Sketchy Pharma 2 Flashcards
-Gi and Endo drugs -Antimetabolites -Neuropsych drugs
Mechanism of
(a) Fondaparinox
(b) Bivalirudin
(c) Rivaraoxaban
(d) Enoxaparin
Mechanism
(a) Fondaparinox = indirect thrombin inhibitor, acts like LMWH to bind ATIIII (which inactivates Xa)
(b) Bivalirudin = direct thrombin inhibitor
(c) Rivaraoxaban = direct Xa inhibitor (‘Xaban’)
(d) Enoxaparin = LMWH = Lovenox, binds ATIII
Mechanism of
(a) LMWH
(b) Dabigatran
(c) Apixaban
Mechanism
(a) LMWH = Enoxaparin = binds ATIIII (which inactivates Xa)
(b) Dabigatran = direct thrombin inhibitor
(c) Apixaban = direct Xa inhibitor ‘Xaban’
Mechanism of
(a) Argatroban
(b) Rivaroxaban
(c) Heparin
(d) Fondaparinox
Mechanism
(a) Argatroban = direct thrombin inhibitor
(b) Rivaroxaban = direct Xa inhibitor ‘Xaban’
(c) Heparin = binds ATIII to irreversibly inhibit thrombin and Xa
(d) Fondaparinox = indirect thrombin inhibitor that binds and inactivates ATIII
Name the 3 indirect thrombin inhibitors
3 indirect thrombin inhibitors: bind ATIII
Heparin (unfractionated)
LMWH (Enoxaparin)
Fondaparinux
Unfractionated heparin vs. LMWH
(a) Activity
(b) Monitoring
(c) When need to use unfractionated
(a) Unfractionated heparin binds ATIII w/ higher affinity so inhibits both thrombin and Xa, while LMHW binds ATIII to inhibit Xa w/ less effect on thrombin
(b) LMWH doesn’t require monitoring, much more predictable response => just give a weight-based dose
(c) LMWH renally excreted, so need to use unfractionated in renal insufficiency
AC in pregnancy
Heparin (and esp. LMWH) are very safe in pregnancy
“keep the baby heppy w/ heparin”
While coumadin is teratogenic: can cause hemorrhage and abnormal bone formation in utero
Name 3 main clinical indications for indirect thrombin inhibitors
Indirect thrombin inhibitors (heparin, LMWH, fondaparinux)
- Acute tx of DVT and PE
- Ppx of DVT and PE
- Acute tx of MI
Name an electrolyte abnormality seen as an AE to long term heparin therapy
Long term heparin therapy can result in hyperkalemia 2/2 hypoaldosteronism (reduced aldo release from adrenal cortex)
Differentiate the effect of protamine sulfate on indirect thrombin inhibitors
Protamine sulfate = heparin reversal agent
-less effective against LMWH and does not at all reverse fondaparinux
Why does warfarin have so many drug interactions?
B/c it’s metabolized by cyt p450
=> any drug that activates p450 (ex: rifampin, isoniazid) can decrease circulating levels
=> any drug that inhibits p450 can increase risk of warfarin toxicity
Differentiate the risk of HIT w/ the different indirect thrombin inhibitors
HIT risk highest w/ unfractionated heparin
- intermediate risk w/ LMWH (enoxaparin)
- low to no risk w/ fondaparinux
Fondaparinox vs. Enoxaparin
(a) Mechanism of action
(b) Risk of AE
Fondaparinox (binds ATIII so indirect thrombin inhibitor) vs. Enoxaparin (LMWH also binds ATIII)
(a) Both are indirect thrombin inhibitors, but fondaparinox binds ATIII w/ different affinity so inhibits Xa stronger w/ less effect on thrombin
(b) Fondaparinox has lowest risk (almost no risk) of HIT
Main shared indication of Bivalirudin and Argatroban
Bilvalirudin and Argatroban (and Dabigatran) are direct thrombin inhibitors that are used for anticoagulation in HIT
Name the 2 direct Xa inhibitors
Direct Xa inhibitors have ban Xa in their name!!!
Apixaban
Rivaroxaban ‘Xa-ban’
Mechanism of warfarin
Warfarin inhibits VKOR (vitamin K epoxide reductase) enzyme in the liver that activates vit K
-so vit K is inactive and can’t gamma carboxylate protein C/S, factors 1972
What test is best for monitoring warfarin therapy and why?
Warfarin therapy best monitored by PT/INR (INR is just an internationally standardized PT) b/c PT measured extrinsic pathway and common pathway
Extrinsic pathway involves just factor VII and X, and factor VII has the shortest half life of the vitamin-K dependent clotting factors so best to monitor for warfarin effect
What to do when you get symptomatic bleeding on warfarin therapy
- Stop warfarin therapy
- Give factors
- need to immediately replace factors, b/c stopping warfarin and giving vitamin K only allows for synthesis of new factors, still takes time for these factors to be made, so need to treat immediately by giving factors - Give vitamin K
Why does warfarin have so many drug interactions?
B/c it’s metabolized by cyt p450
=> any drug that activates p450 (ex: rifampin, isoniazid) can decrease circulating levels
=> any drug that inhibits p450 can increase risk of warfarin toxicity
Mechanism of
(a) Fondaparinox
(b) Clopidogrel
(c) Rivaraoxaban
(d) Abcximab
Mechanism of
(a) Fondaparinux = indirect thrombin inhibitor by binding ATIII (antithrombin III)
(b) Clopidogrel = ADP-receptor antagonist
- ADP receptor (P2-Y12) on plts is what allows ADP to bind and activate plts to aggregate
(c) Rivaraoxaban = direct Xa inhibitor
(d) Abcximab = monoclonal ab against plt receptor Gp2b3a
TXA2 released by plt degranulation
(a) Where and how produced
(b) Function
TXA2 (thromboxane A2)
(a) Produced by COX enzyme in plts- so this is inhibited by plts (mechanism by which plts inhibit plts)
(b) Function to activate plts to degranulate and aggregate
Mechanism by which aspirin inhibits platelets
ASA inhibits COX1 and COX2 (irreversibly via covalent acetylation) => decreased production of TXA2 which stimulates plt degranulation and aggregation
What is dual plt therapy?
Dual therapy = both
- Aspirin (inhibits TXA2 production by inhibiting COX)
- ADP receptor (P2-Y12) inhibitor that prevents ADP’s activation of plts to cause aggregation
Describe aspirin pseudo-allergy
(a) Clinical symptoms
(b) Why ‘pseudo’
(c) Seen in what pts?
ASA pseudo allergy
(a) Hives, itching, SOB shortly after ASA administration
(b) Pseudo b/c not due to IgE cross-linking, instead is due to increased leukotriene synthesis (AA shunted down LOX since COX is inhibited)
(c) More common in pts w/ h/o asthma, atopy
Why is aspirin held for a few days and not just one dose before surgery?
Aspirin irreversibly inhibits COX enzyme by covalently acetylating COX
-so can’t make any more TXA (no more active COX) until gene transcription upregulated and new COX enzyme is produced
Key is that aspirin irreversibly covalently acetylates COX
Name some indications for anti-platelet therapy
Antiplatelet: often use ASA first line, ADP-inhibitor (Clopidogrel) if ASA pseudo-allergy
- reduce CV events in pts w/ PAD
- prevent coronary stent thrombosis
- prevent stroke in pts w/ atherosclerosis
Why is clopidogrel first line before ticlopidine
Both clopidogrel and ticlopidine are ADP receptor inhibitors (prevent ADP from binding to and therefore activating plts)
But ticlopidine carries risk of agranulocytosis => clopidogrel used as first line
Drugs that inhibit
(a) Platelet adhesion
(b) Plt aggregation
Drugs that inhibit
(a) Plt adhesion requires vWF, Gp1b,
(b) Plt aggregation requires TXA2 (production inhibited by aspirin), ADP (receptors blocked by clopidogrel), and Gp2b3a (receptors blocked by abcximab)
Abcximiab
(a) Mechanism
(b) Side effect
Abcximab
(a) Monoclonal IgG to Gp2b3a = plt receptor required for aggregation
- fibrinogen molecules bind to multiple Gp2b3a on plts to aggregate plts
(b) Side effect = drug-induced thrombocytopenia
- so need to monitor plts in pts on abcximab
Mechanism by which phosphodiestrase inhibitors inhibit platelets
Phosphodiesterase inhibitors increase cAMP in plts which activates PKA and decreases plt activity
Differentiate indication of dipyridamole and cilostazol
Both dipyridamole and cilostazol are phosphodiesterase inhibitors. PDE breaks down cAMP => PDE inhibitors cause increased cAMP in plts which activates PKA and interferes w/ plt function
Dipyridamole = anti-plt agent often combined w/ ASA to prevent stroke
Cilostazole = anti-plt also w/ vasodilatory properties => used in tx of claudication
Which anti-platelet agent is indicated in coronary steal phenomenon?
Dipyridamole implicated in coronary steal (circulation shunted away from stenosed vessel)
Dipyridamole = phosphodiesterase inhibitor that causes vasodilation and plt inhibition
Narrowed coronaries are already maximally dilated, so adding vasodilator shunts blood away from coronary vessels => worsens ischemia
First clotting factor to disappear when pt is put on warfarin therapy
Well first protein C and S (which are anti-coagulants) have the shortest half life = explains the transient hypercoagulable state when first starting warfarin therapy
Then factor VII (7) has the shortest t1/2 of the clotting factors (about 6 hrs), full clinical effect of warfarin can take 3 days
Risk of warfarin therapy in pts w/ protein C/S deficiency
Warfarin doesn’t acutely stop coagulation (that’s what heparin is for), instead it prevents formation of new clots by inhibiting VKOR enzyme needed to activate vitamin K
So doesn’t touch existing factors, just prevents formation of new ones, so effect only starts when existing factors die off
Protein C/S have the shortest half life => die off before clotting factors 1972 do = transient hypercoagulable state when first start coumadin therapy (why pts are kept on heparin bridge)
Pts w/ protein C/S deficiency are hit harder by this initial hypercoagulable state and therefore at higher risk of warfarin-induced necrosis
Risk of warfarin therapy in pts w/ protein C/S deficiency
Warfarin doesn’t acutely stop coagulation (that’s what heparin is for), instead it prevents formation of new clots by inhibiting VKOR enzyme needed to activate vitamin K
So doesn’t touch existing factors, just prevents formation of new ones, so effect only starts when existing factors die off
Protein C/S have the shortest half life => die off before clotting factors 1972 do = transient hypercoagulable state when first start coumadin therapy (why pts are kept on heparin bridge)
Pts w/ protein C/S deficiency are hit harder by this initial hypercoagulable state and therefore at higher risk of warfarin-induced necrosis
Risk of warfarin therapy in pts w/ protein C/S deficiency
Warfarin doesn’t acutely stop coagulation (that’s what heparin is for), instead it prevents formation of new clots by inhibiting VKOR enzyme needed to activate vitamin K
So doesn’t touch existing factors, just prevents formation of new ones, so effect only starts when existing factors die off
Protein C/S have the shortest half life => die off before clotting factors 1972 do = transient hypercoagulable state when first start coumadin therapy (why pts are kept on heparin bridge)
Pts w/ protein C/S deficiency are hit harder by this initial hypercoagulable state and therefore at higher risk of warfarin-induced necrosis
Effect of streptokinase on PT and PTT
Streptokinase (endogenously produced by streptococcus bacteria) lyses clots by activating plasminogen to plasmin (same mechanism as recombinant tPA agents Alteplase and reteplase)
Prolongs both PT and PTT (b/c inhibits end of both coagulation cascade pathways)
Name some contraindications to thrombolytic therapy
Contraindications to tPA (alteplase/reteplase) and streptokinase
- any e/o internal bleeding: esp need to r/o intracerebral hemorrhage
- recent head trauma or major surgery
- severe HTN
Risk of streptokinase over alteplase
Streptokinase carries small risk of allergic rxn, can even be as severe as anaphylaxis
Name 2 reversal agents of thrombolytics
- aminocaproic acid (lysine derivative that inhibits plasmin)
- tranexamic acid
Name 2 reversal agents of thrombolytics
- aminocaproic acid (lysine derivative that inhibits plasmin)
- tranexamic acid
Differentiate VLDL and LDL
VLDL = mostly (60%) TG, VLDL directly excreted from liver then –> IDL –> LDL as lose TG to peripheral tissue
LDL = high proportion of cholesterol (less TG than VLDL), delivers cholesterol to peripheral tissue
Main transporter of the following to peripheral tissue
(a) TG
(b) Cholesterol
Main transporters
(a) TG given to peripheral tissues by both chylomicrons (intestines to liver) and VLDL (excreted from liver)
(b) Cholesterol bought to tissues by LDL, then removed from peripheral tissues to be returned to liver by HDL
Which apolipoprotein marks the ‘bad’ cholesterol
‘Bad’ cholesterol = VLDL and LDL, b/c when these are in serum in excess they deposit in BV walls
ApoB100 = major apoprotein on VLDL and HDL
2 mechanisms by which statins lower lipids
Statins- reduce LDL by 30-60% (first line agent)
- Inhibit HMG-CoA reductase = rate limiting step in endogenous cholesterol synthesis
- Increase LDL-R expression to remove more LDL from serum
Indications for statins
They have a mortality benefit!!! Basically give to errybody…
- secondary prevention for pts w/ diabetes, PAD, h/o stroke or TIA
- first line LDL-lowering agent
- reduce risk of cardiac complications after ACS
MC complication of statin therapy
Myopathy! Usually presents as proximal symmetric muscle weakness/soreness
2 lab abnormalities seen 2/2 statin therapy
- CK elevation 2/2 myopathy
- LFT elevations
- reversible
2 lab abnormalities seen 2/2 statin therapy
- CK elevation 2/2 myopathy
- LFT elevations
- reversible
Mechanism of
(a) Cholestyramine
(b) Ezetimibe
(c) Gemfibrazil
(a) Cholestyramine = bile acid resins, bind bile acids in intestinal lumen to make sure they go to ‘cholon’ (aka excreted instead of reabsorbed and recycled to liver)
(b) Ezetimibe = binds intestinal cholesterol, preventing absorption into enterocyte
(c) Gemfibrazil = fibrate, activates PPARgamma to upregulate LPL activity
Mechanism of PCSK-9 inhibitors
PCSK-9 degrade LDL receptors => when inhibited there are more LDLR on hepatocytes available to remove LDL from serum
Reduction in LDL 2/2
(a) Cholestryamine
(b) Ezetimibe
(c) Gemfibrazil
None of these are first line (ummm statins still run the show), so use in conjunction w/ statins for hyperlipidemia
(a) Cholestyramine (bile acid resin) reduces LDL by about 20%
(b) Ezetimibe (chol reabsorption inhibitor) reduces LDL by about 25%
(c) Gemfibrazil (fibrate) reduces LDL very minimally, really work to reduce VLDL 35-50%
Result in liver of decreased bile acid recycling
Decreased bile acids recycled to liver => liver revs up bile acid production, also means stimulation of HMG CoA reductase and upregulation of LDL-R
-so are slightly increasing exogenous cholesterol production, but removing more LDL from the circulation => overall reduce serum LDL
Limitation of bile-acid resins
(a) Can’t use w/ what other concomitant lipid abnormality
(b) Risk
Bile acid resins (Cholestyramine)
(a) Can increase TG => don’t use if pt has concomitant hypertriglycerides (can only really use in isolated LDL elevation)
(b) Increased risk of cholesterol gallstones
Which other lipid lowering agent needs to be spread out from statin therapy (aka not taken at the same time)
Bile acid resins (cholestyramine) reduces statin absorption => suggested to take them 4 hrs apart
Differentiate risk of cholestyramine from Ezetimibe
Cholestyramine carries increased risk of cholesterol gallstones (b/c decreases bile acid recycling) and increased TG
While Ezetimibe (reduces chol absorption) can cause elevated LFTs and diarrhea
Mechanism of fibrate therapy
Fibrates (Gemfibrazil, Fenofibrate) activate PPARalpha to upregulate extrahepatic LPL => accelerate VLDL and chylomicron hydrolysis
-so reduce VLDL
Also reduces VLDL secretion from the liver
Dangerous of TG over 1,000
RIsk of acute pancreatitis
MC side effect of
(a) Fibrates
(b) Niacin
(a) Fibrates => muscle toxicity, especially if taken w/ statin
(b) Niacin => cutaneous flushing and warmth shortly after taking agent or increasing dose, 2/2 prostaglandin release
- effect blunted by taking ppx NSAID before niacin dose
Most effective HDL-raising agent
HDL raising agent = Niacin (vit B3)
Benefit of fish oil therapy
Fish oil (omega-3 FAs) reduce VLDL and apoB production => reduces serum TG
Benefit of niacin therapy
Niacin therapy: reduces VLDL, raises HDL (main benefit), and mildly reduces LDL
-but don’t forget cutaneous flushing/warmth from therapy (can avoid w/ ppx NSAID)
Why is aspirin risky in pts w/ hypotension
Aspirin (and other NSAIDs) inhibits COX1 and COX2, both of which produce prostaglandins that are needed to dilate the afferent arteriole and maintain renal perfusion
-also why NSAIDs are renally risk w/ ACEi (which also vasoconstrict afferent arteriole)
3 functions of prostaglandins produced by COX2
COX2 catalyzes arachidonic acid into prostacyclins that
- increase sensitivity to pain
- induce fever
- increase vascular permeability
Difference btwn aspirin and indomethacin mechanism
Both aspirin and indomethacin are NSAIDs (non-selectively inhibit both COX1 and COX2), but aspirin is irreversible!!!
- aspirin irreversibly covalently acetylates COX
- indomethacin reversibly inhibits
Name some NSAIDs
- ibuprophen (aspirin)
- diclofenac
- ketorolac (Toradol)
- indomethacin
- meloxicam and piroxicam
2 ways of preventing NSAID-induced gastric ulcers
Add PPI or misoprostol (PGE1 analogue) to reduce gastric acid secretion
Explain how NSAIDs increase the risk of gastric bleeding
NSAIDs block COX1 production of TXA2, thromboxane A2 activates plt aggregation, so by decreasing TXA2 production NSAIDs decrease ability to clot
=> increased risk of mucosal bleeds- manifests as GI bleeding
2 feared renal complications of NSAIDs
- AKI 2/2 reduction of prostaglandins that are used to keep afferent arteriole dilated
- Renal papillary necrosis from ischemia due to reduced renal perfusion
Bipolar pt takes something for a pain for 5 days straight after bumping her knee, develops N/V and has seizure
Explain
NSAIDs can induce AKI by decreasing prostaglandins used to dilate afferent arteriole
Lithium is fully renally excreted, similarly to Na+ it’s freely filtered than most reabsorbed in PCT
So by inducisng AKI, NSAIDs reduce Lithium excretion => precipitated lithium toxicity
pH disturbance caused by aspirin
Aspirin
- acutely can cause respiratory alkalosis (b/c stimulates respiratory centers so blow of tons of CO2)
- then later on causes metabolic acidosis (MUD PILES)
Tx of
(a) Acute aspirin toxicity
(b) Acute acetaminophen toxicity
Tx of
(a) Acute aspirin (ibuprophen/advil) toxicity: activated charcoal, then alkalinize serum/urine w/ NaHCO3 to draw acid (aspirin is salicyclic acid) out into urine
(b) Acute acetamiophen (tylenol) causes toxicity by overwhelming hepatic glutathione and overproducing NAPQI, give activated charcoal (if w/in 4 hrs) then N-acetylcholine to replenish hepatic glutathione stores to metabolize NAPQI to excretable substance
Two contraindications to NSAID use
- 3rd trimester b/c can cause premature closure of the ductus
- CKD b/c NSAIDs decrease prostaglandins used to dilated afferent arteriole => can induce AKI, esp in pts w/ underlying kidney disease
Selective COX2 inhibitor Celecoxib
(a) Benefits over NSAID
(b) Risk
Celecoxib = COX2 inhibitor
(a) None of the side effects from inhibiting COX1 => no increased risk of peptic ulcers and not an anti-platelet agent
(b) Risk = actually increases cardiovascular risk, so shouldn’t use in pts w/ angina or MI etc
Mechanism of action of acetaminophen
Acetaminophen = Tylenol, good as anti-pyretic and anelgesic, but not as an anti-inflammatory!
Inhibits COX2 but not an anti-inflammatory like NSAIDs :-(
Mechanism of colchicine
Colchicine = binds intracellular tubulin to prevent microtubule polymerization
-disrupts the neutrophil cytoskeleton so inhibits neutrophil (first inflammation responder) migration, phagocytosis, and degranulation
Indications of colchicine vs. allopurinol in gout
Colchicine can be used to tx acutely gouty flare to reduce inflammation by inhibiting neutrophil cytoskeleton (binds intracellular tubulin to prevent microtubule polymerization)
Allopurinol (xanthine oxidase inhibitor) for chronic gout tx- be careful to NOT use this in acute flares b/c can mobilize further urate stores and exacerbate flare
Name other indications of xanthine oxidase inhibitor in addition to chronic gout tx
Xanthine oxidase inhibitor (Allopurinol) also used in
-prevention of tumor lysis syndrome when starting leukemia/lymphoma pt on cytotoxic agents
Mechanism of hydroxyurea as cancer drug
Hydroxyurea is an antimetabolite that works at S-phase of the cell cycle (similar to 5-FU and MTX)
Hydroxyurea inhibits ribonucleotide reductase (UDP –> d-UDP) to reduce pyrimidine synthesis
-Sidebar: another indication is to increase HbF in SCD
Indication for leucovorin
Leucovorn = folinic acid = THF derivative that doesn’t require conversion by DHT reductase => allows THF w/o the enzyme inhibited by MTX
‘Leucovorin rescue’ = giving folinic acid either for MTX overdose or along w/ MTX to protect bone marrow and GI mucosa
-can also give leucovorin w/ 5-FU, but not for protection but to potentiate 5-FU effect on inhibiting thymidylate synthesis
Main side effect of antimetabolite therapy
Antimetabolites (MTX, 5-FU, hydroxyurea: inhibit DNA synthesis, specifically pyrimidines) side effects:
- Myelodepression and pancytopenia (b/c bone marrow needs tone of DNA precursors to make immune cells) => immunosuppression
- pulmonary fibrosis
- hepatotoxicity (direct damage to hepatocytes)
- alopecia
- stomatitis (soreness of mouth b/c oral mucosa rapidly turns over)
- mucositis
Basically affects things that are rapidly producing cells (so need a lot of precursors) = bone marrow, mucosal surfaces
Main indications of azathioprine
Azathioprine (converted to 6-MP) is an anti-metabolite that inhibits de novo purine synthesis
Uses
- transplant rejection
- Crohn’s
- RA
Differentiate mechanism of 5-FU and 6-MP
Both are cell-cycle specific (S-phase) anti-metabolites that work by inhibiting de novo DNA/RNA synthesis
5-FU inhibits thymidylate synthase needed for pyrimidine (T, U, C) synthesis
while 6-MP inhibits purine (A, G) synthesis by inhibiting synthesis of IMP (AMP, GMP precursor)
Main toxicities of azathioprine
Azathioprine = antimetabolite, inhibitor of de novo purine synthesis
Toxicities: myelosuppression => immunosuppression
-pancreatitis and hepatitis
Tx of choice for Hairy Cell Leukemia
Tx hairy cell leukemia w/ cladribine = cytotoxic purine analog that works by inhibiting DNA polymerase
Name the two ways the pyrimidine synthesis pathway is inhibited by cancer drugs
- inhibiting folate cycle
- 5-FU and MTX - inhibiting DNA polymerase w/ pyrimidine analogus
- Cladribine, Cytazabine, Gemcitabine
Differentiate cytaxabine and gemcitabine
Both cytaxabine and gemcitabine are cytotoxic pyrimidine analogs that block DNA polymerase to inhibit de novo pyrimidine synthesis
-S-phase specific
Cytaxabine is only used against hematologic malignancies, while gemcitabine can be used in both hematologic malignancies and solid tumors
Mechanism of cyclophosphamide
(a) Metabolism
Cyclophosphamide = alkating agent, adds alkyl groups to DNA causing cross linking that halts DNA synthesis
Cell cycle nonspecific (doesn’t work at any particular step in the cell cycle)
(a) Cyclophosphamide is metabolized/activated by cyt p450
Medication taken w/
(a) Cyclophosphamide to reduce SE
(b) Cisplatin to reduce SE
(a) Cyclophosphamide associated w/ hemorrhagic cystitis (bleeding from bladder ewwww) => co-administer MESNA to bind toxic metabolite that damages bladder
(b) Cisplatin (cytotoxic platinum analog) causes ATN => take amifostine to scavenge free radicals produced by cisplatin in the kidney
Differentiate indication of Busulfan and nitrosoureas
Both busulfan and nitrosoureas are alkalating agents that kill cells (cytotoxic) by transferring an alkyl group to DNA, causing DNA cross links halting DNA synthesis
-cell cycle nonspecific
Busulfan is extremely potent against the bone marrow, so is used as a conditioning agent prior to bone marrow transplant
Nitrosoureas are highly lipophilic => can cross BBB => use for CNS malignancies (glioblastoma multiforme)
4 risks of cyclophosphamide therapy
- Bladder stuff :-( Strong association w/ hemorrhagic cystitis (hence why co-administer MESNA)
also increased risk of bladder transitional cell cancer - Hyponatremia 2/2 SIADH
- Infertility
- Myelosuppression
Differentiate mechanism of cyclophosphamide and cisplastin
Both are cancer drugs to inhibit DNA synthesis
Cyclophosphamide halts DNA synthesis by causing crosslinks in DNA by adding alkyl groups
-alkalating agent
Cisplastin halts DNA synthesis also by crosslinking DNA, but this time by adding platinum to DNA instead of alkyl groups
-cytotoxic platinum analog
3 specific adverse effects connected to Cisplatin therapy
Cisplatin = cytotoxic platinum agent (halts DNA synthesis by crosslinking DNA w/ platinum)
Adverse effects:
- peripheral neuropathway: stocking glove distribution
- ototoxicity: dose dependent sensorineural hearing loss and tinnitus
- nephrotoxocity: causes ATN (muddy brown casts on UA), prevent w/ amifostine that scavenges free radicals produced by cisplatin that damage nephrons
Mechanism of bleomycin
Bleomycin = small peptide w/ binding sites for both DNA and iron, binds DNA and produces free radicals that cause both single and ds-DNA breaks
Arrests cells in G2
Main toxicity of
(a) Bleomycin
(b) Anthracyclines
Main toxicity
(a) Bleomycin- pulmonary toxicity (pneumonitis, infiltrates on CXR)
(b) Anthracyclines- (Doxorubicin) irreversible, dose dependent cardiomyopathy
Name 3 cancer drugs that are microbial/bacterial products w/ anti-cancer effects
Abx w/ anti-cancer effects
- Bleomycin
- Anthracyclines (‘rubicin’): doxorubicin
- Actinomycin D
Main indications for actinomycin D
Actinomycin D (binds and intercalates DNA) used on childhood tumors: ‘children act out’
Wilms tumor
Rhabdomyosarcoma
Ewing’s sarcoma
What part of the cell cycle do topoisomerase inhibitors work at?
Topoisomerase inhibitors inhibit the re-ligation needed to repair the breaks made by the topoisomerase, so chromosome breaks accumulate until the cell dies
Blocks S-phase mostly, also G2 (if cell gets past S-phase)
Give the mechansim of topoisomerase II inhibitors
Topoisomerase II inhibits (etoposide, teniposide) work by preventing the re-ligation of the double stranded breaks caused by tII (tII causes double strand break to fix both positive and negative supercoiling)
W/o ability to re-ligate, tons of chromosomal breaks accumulate and cell dies
Role of topoisomerase enzyme
Topoisomerase enzyme job is to relieve the supercoiling of DNA produced during the unwinding and separation of the two strands by helicase
Mechanism of the vinca alkaloids
Vinca alcaloids (vincristine, vinblastine, paclitaxel) work by inhibiting microtubule production and mitotic assembly => kills cell in M-phase
Main toxicity of vincristine
Vincristine = vinca alkaloid that inhibits microtubule formation (halts cell in M-phase) main toxicity = peripheral neuropathy
Can also cause autonomic dysfunction => paralytic ileus = constipation
Differentiate the mechansim of vincristine and paclitaxel
Both vincristine and paclitaxel are vinca alkaloids that halt cell in M-phase
Vincristine binds beta-tubulin to prevent microtubule formation, while paclitaxel (and the class of taxanes) bind to the microtubules to prevent their destruction
Two indications for Imatinib
Imatinib = small molecule tyrosine kinase inhibitor
=> used mainly in CML
-Imatinib also blocks c-kit => also used in GIST (GI stromal tumors)
In addition to BRR-ABL fusion protein, name 2 more targets for tyrosine kinase inhibitor therapy
- anti-VEGF-receptor to prevent angiogenesis, super good in renal cell carcinoma
- anti-EGFR: first line against nonsmall cell lung cancer
Sidebar: there are monoclonal Abs against both of these targets as well: Beracizumab and Cetuximab respectively
Name an adverse effect of monoclonal antibodies only seen w/ chimeric Abs
Serum sickness 2/2 mouse portion of the Ab (so seen in chimeric Abs): type III hypersensitivity p/w fever, rash, and arthralgia when immune system attacks mouse-portion and immune complexes deposit in tissues
Why are pts often given ppx NSAIDs and anti-histamines prior to Rituximab infusion?
Infusion reaction- w/in 1 hr of infusion get HA, fever, rash, pruritis, can get dyspnea and hypotension. Ab binding antigen and causing huge cytokine release => often administer infusion w/ ppx NSAIDs and anti-histamine
Differentiate long acting vs. shorting benzos
(a) Name the drugs
(b) Which are more addictive
(a) Long acting (Diazepam) have longer t1/2 than short acting (ATOM- alprazolam, triazolam, oxazepam, midazolam): all are metabolized by liver but diazepam’s metabolites are active (so longer t1/2)
- while lorazepam is intermediate
(b) Short acting are more addictive b/c shorter on, shorter off
Describe the mechanism of alcohol tolerance
Tolerance meaning over time you need more of the drug (more EtOH) to achieve the same effect
Tolerance to EtOH is due to reduced GABA receptor sensitivity to EtOH and down-regulation of GABA receptors
-EtOH works by binding GABA-A to enhance inhibitor tone
Explain the mechanism of EtOH withdrawal
Withdrawal b/c tolerance develops from chronic use b/c of downregulation and decreased sensitivity of GABA receptors
So when abruptly stop, body has abrupt loss of GABA tone => loss of inhibitory tone
- autonomic instability: tachycardia
- insomnia, tremors, anxiety, diaphoresis
EtOH withdrawal symptoms
(a) 8-12 hrs
(b) 12-48 hrs
(c) 48-965 hrs
EtOH withdrawal from loss of GABA inhibitory tone => autonomic instability
(a) 8-12 hrs: tachycardiac, tremors, insomnia, anxiety, diaphoresis
(b) 12-48 hrs: seizures
(c) 48-96 hrs: DT- fever, disorientation, severe agitation
3 main indications for IV benzos
- EtOH withdrawal
- b/c gives GABA tone that is lacking - status epilepticus: rapidly depresses CNS activity
- conscious sedation, ex: Medazolam used in endoscopy so pt is sedated but can protect own airway
Clinical manifestations of CNS depression from benzodiazepines
- central ataxia => risk of falls (esp in elderly)
- confusion (esp in elderly)
- anterograde amnesia: so you get the endoscopy and it’s uncomfortable, but you don’t remember it’s uncomfortable
How to reverse oversedation from benzos
(a) Risk
Flumazenil = competitive inhibitor of the benzo binding site on GABA-A Cl- ion channel
(a) Risk of withdrawal seizure
What other drugs bind to the same site on GABA-A as benzos
Nonbenzo hypnotics used as less-addictive med for insomnia = Zolpidem, Zaleplon, Zopiclone
Name 3 drugs you don’t want to combine w/ benzos
Don’t want to combine CNS depressants => don’t give benzos with
- 1st generation H1 blockers (anti-histamines) that have central effects
- Barbiturates
- Alcohol
Sleep aid very safe in elderly
Ramelteon = melatonin agonist- activates melatonin receptors in suprachiasmatic nucleus of the hypothalamus (nucleus right above the optic chiasm)
-few side effects => safer than nonbenzo hypnotics and benzos in elderly
Barbiturate mechanism of action
(a) Name the two barbiturates still used
Barbiturates prolong GABA-A (Cl-channel) duration of opening => neuronal hyperpolarization = CNS inhibition
(a) Most not used anymore b/c super sedating and can cause hypotension and respiratory depression, but
1. Theopentol- very short acting (action in 30 seconds, lasts for only 5-10 mins) used for anesthesia induction
2. Phenobarbital used for refractory seizures
Dangers of barbiturates
Not only sedation, but can cause respiratory depression and hypotension
- most likely sedative hypnotic to cause coma in adults
- high risk of addiction 2/2 tolerance and dependence
- also barbs are a potent inducer of cyt p450
Name the IV anesthetics used for induction of anesthesia
Induction agents = Propofol, etomidate, ketamine, benzos, barbs (but not really anymore)
Differentiate the two classes of inhaled anesthetics
(a) Solubility
Inhaled anesthetics = N2O (laughing gas) and volatile anesthetics which are fluorinated gases (Halothane)
(a) Halothane is more soluble: takes longer to saturate blood (b/c more needs to dissolve) => slower onset of action and longer duration of action
Partition coefficient of laughing gas vs. halothane
Laughing gas (N2O) is less soluble than fluorinated volatile anesthetics (Halothane), so less N2O needed to saturated blood => faster onset and shorter duration of N2O
Halothane has higher partition coefficient = slower onset of action and longer duration
Distinguish potency and MAC
MAC = minimum alveolar concentration = dose of inhaled anesthetic that causes 50% of pts to become unresponsive to painful stimuli
Potency = 1 / MAC
-so high dose needed to anesthesize = high MAC = low potency
Cause of malignant hyperthermia
(a) Mechanism of disease
Malignant hyperthermia from volatile anesthetics (halothane) and succinylcholine
(a) Due to skeletal muscle hypersensitivity. Defect in ryanodine receptor on SR surface causing excess Ca2+ release => excessive ATP-dependent uptake of Ca2+ by SR = crazy high heat production and ATP consumption = muscle damage
- elevated CK, hyperkalemia (rhabdooooo)
Tx of malignant hyperthermia
Dantrolene = muscle relaxant that lessens excitation-contraction coupling in skeletal muscle cells by inhibiting Ca2+ release from the SR
Which analgesic can have a potentially paradoxical reaction causing increased sensitivity to pain?
Opioid induced hyperalgesia is a thing! Where pts paradoxically get increased susceptibility to pain from chronic use of opioids
Why is methadone used for opioid withdrawal, won’t they just get addicted to that instead…?
Methadone has a longer half life, so withdrawal is much less intense and the drug is easier to taper
-so much less addictive than fast-acting, quickly rewarding heroin
Differentiate methadone and bupenorphine
Methadone = full mu agonist
Bupenorphone = partial mu agonist, so lower effect even at max dose, much lower risk of overdose
Presentation of neonatal abstinence syndrome when neonate born to heroin-addicted mother
Opioids can cross placental barrier => when baby is born (and no longer has opioid from mother), undergoes withdrawal :-(((
Irritable (crying, tachypneic), moist (sweating, sneezing, dio)
Danger of switching pt from full to partial mu agonist
Partial mu agonist switch can put pt in withdrawal
Naloxone vs. naltrexone
Both are mu receptor antagonists
Naloxone (Narcan) = rapid acting and very potent antagonist, so immediately (like 1-3 mins) kicks opioids off receptor
- used to reverse opioid overdose
- puts pt in immediate withdrawal (so be careful…)
Naltrexone = opioid/EtOH blocking agent, help maintain abstinence in heroin and alcohol addicts
-can even be added to buproprion for wt loss
MC acute vs. chronic side effects of Li
MC acute side effect of Li = GI symptoms
vs. chronic side effect = neurologic
- tremors (common!!!!), confusion,ataxia (especially in elderly)
Adverse effects of chronic Li tx
(a) Endocrine
(b) Renal
(c) Obstetrics
Adverse events of chronic lithium
(a) Hypothyroidism- so if pt on Li p/w wt gain, dry skin, hair loss, constipation, think hypothyroidism
(b) Nephrogenic DI (other causes are hypercalcemia and demeclocycline)
Name 3 mood stabilizers besides Lithium that can be used for bipolar
Mood stabilizers in addition to lithium = 3 AEDs
- Valproic acid: can be used for both acute mania and maintenance
- Carbamazepine: again for both acute mania and maintenance
- Lamotrigine: for maintenance only (not acute mania)
Drug besides Lithium and AEDs that can be used to tx acute mania
In addition to lithium, valproate and carbamazepine, can use both 1st gen (Haloperidol) and 2nd gen (Quetiapine) antipsychotics to tx acute mania
Interaction btwn NSAIDs and Li
Li is a small monovalent cation, so doesn’t get metabolized rather gets excreted fully in urine, so excretion of lithium depends fully on GFR
NSAIDs decrease PGE production which decreases GFR => NSAIDs can decrease clearance of Lithium
-basically so can anything that decreases GFR (ex: HCTZ)
Teratogenicity of
(a) Lithium
(b) Valproate
(c) Carbamazepine
Teratogenic
(a) Lithium increases risk of Ebstein’s anomaly = cardiac abnormality where you get atrialization of the LV and tricuspid valve malformation
(b, c) Valproate and CMZ increase risk of neural tube defects, esp spina bifida
Differentiate
(a) Generalized and focal seizures
(b) Simple vs. complex focal seizures
(a) Focal seizures start in a single focus (one hemisphere) in the brain, while generalized seizures start in both hemispheres
- can also have secondarily generalized
(b) Simple has no LOC, complex has LOC
Mechanism of action of most AEDs
AEDs: basically work to inactivate Na+ channels
-reduce depolarization of neurons by either hyperpolarizing cell or blocking Na+ channels
Which AED carries increased risk of
(a) Acute angle closure glaucoma
(b) Acute pancreatitis
(c) TEN
(d) DRESS syndrome
(e) Gingival hyperplasia
AED adverse effects
(a) Acute angle closure glaucoma w/ Topiramate
(b) Acute pancreatitis w/ Carbamazepine
(c) TEN/SJS in both Lamotrigene (highest risk) and carbamazepine (associated w/ HLA-B1502 in Asians)
(d) DRESS syndrome in carbamazepine and phenytoin
(e) Gingival hyperplasia seen in almost 50% of pts on chronic phenyotin therapy
AED that is first line for
(a) Trigeminal neuralgia
(b) Fibromyalgia
(c) Varicella-Zoster pain
AED first line for
(a) Trigeminal neuralgia = carbamazepine
(b) Fibromyalgia = gabapentin
(c) VZV pain = gabapentin
Mechanism of Ethosuximibe
Ethosuximibe (first line for absence seizures): blocks T-type Ca2+ channels in the thalamic neurons
First line med for pt w/ absence seizures and a h/o GTC seizures
Valproate: effective against both absence seizures and GTC
Main symptoms caused by D2 activation in the periphery
D2 activation in periphery (ex: L-dopa w/o carbidopa) => N/V,cardiac arrhythmias, and orthostatic hypotension
Main side effects of D2 central activation
D2 activation centrally (L-dopa side effects not ameliorated by carbidopa) = neuropsychiatric agitation: anxiety, agitation, insomnia, confusion, hallucinations
Describe the following phenomenons of L-dopa therapy
(a) Wearing off rxn
(b) On-off phenomenon
W/ length of therapy, response to L-dopa treatment becomes more and more unpredictable
(a) Wearing off- akinesia and dyskinesia re-emerge at the end of each dose
(b) On-off: motor fluctuations, alternating akinesia w/ symptom-free periods, unpredictable
Contraindication of L-dopa therapy
Psychosis!
Psychosis you want D2 BLOCKER! Not to potentiate dopaminergic effect
Mechanism of carbidopa
(a) Doesn’t decrease which side effects of L-dopa
Carbidopa = peripheral DOPA decarboxylase inhibitor
DOPA decarboxylase catalyzes L-dopa to dopa, so inhibiting this in the periphery
- decreases side effects of peripheral D2 agonism
- increases amount of L-dopa around
Trihexyphenidyl
(a) Mechanism
(b) Indication
Trihexyphenidyl = anti-muscarinic agent used to tx EPS
EPS arise when there is an imbalance of DA and cholinergic activation in the nigrostriatal pathway
-so trihexyphenidyl can help restore the DA/ACh balance in the basal gnalgia
(a) Anti-muscarinic
(b) Tx EPS that arise from antipsychotics and Parkinson symptoms
- improves tremor and rigidity of Parkinsons w/ no effect on bradykinesia
