pancreatitis, weakness, osteoporosis, mood changes
Resistance occurs due to absence or mutation of receptor
Tamoxifen
- SERM: selective estrogen receptor (ER) modulator
- administered orally, metabolized in the liver metabolites behave as antagonists and/or agonist of ERs, depending on the target tissue
- in estrogen-sensitive breast cancer cells: prevents ER-mediated gene expression = decreased tumour growth
- currently used to treat & prevent estrogen-dependent breast cancer
AEs: hot flashes, irregular periods, blood clots, reduced cognition, uterine cancer
______________________ can be used instead of tamoxifen to treat breast cancer because they do not induce _____________________.
Aromatase inhibitors (e.g. anastrozole); uterine cancer
Enhanced efflux occurs through…
Expression of transmembrane protein which enhances excretion of drug from cancer cell
Multi-drug resistance
- efflux pump that affects several drugs
- observed in several cancers: ovarian, breast, prostate, GI tract, lung, neuroblastoma, lymphoma, leukemia
- protein examples: P-glycoprotein, MDR- associated protein (multiple subtypes), lung-resistance protein, breast cancer resistance protein
P-glycoprotein
- aka: MDR1, ABCB1, CD243
- 170 kDa transmembrane ATP-binding transporter expressed in: intestinal epithelium, hepatocytes, pancreatic, renal tubule, capillary endothelial (BBB) cells
- protects cells against toxins but increased expression in tumour cells interferes w/ chemotherapeutic agents
MOA: ATP & drug bind; ATP hydrolysis releases phosphate to shift position of drug = excretion
in some cancer cells
- estrogen down-regulates protein expression of P-glycoprotein
- tamoxifen inhibits efflux of some drugs by P-glycoprotein
- cisplatin or doxorubicin can induce P-glycoprotein expression
Types of breast cancer
Most common:
- ductal - inside milk duct (in situ or invasive)
- lobular - inside milk-producing gland (in situ or invasive)
Rare:
- inflammatory breast cancer
- male breast cancer
Treatment for stage I breast cancer
Surgery
Treatment for stage II (no lymph node involvement) breast cancer
Surgery & radiation
Treatment for stage II (w/ lymph node involvement; less than 4) breast cancer
Surgery and/or radiation & chemotherapy*
*refer to image for several traditional combos
Treatment for stage III & IV breast cancer
Treatment options often considered palliative > curative; some women live several years w/ metastatic breast cancer
Bevacizumab (Avastin)
- targeted therapy
- angiogenesis inhibitor
- approved by FDA in 2008 for use in combo w/ paclitaxel for metastatic breast cancer but withdrawn in 2011
- approved for some metastatic cancers (ovarian, kidney, colon, lung)
MOA: antibody binds VEGF & acts as antagonist of VEGFR2
AEs: inhibition of blood vessel growth for maintenance & healing; hypertension, bleeding
Trastuzumab (Herceptin)
- targeted therapy
- approved for HER2 overexpressing breast cancer; Herceptin & paclitaxel — first-line treatment of HER2 over-expressing metastatic breast cancer
AEs: fever, aches, chills, nausea, and diarrhea; cardiac dysfunction including congestive heart failure (downregulates expression of neuregulin 1 which is involved in the activation of cell survival pathways in cardiac myocytes)
Olaparib
- targeted therapy
- orally administered PARP inhibitor
- metastatic, HER2-negative breast cancer w/ BRCA gene mutation & already had chemotherapy (2018 approval); BRCA mutated advanced ovarian cancer (2014 approval)
AEs: bone marrow suppression, GI disturbances (nausea, vomiting), anorexia, fatigue, muscle & joint pain
Atezolizumab
- immunotherapy
- monoclonal antibody against the PD-L1 protein (blocking allows T cell to kill tumour cell); administered by slow IV infusion (every 2 to 4 weeks)
- triple-negative breast cancer (does not express ER, PR and HER2) - FDA approved 2019; previously approved for some advanced, resistant and/or high PD-L1 expressing lung, bladder & liver cancers
AEs: nausea, anorexia, fatigue, UTI
Structure of a virus
- RNA or DNA
- protein coat (capsid)
- lipid-rich envelope (some viruses)
Viral replication
- Virus attaches to host cell; mediated by proteins on viral surface that bind to host membrane component
- Virus adsorbs/enters host cell membrane
- Virus loses enough capsid proteins (uncoating)
- Nucleic acid becomes available for transcription into mRNAs then undergoes translation on ribosomes
- DNA/RNA replication
- Protein synthesis
- Synthesized viral proteins assemble w/ viral genomes within host cell; followed by viral maturation
- Release from cell by lysis or budding through cell membrane
antiviral drugs target these steps of viral cell cycle
Types of infection (examples)
Acute: smallpox, influenza, rhinovirus, ebola, SARS
Chronic: hepatitis B & C
Latent: herpesviruses
Progressive: HIV
Cancer: HPV, Epstein-Barr
Remdesivir
- first approved antiviral for COVID-19 (authorized w/ conditions in Canada (July 2020))
- administered IV within 7 days of infection (severe cases)
MOA: blocks viral replication; metabolized to nucleoside monophosphate —> triple phosphorylated (ATP analog incorporated into newly synthesized RNA strand = premature termination of RNA product)
AEs: infusion site reactions, low blood pressure, nausea, vomiting, chest tightness, respiratory failure, altered liver enzymes, back pain, echocardiogram abnormalities, renal impairment
Resistance occurs due to…
- mutations in viral RdRP (ATP analog not incorporated into RNA)
Nirmatrelvir/ritonavir (Paxlovid)
- approved for patients w/ mild-moderate symptoms at risk of severe COVID-19 (FDA - Dec 2021; Canada - Jan 2022)
*Nirmatrelvir: inhibitor of Mpro (viral protease in all coronaviruses known to affect humans) —> inhibits viral polyprotein processing
Ritonavir: protease inhibitor (high dose) or booster (low dose) —> slows down metabolism*
AEs: change in taste, muscle aches, swollen joints, headache, blurred vision, changes in heart rate
*Resistance occurs due to…
- multiple mutation identified in SARS-CoV-2 Mpro near its binding site
Oseltamivir (tamiflu)
MOA: inhibits neuraminidase (sialidase); sialic acid analog
neuraminidase cleaves sialic acid on surface of infected host cells to promote release of newly synthesized virus
PK: administered as prodrug, metabolized to active form in liver & GI tract
AEs: nausea, GI discomfort
Clinical uses: prevention & treatment of early infection by many influenza A & B sub-types
Resistance occurs due to…
- mutation in neuraminidase (mutant strains often less virulent)
H1N1 (2009; ~ 1 day sooner in alleviation)
Amantidine
MOA: inhibits proton ion channel (M2) in viral envelope of influenza A —> inhibits H+ transport (necessary for proper viral protein synthesis) —> inhibits uncoating of virus —> inhibits release of viral RNA-protein complex
PK: distributed throughout the body (including CNS); excreted unchanged in kidney
AEs: GI disturbances, CNS disturbances (nervousness, insomnia, difficulty concentrating), renal damage in patients w/ renal insufficiency
Resistance occurs due to…
- mutation in M2 (~50%)
Clinical uses: treatment of early infection by influenza A (not H1N1)
Acyclovir
MOA: guanosine analogue activated by viral thymidine kinase (infected cells most susceptible); triphosphate acyclovir competes w/ dGTP during DNA synthesis —> DNA chain termination (inhibit viral DNA synthesis)
PK: oral, IV or topical formulations; distributed throughout the body (including CNS)
AEs: nausea, vomiting, diarrhea, headache, renal damage (high doses or dehydrated patients, accumulates in patients w/ renal failure)
Resistance occurs due to…
- altered or deficient thymidine kinase
Clinical uses: treatment of active herpes infection
HIV positive
- infected w/ virus
- generally symptom free
- w/o treatment: clinically latency of 2-10 years
AIDS present
- symptoms (opportunistic infections)
- life-span w/o treatment: 1-2 years
HIV infects ___________________ via CD4 & co-receptor. The majority (up to 90%) of newly transmitted HIV uses the _________ co-receptor. ______________ virus emerges in ~ 50-60% of infected individuals; average time to emergence = ______________.
Immune cells (CD4+ T cells, macrophages, dendritic cells); CCR5 (R5-tropic); X4-tropic; 5 years
Treatment of HIV
- first-line treatment (combo of 3 antiviral agents; typically begins w/ 2 NRTIs + 1 of NNRTI/INI/PI)
originally called HAART, now ART or cART
Azidothymidine (AZT)
- nucleoside reverse transcriptase inhibitor (NRTI)
MOA: thymidine analogue activated/phosphorylated by mammalian kinases (viral RT not selective —> competes w/ dTTP during DNA synthesis —> DNA chain termination)
can affect human DNA polymerase at very high doses
PK: well absorbed & distributed (even in CNS); metabolized in liver (glucuronidation)
AEs: bone marrow (anemia, leukopenia), CNS (headaches, seizures)
Drug interactions: drugs that compete for glucuronidation (acetaminophen, benzodiazepines)
Resistance occurs due to…
- RT mutation, inefficient kinase activation
1/3 of patients develop resistance w/ AZT monotherapy
Nevirapine
- non-nucleoside reverse transcriptase inhibitor (NNRTI)
MOA: binds to non-catalytic site & inhibits viral RT
PK: well absorbed & distributed (CNS, fetus, maternal milk), metabolized in liver (oxidation (CYP3A4 & CYP2B6) —> glucuronidation)
AEs: rash, hepatotoxicity
Drug interactions: increased CYP3A4 —> increases metabolism of certain drugs (itself, oral contraceptives, azoles, methadone, protease inhibitors)
metabolism affected by drugs that increase or decrease CYP3A4 or CYP2B6
Resistance occurs due to…
- RT mutation
Raltegravir
- integrase inhibitor (INI)
- initially approved by Health Canada (Nov 2007) for patients w/ ART resistant HIV; now approved for all (decreased viral load earlier in patients taking raltegravir + ART drugs, compared to those taking ART drugs alone)
effect as preventative treatment under investigation
MOA: inhibits viral integrase —> decreases transfer of viral DNA into host genome
Resistance occurs due to…
- viral integrase mutation
Biktarvy (fixed dose drug combination)
Ritonavir
- protease inhibitor (PI)
MOA: inhibits HIV aspartyl protease (cleaves viral polyprotein into specific proteins: Phe-Pro); inhibits CYP3A4 = given at low doses as enhancer of other HIV drugs (including other PIs)
PK: good bioavailability, metabolized by CYP3A4
AEs: GI disturbances, insomnia, hyperglycaemia, metabolic abnormalities (lipid levels, liver enzymes)
Resistance occurs due to…
- mutations in viral protease
Maraviroc
- viral fusion/entry inhibitor
- approved in 2007; decreased viral load in patients w/ maraviroc compared to placebo (all participants received optimized ART)
- indicated for use in individuals w/ R5-tropic virus
MOA: CCR5 receptor antagonist blocks binding of viral gp120 to CCR5 = prevents viral entry
AEs: muscle/joint pain, cold symptoms, dizziness, GI disturbances, rare but potentially serious liver damage & allergic reactions
Parasites of people
- Macroscopic parasites
- taenia species (tapeworms)
- enterobius (pinworm)
- pediculus (head louse) - Microscopic parasites
- entamoeba (amebiasis)
- giardiasis (beaver fever)
- trichomonas (trichomoniasis)
- plasmodium (malaria)
Praziquantel
- cestocidal drug
MOA (exact unknown): binds to parasite integumentary = focal vacuolisation; influx of Ca2+ = muscle contraction (in seconds)
impaired function of hooks & suckers at anterior end = paralysis dislodgement, death
PK: synthetic isoquinoline derivative; systemic bioavailability ~80% after oral dosing
AEs: mild, transient reactions (common) — nausea, headache, abdominal discomfort
Clinical uses: effective against most cestode infections (drug of choice); safe & effective as single oral dose; swallow w/o chewing (bitter taste = retching/vomiting)
Niclosamide
- cestocidal drug
MOA: rapidly kills scolex & segments of adult tapeworms; inhibits mitochondrial anaerobic phosphorylation of ADP = decreased ATP production
PK: salicylanilide derivative; minimally absorbed from GI tract
AEs: minor GI complaints rarely encountered (nausea, vomiting, diarrhea)
Clinical uses: second-line choice for treatment of taenia saginata & taenia solium; single oral dose effective; cheap & readily available in many parts of the world
Mebendazole
- treatment for enterobius vermicularis
MOA: binds to beta-tubulin (inhibits polymerization to microtubules; inhibits parasite motility, glucose uptake, cell division)
slow kill = expelled in feces; efficacy varies w/ GI transit time
PK: benzimidazole (broad spectrum); administered orally (chewable tablets) — less than 10% absorbed
AEs: short term therapy (nearly free of AEs); embryotoxic & teratogenic in animals
Clinical uses: approved for pinworms (treat twice at 2-week interval)
Pyrantel
- treatment for enterobius vermicularis
MOA: “nicotinic anthelmintic”; acts selectively at neuromuscular junction of parasite on nicotinic acetylcholine receptors (release of acetylcholine & inhibition of acetylcholinesterase; paralysis = expulsion)
PK: tetrahydropyrimidine; poorly absorbed from GI tract (activity within)
AEs: mild, transient (nausea, vomiting, diarrhea)
Clinical uses: approved for pinworms (treat twice at 2-week interval)
Permethrin
- treatment for pediculus capitis
- synthetic pyrethroid
- used on nets as mosquito repellent & insecticide; residual activity (2 weeks to 6 months); biodegraded in 1-20 weeks
MOA: causes voltage-gated sodium channels to remain open = membrane depolarization = rapid paralysis
PK: absorption through skin (minimal); rapidly degraded to inactive metabolites in liver; resistance to permethrin in ~50% head lice (USA)
AEs: itching/mild burning sensation of scalp (inflammation of skin in response to agents; can persist for many days after lice are killed)
not significantly ovicidal; more than one application typically required (retreat at 9-10 day interval)
Malathion
- treatment for pediculus capitis; when permethrin fails
- organophosphate
MOA: irreversible inhibitor of acetylcholinestrase (accumulation of acetylcholine = rapid paralysis)
PK: hydrolysed & activated by plasma carboxylesterases much faster in humans than in insects
AEs: itching/mild burning sensation of scalp (inflammation of skin in response to agents; can persist for many days after lice are killed)
not significantly ovicidal; more than one application typically required (retreat at 9-10 day interval)
If living lice on scalp 24+ hours after treatment…
- incorrect use of drug
- hatching of lice eggs after treatment
- re-infestation
- drug resistance
Entamoeba histolytica
Causes the infection amebiasis
Clinical presentations:
- asymptomatic intestinal infection
- mild to moderate colitis
- severe intestinal infection (dysentery)
- ameboma (pseudotumoral lesion)
- liver abscess/other extra-intestinal infection
Amebicidal drugs (chemotherapy):
- luminal (parasites in bowel lumen; used: i) after treatment of invasive intestinal or extra-intestinal amebic disease; ii) for treatment of asymptomatic infections)
- systemic (parasites in intestinal wall & liver)
- mixed (both)
Metronidazole (Flagyl)
- mixed amebicide
- choice for E. histolytica (diarrhea/dysentery) — kills trophozites, not cysts)
- extensive use in treatment of: giardia lamblia, trichomonas vaginalis, anaerobic cocci, anaerobic gram-negative bacilli, pseudomembranous colitis (clostridium difficile)
- not reliably effective for luminal parasites; must be used w/ luminal amebicide (iodoquinol; paromomycin (aminoglycoside))
MOA: some anaerobic protozoal parasites lack mitochondrial activities for generating ATP & disposing of electrons; instead, ferredoxin-like, low redox potential, electron-transport proteins can transfer electrons to nitro groups of metronidazole (cytotoxic reduced products; bind to DNA & proteins)
PK:
- nitroimidazole
- administered orally (readily absorbed; extensive tissue distribution (simple diffusion)
- therapeutic levels in vaginal & seminal fluids, saliva, cerebrospinal fluid
- metabolism (hepatic oxidation by mixed-function oxidase then glucuronylation)
- excreted in urine along with metabolites
- rate of plasma clearance decreases if liver function impaired
- simultaneous treatment w/ inducers of hepatic mixed-function oxidase (e.g. phenobarbital) = enhanced metabolism
- drugs that inhibit hepatic mixed-function oxidase (e.g. cimetidine) = prolonged excretion
AEs: *nausea, *vomiting, headache, abdominal cramps, metallic taste in mouth (common); mutagenic in bacteria (best avoided in pregnant or nursing women)
*if alcohol ingested simultaneously
Iodoquinol
- drug of choice for asymptomatic luminal infections
- active against luminal stages (trophozites & cysts)
- unknown MOA
- side effects: rash, diarrhea, dose-related peripheral neuropathy (including rare optic neuritis)
- long-term use should be avoided
Metastatic infections
usually hepatic abscesses
need to kill parasites within liver abscess, intestinal wall & lumen
- high dosage of metronidazole used to eliminate trophozoites in liver abscess & intestinal wall (not gut lumen)
- followed by iodoquinol to treat intestinal infection & prevent further amebic liver abscesses
Giardia lamblia (“beaver fever”)
- most common intestinal parasitic infection of people
- no tissue development
- two life-cycle stages: i) trophozoite; ii) cyst
- infection (ingestion of cysts) — usually in water
- people-specific & zoonotic genotypes
- many infections = asymptomatic; severe diarrhea can occur
- drug of choice: metronidazole (dosage much lower than for amebiasis — better tolerated; typically not used for asymptomatic infections — self clearance)
Risk factors for infection in humans:
- ingesting contaminated drinking or recreational water
- children in childcare settings
- close contact w/ infected persons/animals, male-male sex
- taking part in outdoor activities
Trichomonas vaginalis
- parasites reside in: i) female lower genital tract; ii) male urethra & prostate
- does not have cyst form; trophozoite replicates by binary fission; does not survive in external environment
Trichomoniasis
- one of most common STIs; symptoms? — women & men
- treatment: metronidazole (single (typically more effective; requires compliance) & multiple dose regimens); resistant? failure! repeat at higher doses; systemic > topical (multi focal nature of infection); simultaneous treatment of sexual partner!!
Malaria
- caused by plasmodium falciparum*, p. vivax, p. malariae, p. ovale
- drug resistance = major prophylactic & therapeutic problem
**only erythrocytic parasites —> clinical illness
*most serious clinical disease = death:
- incubation period — generally 9-14 days; headache, pain in back & limbs, anorexia, nausea, fever, chills, anemia (young children)
- cerebral malaria (severe) — usually ill for 4-5 days w/ fever, slowly lapse into coma (+/- convulsions), mortality = ~15-20%
Drugs that eliminate:
- liver stages = tissue schizonticides
- erythrocytic stages = blood schizonticides
- sexual stages = gametocides
**killed by effective chemoprophylactic agents (before growing in #’s = disease)
Treatment of people w/ clinical malaria:
p. falciparum & p. malariae
- one cycle of multiplication in liver (liver infection ceases < 4 weeks); elimination of erythrocytic parasites cures infection
p. vivax & p. ovale
- dormant hepatic stage (hypnozoite) — not killed by most drugs; must eliminate both erythrocytic & hepatic parasites
Prevention:
- resistance of parasites to drugs is only increasing; no chemoprophylactic regimen is 100% protective!
- counsel people = prevent mosquito bites
Enterobius vermicularis
- most common nematode infection in temperate countries
- transmission: female parasite on perianal skin → pruritus (eggs → hands → ingestion); eggs sticky & can survive long periods in environment; contamination of nightclothes / bedding; eggs → wide dispersal in bedrooms / house
- clinical presentation: most frequent in school age children; most infections asymptomatic; itching → irritability, incontinence, weight loss
- minimise risk of infection: personal hygiene (handwashing, fingernail cleaning, regular bathing); keep bedrooms scrupulously clean & dust free; bed linen / nightclothes (change and launder frequently)
Chloroquine
- chemoprophylaxis if only chloroquine-S parasites in area
- treatment of chloroquine-S P. falciparum
- parasite in RBC: digests host hemoglobin (essential amino acids); polymerizes heme (toxic to parasite) = hemozoin (sequestered in food vacuole)
MOA: unclear; drug concentrated in parasite’s acidic food vacuole; prevent polymerization of heme = hemozoin; oxidative damage (lysis of parasite & RBC)
PK: synthetic 4-aminoquinoline (oral use); rapidly absorbed and distributed to tissues; blood schizonticide; no activity against liver parasites; dealkylated by hepatic mixed function oxidase system (parent drug + metabolites → urine)
AEs: minimal at low doses for chemoprophylaxis; nausea, vomiting, blurred vision (higher doses); dosing after meals decreases AEs
Resistance (very common in P. falciparum) occurs due to…
- mutations in membrane transporter
Mefloquine
Clinical uses: recommended chemoprophylactic drug in areas w/ chloroquine-R P. falciparum; taken weekly per os
MOA: blood schizonticide; no activity against hepatic stages or gametocytes; concentrated in parasite by unknown mechanism; may inhibit heme polymerization = membrane damage
PK: synthetic 4-quinoline methanol (chemically related to quinine); given orally (well absorbed); extensive distribution in tissues (eliminated slowly)
AEs: weekly dosing for chemoprophylaxis — neuropsychiatric toxicities (much publicity); nausea, vomiting, dizziness, sleep and behaviour disturbances; frequency of serious AEs no higher than other anti-malarials?
Contraindications: history of epilepsy, psychiatric disorders
risks of mefloquine use must be balanced with risk of contracting falciparum malaria
Resistance (uncommon except in regions of Southeast Asia w/ high rates of MDR) associated with resistance to quinine and halofantrine, not chloroquine
Doxycycline
Clinical uses: standard chemoprophylactic drug in areas of. Southeast Asia with MDR parasites (including mefloquine-R); administered daily per os; should not be used as a single agent (slow action); commonly used for treatment of P. falciparum in conjunction w/ quinidine or quinine (allows shorter & better tolerated course of these drugs)
MOA: inhibits protein synthesis (as in bacteria); blood schizonticide; not active against liver stages
AEs: infrequent GI symptoms; photosensitivity
