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Pharmacology - PMC 621 > Exam 3 > Flashcards

Exam 3 Flashcards

1
Q

What do anticoagulants do, in general? What are some examples?

A
  • Inhibit fibrin formation
  • Examples:
    • Heparin
    • LMW-Heparin (Enoxaparin, Dalteparin, Tinzaparin)
    • Warfarin
    • Fondaparinux
    • Argatroban
    • Dabigatran
    • Apixaban, Rivaroxaban
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2
Q

What do antiplatelets do, in general? What are some examples?

A
  • Inhibit platelet aggregation
  • Examples:
    • Aspirin
    • Dipyridamole
    • Clopidogrel
    • Abciximab
    • Eptifibatide
    • Cangelor
    • Tirofiban
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3
Q

What do thrombolytics/fibrinolytics do, in general? What are some examples?

A
  • Dissolve (lyse) formed fibrin clots
  • Examples:
    • Streptokinase
    • Alteplase
    • Anistreplase
    • Tenecteplase
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4
Q

What does endo-D-glucuronidase do?

A

Cleaves heparin into various fractions/pieces

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5
Q

What is the mechanism of action of heparin?

A
  • Reversibly binds to AT-III
  • Induces conformational change
  • Makes it 1000x faster for AT-III to irreversibly bind II, X, XI, XII (coagulation factors) and inactivate them
  • Heparin can then unbind from AT-III and bind with another AT-III, to continue its function of inhibiting fibrin formation
  • Heparin binding site - specific pentasaccharide sequence, contains a 3-O-sulfated glucosamine residue which recognizes AT-III, requires a minimum of 18 monosaccharide units to bind AT-III and thrombin
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6
Q

What does AT-III do?

A
  • Antithrombin
  • Irreversibly binds coagulant factors (II, X, XI, XII, etc.) to its Arg-Ser site
  • This inactivates the coagulant factors and prevents them from coagulating
  • Suicide substance - once bound, it will not release the factor
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7
Q

How is heparin is used in vitro and in vivo?

A

In vitro:
* Added to blood in a test tube to prevent coagulation

In vivo:
* Treatment of venous thrombosis and pulmonary thromboembolism
* Patency of IV cannulas, angioplasty, etc.
* CAN be used in pregnant women- dones not cross placenta (discontinue 24 hours before labor)

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8
Q

How is heparin administered? How is it monitored?

A
  • Must be injected either s.c. or IV
    • Immediate effect with IV
    • 1-2 hr onset with s.c.
  • IM is contraindicated d/t painful hematoma
  • Large polar molecule –> will not be absorbed orally
  • Dose is expressed in units (not mg/kg)
  • Monitor activated partial thromboplastin time (aPTT)
    • aPTT assesses intrinsic pathway and Factors I, II, X (common pathway)
    • Heparin increases aPTT 1.5-2.5x longer than normal
    • This is better indicator of dose/effectiveness rather than blood concentration
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9
Q

What are the adverse effects of heparin? What are the contraindications?

A
  • Bleeding
  • Increases lipoprotein lipase activity (lipid clearing effect)
  • Thrombocytopenia - can be either immediate (Type I) or delayed (Type II)
  • Type I:
    • Non-immune mediated platelet-heparin interaction
    • Occurs within 2 days
  • Type II:
    • Immune mediated
    • More severe
    • Begins within 4-10 days (treatment is often needed for 5-10 days)
    • Antibodies form against heparin-platelet factor 4 complex and bind on platelet surface, causing aggregation
  • Monitor platelet count in long term use of unfractionated heparin
  • Can cause osteoporosis if given longer than 6 months

Contraindications
* Bleeding disorder
* Presence of pre-existing bleeding sites

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10
Q

How do you reverse heparin-induced bleeding?

A
  • Reverse with plasma, whole blood or protamine
  • Protamine:
    • Complexes with heparin and prevents it from binding to AT-III
    • Do not use if pt uses NPH insulin, or has a fish allergy
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11
Q

What are LMW-heparins? Why are they important?

A
  • Low molecular weight heparin (fractionated from standard heparin)
  • Includes: Enoxaparin, Dalteparin, Tinzaparin
  • Too small to simultaneously bind AT-III and thrombin
  • Specific for enhancing AT-III ability to inactivate factor Xa
  • Has low affinity for thrombin
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12
Q

What are LMW-heparins used for? How are they administered?

A
  • Used for prophylaxis + acute venous thrombosis (DVT) w/ or w/o pulmonary embolism
  • Used for unstable angina or non-Q-wave MI to prevent thrombus
  • Safer and as effective as using unfractionated heparin
  • Can be used in pregnant women
  • Administer s.c.
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13
Q

How do LMW-heparins compare to (unfractionated) heparin?

A

In favor of LMW-heparins:
* Longer half-life (once a day dosing)
* Can be used outpatient
* Lower incidence of thrombocytopenia
* Less binding to platelet protein
* Predictable response
* Do not have to monitor coagulation
* Monitor with anti-Xa activity

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14
Q

What is Fondaparinux?

A
  • Synthetic pentasaccharide
  • Specific for AT-III inactivation of Factor Xa
  • Administer IV or s.c.
  • Used for prophylaxis and acute DVT
  • Can be used in pregnant women
  • Contraindicated in bleeding or severe renal impairment
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15
Q

How can heparin increase AT-III action with Xa and thrombin, BUT LMW-heparin and fondaparinux cannot?

A
  • LMW and fondaparinux is too short to form complexes with thrombin
  • This makes them more specific for Factor Xa
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16
Q

What is the warfarin mechanism of action?

A
  • Warfarin inhibits the synthesis of biologically-active Vitamin K-dependent clotting factors
    • Inhibits Vitamin K epoxide reductase (VKORC), which increases the levels of Vitamin KO (epoxide) and decreases the levels of Vitamin KH2 (Hydroquinone)
    • Hydroquinone form is needed to convert a clotting factor to its form that can bind calcium
  • Clotting factors are still present but cannot bind calcium
  • Warfarin only works in vivo (does not work when added directly to blood, in vitro)
  • In general, Warfarin inhibits hepatic synthesis of biologically active factors II, VII, IX, X by stopping this pathway
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17
Q

What is Warfarin used for? What are some pharmalogical principles (administration, monitoring, etc.)?

A

Used for:
* Prophylaxis for DVT and pulmonary embolism
* Prosthetic heart valves
* Arterial thromboembolism prophylaxis in atrial fibrillation

  • Activity begins in < 24 hours but takes 5-7 days to gain enough coagulation factors that cannot bind calcium
  • Monitor using INR (Internationally Normalized Ratio) values - standardization of prothrombin time
  • Prothrombin time monitors the extrinsic pathway and some of common pathway
    • “Kit” includes plasma + calcium + tissue thromboplastin
  • Therapeutic goal of INR = 2.0-3.0
    • Heart valve replacement INR = 2.5-3.5
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18
Q

What are the clotting factors of vitamin K dependent coagulation pathway? What are their half lives?

A

Factor II - 2.5 days
Factor VII - 3-5 hours
Factor IX - 25 hours
Factor X - 2-3 days

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19
Q

What is INR?

A
  • INR: International Normalized Ratio
    • (Patient PT/Mean normal PT)ISI
    • ISI: international sensitivity index
  • Citrate plasma is incubated with tissue thromboplastin and calcium
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20
Q

When are adverse reactions most likely to occur when taking Warfarin?

A
  • Changes in absorption and/or metabolism of Warfarin
  • Changes in synthesis and/or catabolism of Vitamin K or coagulation factors (decreased hepatic function)
  • Changes in platelet function
  • Alterations in fibrin degradation
  • Genetic variants in CYP2C9 and VKORC genes (polymorphisms)
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21
Q

How should Warfarin doses be adjusted to account for polymorphisms?

A
  • CYP 2C9 and CYP 2C9*1 are normal
  • Reduce dose by 30% for hetero- and homozygotes of 2C9*2 AND heterozygotes of 2C9*3
  • Reduce dose by 90% for homozygotes of 2C9*3
    • Occurs around 10% in Caucasians and 2% in African/Asians
  • VKORC1 G allele is normal
  • Reduce dose if pt has VKORC1 A allele
    • This allele synthesizes less VKORC1, and therefore, the pt needs less Warfarin
    • Occurs in 37% Caucasions and 14% Africans
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22
Q

What are specific drug interactions or conditions that increase warfarin’s effects? Decrease the effects?

A

Increases Warfarin effects
* Aspirin + ibuprofen
* Decreases platelet aggregation
* Ketoconazole + erythromycin
* Inhibits CYP 3A4
* Cimetidine
* Inhibits CYP 3A4 and 2C9
* Cephalosporins
* Alters GI flora
* Sulfamethoxazole/ trimethoprim
* Binding displacement (Warfarin is 99% bound)
* Causes INR values to increase
* Vitamin K deficiency, hepatic disease, thyroid hormones

Decreases Warfarin effects
* Cholestyramine
* Inhibits absorption
* “Fix” this by staggering the Warfarin and Cholestyramine administration
* Rifampin + Phenobarbital
* Enzyme inducers
* Cigarette smoking
* Combo oral contraceptives
* Excessive ingestion of Vitamine K enriched foods

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23
Q

What are the contraindications of Warfarin?

A
  • Presence of bleeding disorder or bleeding site
  • Pregnancy
    • First trimester - associated with nasal hypoplasia
    • Second + third trimester - Increased risk of fetal death
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24
Q

How do you treat a Warfarin overdose?

A
  • Administer whole blood or plasma
  • Administer Vitamin K1 (phytonadione)
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25
Q

What is Argatroban?

A
  • Directly blocks active site on thrombin
    • Active on free and fibrin bound thrombin
    • Action is independent of AT-III
  • IV administration
  • Used in patients with risk of heparin-induced thrombocytopenia (HIT)
  • Used for treatment and prophylaxis in thrombosis patients
  • Monitor with aPTT
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26
Q

What is Dabigatran Etexilate Mesylate (DEM)?

A
  • Anticoagulant - direct thrombin inhibitor
    • Active on free and fibrin bound thrombin
    • Action is independent of AT-III
  • Oral administration
  • Used for prophylaxis DVT and thromboembolism (atrial fib)
  • Primarily excreted in the urine
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27
Q

What are the chemical principles of DEM?

A
  • DEM (prodrug) is converted to Dabigatran (active) by plasma esterases
  • Converted to 4 different glucuronide metabolites (active)
  • Not a P450 substrate (so it has less drug interactions)
  • Substrate for P-glycoprotein transport
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28
Q

What is the antidote for excessive bleeding caused by DEM?

A
  • Antidote: Idarucizumab
  • Humanized monoclonal antibody that binds to dabigatrin
  • 350x higher affinity for dabigatran than thrombin
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29
Q

What drugs are direct Factor Xa inhibitors? What is their MOA and other pharmacological properties?

A
  • Drugs: Rivaroxaban, Apixaban
  • MOA: Binds directly to Factor Xa and prevents Xa from cleaving prothrombin to thrombin
  • Both drugs are substrates for CYP 3A4 and P-glycoprotein
  • Administration: Oral

Uses:
* Treatment for DVT and embolism
* Prevent DVT following hip or knee replacement surgery
* Reduce risk of srtoke in nonvalvular atrial fibrillation

Side Effects:
* Black box warning- bleeding can be life threatening
* Bruising

Antidote for overdose
* Andexant recombinant factor Xa

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30
Q

When are antiplatelet drugs primarily used?

A
  • Aterial Thrombotic Disease, such as:
    • Transient ischemic attacks
    • Unstable angina
    • History of Myocardial infarction
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31
Q

What is aspirin? What is the MOA and adverse effects?

A
  • Antiplatelet drug
  • MOA: Inhibits platelet prostaglandin formation
    • Irreversible inhibitor of COX-1& COX-2 (acetylates the enzyme)
  • Reduces risk of second heart attack
  • Platelet prostaglandin formation (TXA2 is inhibited by 80-160 mg/day

Adverse effects:
* Bleeding
* GI irritation and ulcers

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32
Q

What is Dipyridamole? What is its MOA and therapeutic use?

A
  • Antiplatelet drug - inhibits platelet aggregation
  • MOA: Inhibits phosphodiesterase, which increases platelet cAMP levels
  • Therapeutic use:
    • Used with other agents, has very little benefit if given alone
    • Given with Warfarin for prevention of thromboembolism in pts with prosthetic heart valves
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33
Q

What is the MOA of P2Y12 receptor inhibitor drugs? What are some examples?

A
  • Drugs: Clopidogrel, Ticagrelor, Cangrelor

MOA:
* Binds to P2Y1 or P2Y12 receptors to inhibit ADP binding
* If ADP binds:
* P2Y1 activation causes TXA2 release, which increases PI hydrolysis and intracellular Ca.
* P2Y12 activation inhibits cAMP formation

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34
Q

What is Clopidogrel? What is its MOA, uses and side effects?

A
  • Antiplatelet drug

MOA:
* Clopidogrel - prodrug
* Metabolized to active thiol metabolite, mediated by CYP 2C19
* Binds irreversibly to ADP P2Y12 receptor on platelets
* Platelets need both P2Y1 and P2Y12 receptors for platelet activation
* Inhibits ADP activation of IIb / IIIa complex needed for platelet aggregation

  • Must generate new platelets to reverse effects
  • Takes 7-14 days for platelet function to return to normal

Uses
* Prophylaxis for thrombosis

Side effects
* Bleeding
* Monitor WBC and platelets
* Thrombocytopenia purpura risk

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35
Q

What is Cangrelor?

A
  • Antiplatelet drug
  • Reversible P2Y12 platelet receptor inhibitor
  • Administered via IV
  • Half-life: 6 minutes
    • Effects reversed in 1 hour
    • Quickly dephosphorylated to the inactive metabolite
  • Used as treatment until oral agent is administered/starts working or during surgery
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36
Q

What are examples of platelet glycoprotein IIb / IIIa receptor antagonists? How are they different?

A
  • Abciximab
    • Monoclonal antibody Fab fragment
    • Binds to IIb / IIIa receptor
    • More effective than Eptifibatide
    • Action lasts longer than the other two (>24 hours)
  • Eptifibatide
    • Peptide derivative
    • Action lasts 4-6 hours
  • Tirofiban
    • Non peptide
    • Action lasts 8 hours
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37
Q

What is the MOA, administration, uses and contraindications of platelet glycoprotein IIb / IIIa receptor antagonists?

A

MOA
* Competitive reversible inhibitors
* Inhibits interactions between Von Willebrand factor and fibrinogen with glycoprotein IIb / IIIa receptor
* Binds to receptor to prevent platelet aggregation and crosslinking with fibrinogen

Uses:
* Acute coronary syndrome (unstable angina)
* Prevents acute Adjunct with Angioplasty

Administration: IV

Contraindications:
* History of hemorrhagic stroke
* Active internal bleeding or GI/genitourinary bleeding in past 6 weeks
* Thrombocytopenia
* Major surgery or trauma in past 6 weeks
* Do not use with Warfarin

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38
Q

What is the thrombolytic/fibrinolytic system? How does it work and how is it naturally regulated?

A
  • Fibrinolytic system is responsible for restricting clot progression beyond a site of injury
    • Also responsible for degrading fibrin during wound healing

How does it work?
* Plasmin - nonspecific protease that degrades fibrin, fibrinogen and other clotting factors
* Plasminogen (in plasma) is the precursor to plasmin
* Converted by t-PA, which is released by endothelial cells
* t-PA binds to fibrin via lysine binding sites and activates bound plasminogen >300x more rapidly than it activates plasminogen in the circulation
* Plasmin action on fibrinogen yields fibrinogen degradation products (FDP) which inhibit further conversion of fibrinogen –> fibrin

Natural regulation of fibrinolysis
* t-PA is inactivated by circulating plasminogen activator inhibitor-1 (PAI-1)
* A2-antiplasmin binds covalently to plasmin at a lysine rich binding site causing inactivation (occurs only with circulating plasmin)
* Lytic state: circulating plasmin > capacity of A2-antiplasmin
* Ideal thrombolytic drug would degrade only desired thrombi and not old fibrin deposits

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39
Q

What is streptokinase and what is its MOA?

A
  • Protein derived from beta-hemolytic streptococci

MOA:
* Combines with 1 molecule of Plasminogen to form a complex
* The complex then converts a second molecule of Plasminogen to plasmin
* Acts of fibrin bound and circulating plasminogen

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40
Q

What is the use, adverse effects and contraindications of streptokinase?

A

Use
* Reperfusion of occluded coronaries following an MI (works best if used within 4-6 hours of chest pain)
* Pulmonary embolism
* DVT
* Arterial thrombosis

Adverse Effects
* 33% of people develop fever
* Bleeding
* Highly antigenic
* Lytic state -
* Excessive bleeding
* Circulating plasmin exceeds capacity of A2-antiplasmin

Contraindications
* Surgery or trauma in past 10 days
* Pre-existing bleeding disorder
* Diastolic pressure > 110 mmHG
* Intracranial trauma

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41
Q

What is anistreplase?

A
  • Streptokinase complexed with human lys-plasminogen
    • Active catalytic center is blocked by an acyl group.
  • Acyl group removed by plasma enzymes
  • Designed to provide more specific binding to thrombi
  • Less lytic state
  • Similar uses and side effects to streptokinase
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42
Q

What is Alteplase t-plasminogen activator (rt-PA)? What is its MOA and therapeutic uses?

A

MOA:
* t-PA has high affinity for fibrin
* Rapidly binds fibrin and activates fibrin-bound plasminogen
* Low activity for circulating plasminogen
* More specific than other agents for lysis of fibrin clot
* Lower incidence of lytic state

Uses
* Reperfusion of coronary arteries in acute MI
* Pulmonary embolism
* Thrombotic stroke (use within 3 hours)

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43
Q

What is tenecteplase?

A
  • Genetically engineered derivative of alteplase
  • Compared to alteplase, teneceteplase has:
    • More specific binding to fibrin
    • More specific resistance to PAI-1
    • Longer half life
    • Higher incidence of reperfusion and functional outcome for ischemic stroke treated at 4.5 hours
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44
Q

What are the common adverse reactions for all thrombolytics?

A
  • Bleeding
    • Inducing a hypocoagulable state
    • Patients bruise very easily
    • Any bleeding is difficult to stop
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45
Q

What is aminocaproic acid, and what does it do?

A
  • Inhibitor of Plasminogen activation and fibrinolysis
  • Lysine analog competes for lysine binding sites on plasminogen and plasmin
    • Inhibits interaction of plasmin and fibrin
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46
Q

What is the difference between HIV and AIDS?

A

HIV:
* Virus that causes HIV infection
* Damages immune system by killing CD4 cells

AIDS:
* Last stage of HIV infection
* As HIV infection advances to AIDS, the amount of HIV in your body increases and the amount of CD4 cells decrease
* Without medicine, HIV progresses to AIDS in 10-12 years

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47
Q

What is PrEP and PEP, in relation to HIV?

A
  • PrEP: pre-exposure prophylaxis (for HIV)
    • Taken every day before possible exposure
    • Can reduce risk of getting HIV from sex by >90%, and from injection drug use by >70%
  • PEP: post-exposure prophylaxis (for HIV)
    • Taken within 72 hours of exposure
    • Can prevent HIV infection when taken correctly, but not always effective
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48
Q

What is Cabenuva?

A
  • First HIV injectable drug regiment
  • Combination of Cabotrgravir and Rilpivirine
  • Injected 1x/month
  • Before beginning Cabenuva: should take cabotegravir and rilpivirine as tablets (oral form)
    • Ensures the medications are well-tolerated before switching to injectable, extended-release formulation

Side Effects
* Injection site reactions, fever, fatigue, headache, MSK pain, nausea, sleep disorders, dizziness, rash
* Should not be used in pts with previous reaction to cabotegravir or rilpivirine, or in pts who are not virally supressed (HIV-1 RNA > 50 copies/mL)S

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49
Q

What is the HIV life cycle?

A
  1. Binding
    • HIV attaches itself to the CD4 receptor of the T4 cell
  2. Fusion
    • HIV cell fuses to the outside of the cell
  3. Reverse transcription
    • HIV carries 2 strands of RNA, which are released after the binding process
    • Reverse transcriptase (viral enzyme) allows RNA to make a DNA copy (called the proviral DNA)
  4. Integration
    • HIV DNA is carried into the host’s nucleus, where the viral enzyme integrase hides proviral DNA until the cells wants to make more proteins (thus, making more HIV)
  5. Transcription
    • Viral DNA separate and special enzymes make complementary mRNA
  6. Translation
    • mRNA is processed and corresponding strand of HIV proteins are made
  7. Viral Assembly + Maturation
    • Long strands of viral proteins are cut up by protease into smaller proteins that serve as enzymes or elements of new HIV
    • Once new HIV is assembled, they bud off and create a new virus
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50
Q

What are the primary goals of antiretroviral HIV therapy?

A
  • Reduce HIV related morbidity and prolong survival
  • Improve quality of life
  • Restore and preserve immunological function
  • Maximally and durably suppress HIV viral load
  • Prevent vertical HIV transmission
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51
Q

What are 4 tests that can be done when determining what HIV treatment to use?

A

CD4 T Cell Count
* Major clinical indicator of immunocompetence in HIV infections
* Usually the single most important decision to initiate therapy
* Strongest predictor of subsequent disease progression and survival
* Repeated every 3-6 months to reassess

Viral Load Testing
* Obtain plasma viral load at initiation, repeated in 2-8 treatment after treatment initiation or alterations in therapy
* Once antiviral regiment is stable, check every 3-4 months

Genotype Assays
* Detect drug resistance mutations in relevant viral genes
* Turnaround is 1-2 weeks after collection

Phenotypic Assays
* Measure the ability of a virus to grow in different concentration of antiretroviral drugs
* Expensive

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52
Q

What are some AIDS defining indications?

A
  • Candidiasis
  • Cytomegalovirus disease
  • Mycobacterium avium complex
  • Wasting syndrome caused by HIV
  • Pneumocystis carinii pneumonia
  • Cryptococcosis
  • Kaposi’s sarcoma
  • Toxoplasmosis of the brain
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53
Q

What are some opportunistic infections in patients with HIV?

A

CD4 Count < 200
* Pneumocystis carinii pneumonia (PCP)
* Px: Bactrim DS daily, or 3x/weekly

CD4 Count < 100
* Toxoplasmosis
* Px: Bactrim DS daily

CD4 Count < 50
* MAI/MAC + CMV (Mycobacterium, Cytomegalovirus)
* MAC Px: Azithromycin 1200mg/week
* CMV Px: Ganciclovir

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54
Q

What are the benefits to early HIV intervention?

A
  • Maintenance of higher CD4 count
  • Prevention of irreversible damage to the immune system
  • Decrease risk of HIV complications
    • TB
    • Kaposi’s sarcoma
    • Peripheral neuropathy
    • Non-Hodgkin’s lymphoma
    • HIV-associated cognitive impairment
  • Decrease risk of non-opportunisitic conditions
    • CAD
    • Renal disease
    • Liver disease
    • Non-AIDS related malignancies and infections
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55
Q

What are some potential drawbacks to early HIV intervention?

A
  • Development of treatment related side effects or toxicities
  • Development of drug resistance
    • Results in loss of future treatment options
  • Decreased time for patient to learn about disease state of HIV
    • Acceptance of new diagnosis
    • Acceptance of lifestyle changes and notification to significant others
  • Decreased amount of time to prepare for acceptance of adherence to therapy
    • Treatment requirements and options
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56
Q

What are the categories of antiretroviral therapy?

A
  • CCR5 Antagonists (entry inhibitor)
  • Fusion inhibitors (entry inhibitor)
  • NNRTIs (non-nucleoside reverse transcriptase inhibitors)
  • NRTIs (nucleoside reverse transcriptase inhibitor)
  • Integrase inhibitors
  • PIs (Protease inhibitors)
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57
Q

What is Cobicistat (Tybost)?

A
  • Booster of HIV treatment
    • Always used in a combo, no antiviral activity itself
    • Often used with Elvitegravir
    • Part of “Quad Pill” - Stribild
  • Potent inhibitor of CYP 3A
    • Pharmacokinetic enhancer of atazanavir or darunavir
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58
Q

CCR5 Antagonists

What is the MOA, key points and adverse effects of CCR5 Antagonists?

A

MOA
* Binds to the CCR5 receptor of the CD4 T-cell
* Inhibits virus entry into cell

Key Points
* Restricted to HIV infected patients that are infected with CCR5 tropic virus

Adverse Effects
* Abdominal pain
* Rash
* Upper respiratory tract infections/cough
* Dizziness/orthostatic hypotension
* MSK symptoms

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59
Q

Fusion Inhibitor

What is the MOA, key points and adverse effects of fusion inhibitor antiviral drugs?

A

MOA
* Interferes with entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes
* Binds to the first HR1 in the gp41 subunit of the viral envelope glycoprotein
* This prevents the conformational changes required for the fusion of viral and cellular membranes

Key Points
* Administrations: s.c. injection
* Cost, inconvenient delivery system, cutaneous toxicity

Adverse effects
* Hallmark adverse reaction: Injection site irritation
* Nodules, erythema
* Hypersensitivity reaction (< 1%)
* Rash, fever, N/V, chills/rigors, hypotension, elevated liver enzymes

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60
Q

What is the MOA and other pharmacological key points of NNRTIs?

A

MOA
* NNRTIs: Non-nucleoside reverse transcriptase inhibitors
* Bind directly to the reverse transcriptase
* Do not need phosphorylation like the NRTIs
* Not incorporated into the viral DNA

Key points
* Quick resistance may develop
* Extensive resistance across the class
* Mandatory to use w/ 2 other active agents
* Long half life
* May lead to one of these drugs exposed to HIV as monotherapy

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61
Q

What are the side effects of NNRTIs?

A
  • Rash
    • SJS, has highest incidence with Nevirapine
    • Frequently occur within first 2-4 weeks of therapy
  • Neuropsychiatric symptoms
    • Most common with Efavirenz
    • Often subsides after 2-4 weeks
    • Dizzy, drowsy, insomnia, abnormal dreams, confusion, abnormal thinking, impaired concentration, amnesia, agitation, hallucinations, euphoria
  • Increased transaminases reported with most NNRTIs
    • Nevirapine > other NNRTI
    • Nevirapine has greatest risk in AVR naive pts
    • 2 week dose tapering can decrease hepatic effects and rash risk
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62
Q

What is the MOA and other key pharmacological key points of NRTIs?

A

MOA
* NRTIs: Nucleotide Reverse Transcriptase Inhibitors
* Phosphorylated intra-cellularly, then incorporate themselves to block reverse transcriptase
* Similar to the building blocks of RNA and DNA

Key points
* Variable metabolism and renal excretion
* Some very high/low
* Food effects on AUC
* Didanosine: decreased 55% by acidity
* Zidovudine: decreased by 24% with high fat food

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63
Q

What NRTIs are affected by food, and how/how much?

A
  • Didanosine - decreased 55% by acidity
  • Zidovudine - decreased by 24% with high fat meal
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64
Q

What is Tenofovir?

A
  • NRTI, but a nucleoTide, instead of nucleoSide
  • Slightly different mechanism allowing continued efficacy against HIV strains resistant to other NRTIs
  • Adverse effects:
    • Lactic acidosis with hepatic steatosis (fatty liver)
    • Decreased bone density
    • Acute exacerbation of hepatitis, if co-infected with Hepatitis B
  • TDF: tenofovir disoproxil fumarate
    • Associated with proximal renaltubulopathy and decreased bone mineral density
  • TAF: tenofovir alafenamide
    • Preferred tenofovir product
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65
Q

What are some example integrase inhibitor drugs? What is their MOA, key characteristics and adverse effects?

A

MOA
* Inhibits strand transfer of viral DNA to host cell DNA

Key points
* Used for HIV pts that have tried other treatment options already (“treatment experienced”)

Adverse effects
* Nausea, diarrhea, headache
* Fever
* Elevated CPK (muscle weakness, rhabdo)

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66
Q

What are the MOA and other key pharmacology principles associated with protease inhibitors (PIs)?

A
  • MOA: Inhibit HIV-1 protease
    • HIV-1 protease is responsible for cleaving large viral polypeptides into smaller functional virons
  • All PIs are cleared via Hepatic oxidative metabolism
  • All are inhibitors of 3A4, to varying degrees
  • Effects of food on PIs are “all over the board”
  • Ritonavir “booster” allows for lower doses of PIs and takes away the “pill burden” for several antivirals
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67
Q

What are the adverse effects of all PI antivirals?

A
  • Endocrine-type side effects
    • Hyperlipidemia
    • Fat metabolism
    • Insulin resistance/diabetes
    • Osteonecrosis
  • Increased risk of spontaneous bleeding
  • Increased risk of hepatitis (drug induced)
  • In some studies, PIs are associated with MIs and strokes
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68
Q

What is Ritonavir?

A
  • HIV booster
  • Allows for lower dose of HIV antiviral or less “pill burden”
  • Associated with increased LDL, TG, HDL
  • Adverse effects: paresthesias, taste disturbances/anorexia
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69
Q
A
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70
Q

S-phase specific drugs

A

Cytosine arabinoside
Hydroxyurea

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71
Q

S-phase specific self-limiting drugs

A

6-mercaptopurine
Methotrexate

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72
Q

M-phase specific drugs

A

Vincristine
Vinblastine
Paclitaxel

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73
Q

Cell cycle non-specific drugs

A

Alkylating drugs
Nitrosoureas
Antitumor antibiotics
Procarbazine
Cisplatin
Decarbazine

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74
Q

Nitrogen mustard alkylating agents

A

Mecholrethamine
Cyclophosphamide
Ifosfamide
Melphalan
Chlorambucil

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75
Q

Nitrosourea alkylating agents

A

Carmustine
Streptozocin
Bendamustine

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76
Q

Alkyl sulphonate alkylating agents

A

Busulphan

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77
Q

Atypical alkylating agents

A

Procarbazine
Dacarbazine
Temozolomide

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78
Q

MOA of alkylating agents

A
  1. Activation
    • Nucleophilic attack of unstable aziridine ring by electron donor
  2. Mispair substitution
    • Modified guanine can mispair with thymine residues during DNA synthesis, leading to substitution of thymine for cytosine
  3. Excision
    • Alkylation creates lability in the imidazole ring, leading to opening of the ring and excision of the damaged guanine residue
    • Mispairing and imidazole ring opening can lead to attempts to repair the damaged stretch of DNA, causing strand breakage
  4. Cross-linking two nucleic acid chains
    • Bifunctional alkylating agents (like nitrogen mustards) can undergo a similar cyclization reaction and alkylate a second guanine residue or another nucleophilic moiety, resulting in the cross-linking of two nucleic acid chains or linking the nucleic acid to a protein
  • Lethality of DNA alkylation depends on the recognition of the adduct, the creation of the DNA strand breaks by repair enzymes, and an intact apoptotic response
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79
Q

Cyclophosphamide

A
  • Prodrug. Requires in vivo activation by CYP 2B
  • Byproduct is a toxic metabolite called acrolein. Causes hemorrhagic cystitis, which reacts with the bladder wall
  • Side effects caused by acrolein can be prevented with co-administration of 2-mercaptoethanesulfonate (conjugates acrolein in urine)
  • Can cause SIADH
  • Used for: Non-hodgkins, ovarian, breast cancer
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80
Q

Ifosdamide

A
  • Analog of cyclophosphamide
  • Requires in vivo activation by CYP 3A4
  • Common component of high-dose chemotherapy (HDC) with stem cell rescue
  • Toxicity similar to cyclophosphamide
  • Highly neurotoxic, can be prevented with methylene blue
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81
Q

Busfulphan

A
  • Primarily a myelosuppressive agent used for CML
  • Replaced by imatinib mesylate (GLEEVEC)
  • Common after high dose - VOD and pulmonary fibrosis
  • Used in combo with cyclophosphamide to prepare for bone marrow transplantation
  • Suppresses all blood elements, particularly stem cells
  • Produces prolonged and cumulative myelosuppression lasting months. (With myelosuppression comes immune suppression)
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82
Q

Nitrosoureas - carmustine and lomustine

A
  • Important component of CNS malignancies
  • Highly lipophilic
  • Highly carcinogenic and mutagenic
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83
Q

Streptozocin

A
  • High affinity for B-cells in the pancreas
  • Used for inducing insulin-dependent diabetes in experimental animals
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84
Q

Common toxicities and adverse effects among alkylating agents

A
  • All - highly toxic to dividing mucosal cells and to hair follicles, leading to oral mucosal ulceration, intestinal denudation, and alopecia
  • Nitrogen mustards - nausea and vomiting
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85
Q

Melphalan

A
  • Multiple myeloma
  • Nitrogen mustard alkylating agent
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86
Q

Chlorambucil

A
  • Standard for chronic lymphocytic leukemia
  • Nitrogen mustard alkylating agent
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87
Q

MOR to Alkylating Agents

A
  • Decreased permeation of actively transported drugs (mechlorethamine, melphalan)
  • Increased intracellular concentrations of nucleophilic substances (mostly thiols such as glutathione), which can conjugate with/detoxify electrophilic intermediates
  • Increased activity of DNA repair pathways
  • **Increased rates of metabolic degradation of the activated forms of cyclophosphamide and ifosfamide
  • Impaired apoptotic pathways, with overexpression of bcl-2 as an example
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88
Q

Platinum coordination complexes

A
  • Cisplatin, carboplatin, oxaliplatin
  • Part of the alkylating agents superfamily
  • Bind to nucleophilic sites on DNA and cause DNA damage, similar MOA to alkylating agents
  • Mutagenic, carcinogenic, teratogenic
  • Inside cell, chloride is replaces by water and the drug is activated. High concentrations of chloride stabilize the drug, reducing its cytotoxicity
89
Q

Cisplatin

A
  • Very useful for solid tumors: testicular, ovarian, head/neck, lung cancers
  • Milder myelosuppression than alkylating agents
  • Can cause severe CNS toxicity - nausea, vomiting, peripheral neuropathy
  • Nephrotoxicity and ototoxicity - nephro can be reduced by chloride diuresis, oto cannot
90
Q

Antimetabolites

A
  • Designed to block DNA synthesis
  • Based on idea that cancer cells divide more rapidly than normal cells, so more vulnerable
  • Many antimetabolites produce cell death by triggering apoptosis (cytotoxic)
  • Most are nucleoside analogs that interfere with DNA synthesis or block methylation of uracil to thymidylate
91
Q

Folic acid analogs - antimetabolites

A

Methotrexate
Pemetrexed
Trimetrexate

92
Q

Pyrimidine analogs - antimetabolites

A

Fluorouracil
Cytarabine
Gemcitabine

93
Q

Purine analogs (and related inhibitors) - antimetabolites

A

Mercaptopurine
Pentostatin

94
Q

Folate

A
  • Essential dietary factor, from which THF cofactors are formed, which provide single carbon groups for the synthesis of precursors of DNA and RNA
  • DHFR enzyme reduces folate to dihydrofolate and then to tetrahydrofolate
95
Q

Methotrexate and Pemetrexed MOA

A
  • Inhibits dihydrofolate reductase (DHFR) to block biosynthesis of thymidylic acid and purines (which decreases DNA synthesis)
  • Directly inhibits thymidylate synthase, GAR formyltransferase, AICAR formyltransferase
  • Affinity of MTX for DHFR is much higher than folate, so it can selectively bind to DHFR and inhibit it
  • S phase-specific self-limiting
96
Q

Leucovorin

A
  • Citrovorum, folinic acid
  • Minimizes toxic effects of folate depletion (due to MXT and PEM)
  • Bypasses the metabolic block induced by MTX, but does not diminish anti-tumor activity
  • Potentiates 5-FU
97
Q

Methotrexate - Uses

A
  • Critical drug for childhood ALL
  • Intrathecal administration in adults for meningeal leukemia or lymphoma
  • High dose MTX with leucovorin rescue (HDM-L) is used in osteosarcoma
  • Non-neoplastic uses: disabling psoriatic or rheumatoid arthritis
98
Q

Pemetrexed - Uses

A
  • Particularly useful for mesothelioma
  • Many similar uses as MTX
99
Q

Methotrexate - Toxicity

A
  • Limited neurotoxicity (polar compound, cannot cross BBB)
  • Chronic administration for non-neoplastic indications can cause hepatic fibrosis
  • Reduce dose in ptns with renal dysfunction
  • Severe myelosuppression
  • Mucositis and GI toxicity
  • MTX Glu2-5 are retained in hepatic and renal tissues for long periods of time, causing prolonged suppression of DHF in these cells
100
Q

Methotrexate - MOR

A
  • Increased cellular DHFR
  • Altered DHFR
  • Reduced conversion to polyglutamate form
  • Efflux of the drug from the cell
101
Q

Pyrimidine analog MOA

A
  • Either inhibit nucleotide synthesis or get incorporated into the DNA (thus blocking its function)
  • Small structural modifications of the base and deoxyribonucleoside to create each drug
102
Q

5-FU and Capecitabine MOA

A
  • Capecitabine is a prodrug with little pharmacologic activity until it is converted to 5-FU by thymidine phosphorylase
  • 5-FU activated by complex series of enzymatic reactions, to ribosyl and deoxyribosyl nucleotide metabolites
  • FdUMP (metabolite) forms a covalently bound ternary complex with enzyme TS and reduced folate 5,10-methylenetetrahydrofolate
  • This results in inhibition of DNA synthesis through “thymineless death”
  • FUTP (metabolite) is incorporated into RNA, where it interferes with RNA processing and mRNA translation
  • FdUTP (metabolite) can be incorporated into cellular DNA, resulting in inhibition of DNA synthesis and function
103
Q

5-FU + leucovorin - Uses

A
  • Used in colorectal and gastric cancer treatments
  • Combination with platinum compounds dramatically increases efficacy in colorectal cancers
  • May also be used in combo regimens for metastatic breast cancers
104
Q

Pyrimidine analogs - Toxicities

A
  • 5-FU: myelosuppression, alopecia, dermatitis, nausea, vomiting
  • Capecitabine: similar profile as 5-FU, but also increased incidence of hand-and-foot syndrome (tingling/burning/numbness, redness/swelling, flaking/peeling skin, small blisters, sores/breaks in skin, discomfort, pain)
105
Q

Cytidine analogs - MOA

A

Either inhibit nucleotide synthesis or get incorporated into the DNA (thus, blocking its function)

106
Q

Cytarabine (Cytosine Arabinoside, Ara-C)

A
  • Most important antimetabolite used in therapy of AML. Single most effective agent for induction of remission in this disease
  • Potent myelosuppressive agent capable of producing acute, severe leukopenia, thrombocytopenia, and anemia with striking megaloblastic changes
  • Enters cells using hENT1 (nucleoside transporter)
  • Ara-C must be activated to Ara-CMP and eventually Ara-CTP
  • Ara-CTP competes with physiological substrate dCTP for incorporation into DNA by DNA polymerase
  • Incorporated Ara-CMP residue is a potent inhibitor of DNA polymerase, both in replication and repair synthesis, and blocks the further elongation of the nascent DNA molecule
107
Q

Gemcitabine

A
  • Important drug for ptns with metastatic pancreatic; non-squamous, non-small cell lung; and bladder cancer
  • Principle toxicity is myelosuppression. Longer duration infusions = greater myelosuppression and hepatic toxicity
  • Hemolytic uremic syndrome - can occur in rare cases
108
Q

Purine analogs MOA

A
  • Either inhibit nucleotide synthesis or get incorporated into the DNA (thus, blocking its function)
  • Uses HGPRT enzyme in purine salvage pathway to inhibit de novo purine biosynthesis
109
Q

Azathioprine

A
  • Rarely used to treat cancer
  • Most commonly used as an immunosuppressant
  • Prodrug. Must be converted to active metabolite 6-mercaptopurine
  • MOA - drug metabolism results in the incorporation of thiopurine analogs into the DNA structure, causing termination and cytotoxicity
110
Q

6-Mercaptopurine

A
  • Active drug form of Azathioprine
  • Used mostly for treatment of childhood acute myeloid leukemia (AML)
  • Significant toxicity: Myelosuppression
  • S phase-specific self-limiting
111
Q

6-Thioguanine

A
  • Acute lymphoblastic leukemia (ALL)
  • Acute myelogenous leukemia (AML)
  • Myelosuppression
112
Q

Pathway of mosquito-spread diseases

A
  1. Infected mosquito injects sporozoites (when biting a human)
  2. Sporozoites migrate to liver where they form merozoites.
  3. Merozoites are released and invade red blood cells
  4. Rupture of red blood cells release merozoites which can infect other red blood cells.
  5. Female mosquito picks up gametocytes from infected individuals.
113
Q

Drugs that are effective against erythrocytic form (antimalarial)

A

Chloroquine
Quinine
Mefloquine
Pyrimethamine
Chloroguanide

114
Q

Drugs that are effective against gametocytic form (antimalarial)

A

Primaquine

115
Q

Drugs that are effective against exoerythrocytic form

A

Primaquine

116
Q

Suppressive therapy vs clinical cure vs radical cure

A
  • Suppressive therapy: elimination of parasite form responsible for acute symptoms. Does not prevent infection b/c the sporozoites survive and invade the liver with the development of liver-stage parasites
  • Clinical: removal of all parasites from blood
  • Radical: elimination of all parasite forms from the body
117
Q

Chloroquine - MOA, Uses

A
  • MOA
    • Targets blood stage of parasites
    • Inhibitor of the production of hemozoin
    • CYP 2D6 inhibitor
  • Uses
    • Asexual and erythrocytic forms of susceptible parasites
    • Moderate activity against gametocytes
    • Used as chemoprophylactic drug in regions which report chloroquine-sensitive disease
  • No longer primary cure for Malaria due to resistance
  • Not recommended for ptns with epilepsy or myasthenia gravis
118
Q

Chloroquine - Adverse Effects

A
  • Headache, nausea, vomiting, blurred vision, dizziness, fatigue, confusion
  • Rare: depigmentation of hair, corneal opacities, hematological disorders, exacerbation of psoriasis, dose-related retinopathy, hemolysis of G6PD deficient ptns
  • CYP 2D6 inhibitor
  • Not recommended for treating ptns with epilepsy or myasthenia gravis
  • Contraindicated in psoriasis and retinal disease
119
Q

Primaquine

A
  • MOA
    • Not completely understood
    • Targets liver stage parasites, eliminates hypnozoites, gametocytocidal
    • May be acting by generating free radical reactive oxygen species, which kill the parasite
  • Uses
    • Only agent available for treating hepatic primary and hypnozoite forms of P. vivax and P. ovale in liver (radical cure)
    • Used after chloroquine treatment or shortly before/right after chloroquine prophylaxis ends
  • Toxicity
    • Low incidence of toxic side effects in most ptns
    • Mild abdominal distress, methemoglobinemia, hemolysis in G6PD deficient ptns
120
Q

Quinidine

A
  • MOA
    • Not completely understood, may be similar to chloroquine
  • Drug of choice for parenteral therapy in chloroquine-resistant P. falciparum
  • Being replaced by oral and parenteral artemisinins
  • Adverse Effects
    • EKG changes, hypotension
121
Q

Mefloquine

A
  • MOA
    • Targets blood stage parasites
    • Targets 80S ribosome to inhibit protein synthesis in parasites
    • Forms complex with heme, which is toxic to parasites
  • Use
    • Useful chemoprophylactic agent for travelers spending weeks-years in areas where infections are endemic
  • Toxic effects
    • Vivid dreams, neuropsychiatric symptoms in 10% ptns
    • Short-term: nausea, vomiting, dizziness
    • May cause CNS toxicity in ptns with malaria - seizures, confusion, acute psychosis, disabling vertigo
122
Q

Pyrimethamine (+/- sulfadoxazine)

A
  • MOA
    • Binds to and reversibly inhibits DHFR in the parasite (folate synthesis enzyme)
  • Used against P. malariae and Toxoplasma gondii
  • Adverse Effects
    • Hypersensitivity and hematologic reactions
    • Anemia due to decrease in folic acid (leucovorin rescue to help)
123
Q

Atovaquone-proguanil (Malarone)

A
  • Used for malaria chemoprophylaxis and treatment of uncomplicated P. falciparum malaria in adults and children
  • Effective against asexual blood forms and liver stages of P. falciparum (not P. vivax).
  • Moderate activity against gametocytes
  • Atovaquone - mitochondrial toxicant in parasites
  • Proguanil - in cyclic active form, inhibits dihydrofolate-thymidylate synthase (which decreases DNA synthesis)
124
Q

Artemisinin and derivatives

A
  • MOA
    • Targets liver stage parasites, gametocyte-killing activity
    • Production of free radicals
    • Binds covalently to malaria proteins and damage the parasite
    • Produces toxic heme adducts and oxidant stress
  • Use
    • Generally not used alone, but in combo with other drugs for treatment of severe P. falciparum malaria
    • Not for chemoprophylaxis
125
Q

Malaria prophylaxis drugs

A
  • Chloroquine (or hydroxychloroquine) - restricted to areas with chloroquine-sensitive malaria
  • Mefloquine - areas with mefloquine-sensitive malaria
  • Atovaquone-proguanil (Malarone) - all areas
  • Primaquine - short stays in areas with P. vivax; anti-relapse therapy for P. vivax and P. ovale
126
Q

Giardiasis - Giardia Intestinalis

A
  • Symptoms
    • Diarrhea, foul-smelling greasy stools, abdominal cramps, flatulence, fever, malaise
  • Treatment
    • Metronidazole
    • Paromomycin
    • Tinidazole
    • Nitazoxanide
127
Q

Amebiasis - Entamoeba species

A
  • Prevalence
    • Highest in people who are institutionalized, have AIDS, foreign travel, immigrants/migrant workers
  • Presentation
    • Abdominal cramping, bloody diarrhea
    • Right side pain
    • Hepatomegaly - suggests liver abscess
128
Q

Amebiasis Transmission in Humans

A
  1. Ingestion of cysts
  2. Formation of trophozoites
  3. Penetration of intestinal wall
  4. Multiplication of trophozoites
  5. Systemic invasion
  6. Cysts discarded with feces
129
Q

Drugs that target luminal amebicide phase

A

Diloxanide furoate
Paromomycin
Tetracycline
Iodoquinol

130
Q

Drugs that target mixed amebicide (luminal and systemic activity) phase

A

Metronidazole
Tinidazole

131
Q

Drugs that target systemic amebicide phase

A
  • (Drugs that treat liver abscesses and intestinal wall infections)
  • Bowel wall only
    • Tetracycline
    • Erythromycin
  • Liver only
    • Chloroquine
  • Other
    • Emetine
    • Dehydroemetine
132
Q

Metronidazole

A
  • MOA
    • Systemic and luminal activity (mixed)
    • Metabolites of metronidazole bind to DNA and protein of parasite, generating ROS
  • Adverse effects:
    • Abdominal cramping, constipation, metallic taste
    • Inhibits alcohol aldehyde dehydrogenase (no alcohol can be consumed with metronidazole)
133
Q

Iodoquinol

A
  • Luminally active - eradicates luminal trophozoite and cyst forms of E. histolytica
  • Adverse Effects
    • Abdominal cramps, diarrhea
    • Seizures, encephalopathy
    • Dose-dependent peripheral neuropathy
134
Q

Paromomycin

A
  • Only effective against luminal forms of E. histolytica and tapeworm
  • Adverse effects - abdominal cramps, potentially nephro- and oto- toxic
135
Q

Leishmaniasis

A
  • Intramacrophage protozoa of genus Leishmania
  • Transmitted to humans by female sandfly
  • Cutaneous, mucocutaneous, visceral forms
  • Drugs of choice:
    • Sodium Stibogluconate - all Leishmania
    • Miltefosine - Cutaneous, Mucocutaneous, Visceral
    • Liposomal Amp B - Visceral
    • Paromomycin - Cutaneous, Visceral
136
Q

Chagas Disease (American Trypanosomiasis)

A
  • Transmitted by blood-sucking triatomine bugs
  • Acute phase - usually no symptoms, but sometimes fever, rashes, diarrhea, spleen enlargement
  • Chronic phase - irregular heartbeat, enlarged esophagus, heart failure, cardiac arrest
  • Drugs of choice
    • Nifurtimox, Benznidazole
    • Both agents suppress parasitemia and cure the acute phase
    • Both must be taken for long periods
137
Q

Sleeping sickness (African Trypanosomiasis)

A
  • Transmitted by Ts-tse fly
  • Stage 1: parasites detected in blood and lymph; no CNS involvement
  • Stage 2: CNS involvement, inflammation of brain and spinal cord, leading to lethargy and continuous sleep
  • Drugs of choice
    • Pentamidine, Suramin - Stage 1
    • Melarsoprol - CNS involvement
    • Nifurtimox/eflornithine combo (NECT) - Stage 2
138
Q

Toxoplasmosis (Toxoplasma gondii)

A
  • Can contract by:
    • Ingestion of undercooked meat and contaminated vegetable-containing tissue cysts
    • Direct oral contact with feces of cats shedding oocysts
    • Transplacental fetal infection with tachyzoites from acutely infected mothers
  • Drugs of choice
    • Pyrimethamine + sulfadiazine
    • Alternative - Pyrimethamine + clindamycin
    • Spiramycin - for acute acquired toxoplasmosis in early pregnancy
139
Q

Mebendazole (Vermox)

A
  • Drug of choice for Pinworm, roundworm, whipworm, hookworm
  • MOA
    • Selectively binds to helminthic tubulin and blocks microtubule assembly in helminths
    • Inhibits glucose uptake, resulting in immobilization and death
  • Adverse effects - sometimes abdominal pain, but relatively no side effects at normal doses
140
Q

Strongyloidiasis - treatment

A
  • Strongyloidiasis - Threadworm
  • Drug of choice - Ivermectin
  • MOA
    • GABA receptor agonist
    • GABA controls neurotransmission by sending inhibitory signals to motor neurons
    • Ivermectin potentiates these inhibitory signals, and causes paralysis in threadworms
  • Adverse effects
    • Minimal - GI complaints, drowsiness
141
Q

Trematodes (flukes), Cestodes (tapeworms, flatworms) - treatment

A
  • Praziquantel is used to treat all forms of schistosomiasis (flatworms)
  • MOA - increased trematode cell membrane permeability to calcium, causing paralysis of organism
  • Adverse effects - general ill feeling, headache, dizziness, nausea, stomach discomfort, fever, rash
142
Q

Drug(s) of choice for: Enterobiasis

A
  • Enterobiasis - Pinworm

Pyrantel pamoate
Mebendazole
Albendazole

143
Q

Drug(s) of choice for: Ascariasis

A
  • Ascariasis - Roundworm

Pyrantel pamoate
Mebendazole
Albendazole

144
Q

Drug(s) of choice for: Filariasis

A

Diethylcarbamazine

145
Q

Drug(s) of choice for: Trichuriasis

A
  • Trichuriasis - Whipworm

Mebendazole
Albendazole

146
Q

Drug(s) of choice for: Hookworm

A

Albendazole > Mebendazole, Pyrantel pamoate

147
Q

Drug(s) of choice for: Strongyloidiasis

A
  • Strongyloidiasis - Threadworm

Ivermectin
Alternative - Thiabendazole

148
Q

Causes of Gout

A

Idiopathic
Renal clearance mechanisms
Increased nucleic acid turnover
Specific enzyme effects
Local factors
Possible tissue factors

149
Q

Non-pharmacologic treatments for gout

A
  • Avoid obesity and exercise regularly
  • Avoid eating food with high purine content
  • Avoid dehydration
    • Dehydration increases uric acid in serum and can promote urate crystal formation
  • Avoid alcohol
    • Decreased alcohol dehydrogenase can increase levels of uric acid in serum
    • Alcohol promotes lactate formation and decreases pH, which can accelerate urate crystal formation
150
Q

Colchicine - MOA, pharmacokinetics

A
  • MOA
    • Causes cell cycle arrest
    • Depolymerization of microtubules of neutrophils
    • Alters neutrophil motility and chemotaxis
    • Inhibits inflammasome activation
  • Pharmacokinetics
    • Mediated by CYP 3A4
    • Substrate for P-glycoprotein
    • Drug accumulates in liver, kidney, spleen
    • Do not co-administer with CYP 3A4 or P-glycoprotein inhibitors
151
Q

Colchicine - Uses, Administration

A
  • Two consecutive courses should be done at least 3 days apart
  • Ptns with hepatic or renal disease - reduce dose
  • Very effective in acute attack (flare) of gout
  • Prophylactic agent to prevent recurrent attacks of gout
152
Q

Colchicine - Adverse Effects

A
  • GI toxicity - nausea, vomiting, diarrhea, abdominal pain
  • Acute toxicity - multifocal gastric mucosal hemorrhage
  • Myelosuppression, leukopenia, granulocytopenia, thrombopenia, aplastic anemia, rhabdomyolysis
  • Rare - hair loss, corneal opacities, hematological disorders, rash/hives, hemolysis in G6PD deficient ptns
  • Should not be used with CYP 3A4 or P-glycoprotein inhibitors
153
Q

Allopurinol

A
  • Uses
    • Chronic gout, secondary hyperuricemia
    • Often combined with colchicine
    • Used with anti-cancer drugs to prevent hyperuricemia
  • Adverse effects
    • Rash, fever, vasculitis
    • Hepatotoxicity, bone marror toxicity
154
Q

Febuxostat (Uloric)

A
  • Inhibitor of xanthine oxidase
  • Uses
    • Gout attacks
    • Not recommended for treatment of asymptomatic hyperuricemia
  • Adverse effects
    • Rash, nausea, joint pain, liver function abnormalities
155
Q

Rasburicase

A
  • Recombinant urate oxidase (uricase enzyme)
  • Uses
    • Decrease elevated urate levels in pediatric/adult cancer ptns
    • Efficacy can be reduced by presence of autoantibodies
    • Newer uricase agent - Pegloticase - is less immunogenic
  • Adverse Effects
    • Vomiting, fever, nausea, headache, abdominal pain, constipation, diarrhea, mucositis
    • Do not give to ptns with G6PD deficiency
    • Acute renal failure, anaphylaxis
156
Q

Uricosuric Agents

A
  • Probenecid, Lesinurad
  • MOA
    • Probenecid - inhibit reabsorption of urate by URAT-1
    • Lesinurad - inhibit reabsorption of urate URAT-1 and OAT-4 transporters
    • Increase urate excretion, and increase uric acid concentration in urine
  • Adverse Effects
    • May cause attack of gout
    • May cause formation of intrarenal stones
    • GI irritation, peptic ulcers
157
Q

NSAIDs and Glucocorticoids for gout

A
  • Decreases inflammation
  • Reduces pain in acute gout attacks
  • NSAIDs preferred over colchicine to combat gout
  • Preferred in elderly ptns w/ cardiac, renal or GI complications
158
Q

Allergic, idiosyncratic, pseudoallergic

A
159
Q

Macules

A
160
Q

Papules

A
161
Q

Nodules

A
162
Q

Vesicles and Bullae

A
163
Q

Plaque

A
164
Q

Risk factors of drug allergies

A
165
Q

Gell and Coombs Classification

A
166
Q

Anaphylaxis

A
167
Q

Serum Sickness

A
168
Q

Drug Fever

A
169
Q

Jarisch-Herxheimer Reaction (JHR)

A
170
Q

Systemic Lupus Erythematosis

A
171
Q

Interstitial Nephritis

A
172
Q

Hepatic Hypersensitivity Reaction

A
173
Q

Vasculitis

A
174
Q

Maculopapular/Morbilliform Rash

A
175
Q

Urticaria / Angioedema

A
176
Q

Fixed Drug Eruption

A
177
Q

Phototoxicity

A
178
Q

Eczematous Contact Dermatitis

A
179
Q

Erythema Multiforme

A
180
Q

Stevens Johnson Syndrome (SJS)

A
181
Q

Toxic Epidermal Necrolysis

A
182
Q

Pulmonary Drug Reactions

A
183
Q

Eosinophilia

A
184
Q

Aplastic Anemia

A
185
Q

Hemolytic Anemia

A
186
Q

Thrombocytopenia

A
187
Q

Agranulocytosis

A
188
Q

What are the three signals required for T cell activation?

A
189
Q

Site of Action

Glucocorticoids
Cyclosporine
Tacrolimus

A
190
Q

Site of Action

Azathioprine
Mycophenolate mofetil
Sirolimus
Everolimus

A
191
Q

Site of Action

Belatacept
Alemtuzumab

A
192
Q

Site of Action

Muromonab-CD3
Daclizumab, basilixmab

A
193
Q

MOA

Glucorticoids

A
194
Q

MOA

Cyclosporine

A
195
Q

MOA

Tacrolimus

A
196
Q

MOA

Anti-metabolites

A
197
Q

MOA

Azathioprine

A
198
Q

MOA

Mycophenolate Mofetil

A
199
Q

MOA

mTOR inhibitors (Rapamycin)

A
200
Q

MOA

Abatacept, Belatacept

A
201
Q

MOA

Muromonab CD3

A
202
Q

MOA

Basiliximab, Daclizumab

A
203
Q

Anti-TNF alpha drugs

A
204
Q

MOA

Tocilizumab

A
205
Q

Azathioprine drug-drug interaction

A
206
Q

Cyclosporine, tacrolimus: drug-drug interactions

A
207
Q

Drug specific side effects

Cytokine release syndrome
Anaphylactic reactions
Gingival hyperplasia, hirsutism

A
208
Q

Side effects

Myelosuppression
Hyperlipidemia
Neurotoxicity

A
209
Q

Side effects

Nephrotoxicity
Hypertension
Posttransplant diabetes
Delayed graft function

A
210
Q

General side effects of immunosuppression

A
211
Q

How do you prevent GVHD?

A
212
Q

What are additional uses of immunosuppression drugs and therapeutic antibodies?

A
213
Q

Rituximab

A
214
Q

Gemtuzumab

A
215
Q

IL-2 (as a drug)

A
216
Q

Leurolide, goserelin, buserelin

A
217
Q

Megestrol

A
218
Q

Flutamide, bicalutamide

A
219
Q

Allopurinol

A
  • Inhibits xanthine oxidase enzyme
  • Xanthine oxidase catabolizes 6-MP to 6-thiouric acid (inactive)
  • Used to prevent and treat gout
  • Ptns taking antineoplastic drugs often generate large amounts of uric acid and must be co-treated with Allopurinol
  • The dose of mercaptopurine must be reduced by more than 1/2 when taken with allopurinol, b/c allopurinol’s inhibition of mercaptopurine metabolism
  • No interaction with thioguanine

Pharmacology - PMC 621 (3 decks)

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