Lectures 16, 17, 18, and 19 Flashcards
Which clotting factors do oral anticoagulants target?
Xa, IIa, VIIa, and IXa
What are some anticoagulants?
- Vitamin K antagonists (warfarin)
- Direct thrombin inhibitors (bivalirubin, dabigatran)
- Direct Xa inhibitors (rivaroxaban, apixaban)
What is the function of warfarin?
- Inhibits vitamin K1 2,3-epoxide reductase (prevents conversion of vitamin K epoxide to vitamin K, and conversion of vitamin K to vitamin K hydroquinone)
- Inactivates factors VII, IX, X, and II (thrombin)
What are consequences of warfarin action?
- Inhibits reduction of vitamin K
- Reduces gamma-carboxylation of clotting factors (reduces activity of clotting factors)
- Decreases production of new and active clotting factors II, VII, IX, and X
What is the function fo gamma-carboxyl glutamate?
Calcium chelator
Does warfarin have any effect on existing carboxylated clotting factors?
NOOO, they still remain active
How long does it take for warfarin to reach its full anticoagulant effect?
5 days b/c need to clear existing clotting factors
What are the uses of warfarin?
- Prevent venous thromboembolism
- Treat atrial fibrillation
- Prevent clotting w/ prosthetic heart valves
What are side effects of warfarin?
- Bleeding (major) – intracranial bleeding; incidence increases as tx duration and INR increase
- Skin necrosis (rare)
- Allergy
What is warfarin INR?
- International normalized ratio
- Ratio of px prothrombin time to a control (prothrombin time measures the activity of factors I, II, VII, and X)
What does the INR value mean?
- Normal untreated INR = 1
- Typical tx target INR = 2-3
- INR > 5 means overdose
What is needed to reach the target INR?
5 doses over 5 days
What is the antidote to warfarin?
Vitamin K or plasma (has clotting factors)
Which isomer of warfarin is more potent?
S
What is the S isomer of warfarin metabolized by?
CYP 2C9
What is the R isomer of warfarin metabolized by?
CYP 3A4, 1A2, and 2C19
Which drugs interact w/ warfarin?
- ASA (decrease platelet function)
- NSAIDs (GI ulceration)
- Antibiotics (decreased gut vitamin K synthesis)
- Cotrimoxazole (altered warfarin metabolism)
- Acetaminophen, doses over 2g/day (interference w/ vitamin K cycle)
Which drugs will interact w/ warfarin and increase bleeding?
- Metronidazole, macrolides, fluoroquinolones
- Azole antifungals, fluconazole, miconazole
- SSTI
- Clopidogrel, ASA
- NSAIDs, acetaminophen
What are some contraindications w/ warfarin?
- Foods rich in vitamin K
- Crosses placenta and causes birth defects; doesn’t cross into breast milk
What are the types of thrombin inhibitors?
- Direct or univalent (bind to active site of IIa; dabigatran, argatroban)
- Bivalent (bind to active site and exosite; lepiruidin, bivalirudin)
Bivalirudin is a ____ inhibitor of IIa
Non-competitive
What does bivalirudin bind to?
- IIa active site of fibrin-bound and free IIa to reduce platelet activation
- Exosite 1
What is bivalirudin used for?
As an anticoagulent in px undergoing percutaneous coronary intervention, w/ heparin induced thrombocytopenia
Bivalirudin is usually used w/ ___
ASA
What is dabigatran etexilate?
- Pro-drug for oral absorption (metabolized by esterases), but only absorbs in pH less than 3
- Direct thrombin (IIa) inhibitor (binds to thrombin active site and prevents conversion of fibrinogen to fibrin)
- Binds to free and fibrin bound thrombin => decreased platelet activation
Is the binding of dabigatran to thrombin reversible?
Yes
What are some drug interactions w/ dabigatran?
- Other drugs effecting clotting (warfarin, heparin, rivaroxaban)
- Anti-platelet aggregation (aspirin, NSAID, clopidogrel)
- Contraindicated in pregnancy and breast feeding
What are uses of dabigatran?
- Prevent venous thromboembolism following hip or knee replacement
- Prevent atrial thrombus and subsequent stroke in atrial fibrillation
- Alternative to warfarin (esp. if risk of stroke is high)
What are side effects of dabigatran?
- Dyspepsia
- Bleeding/hemorrhage
What is argatroban?
- Direct thrombin competitive inhibitor
- Given as continuous IV infusion
- Used in px w/ heparin-induced thrombocytopenia
What is AZD 0837?
- Direct thrombin competitive inhibitor
- Has to be in a pro-drug form for absorption
What does benzamidine do?
Broad spectrum inhibitor of most serine proteases; acts as a mimic for guanidine group of arginine
What is important about benzamidine when used in inhibitors?
- Fits in S1 site of IIa and Xa, producing potent inhibitors
- Charged at physiological pH, drastically reducing absorption and necessitating formation of a pro-drug
- Removal from IIa and Xa inhibitors reduces potency
What is rivaroxaban and apixaban?
- Direct competitive Xa inhibitor
- Used for prevention of venous thromboembolism in total knee or hip replacement surgery
- Tx of venous thromboembolism or deep vein thrombosis, pulmonary embolism, and prevention of recurrent DVT and PE
- Prevention of stroke and embolism in px w/ atrial fibrillation
What is the mechanism of clopidogrel, prasugrel, and ticagrelor?
- Glycoprotein GPIb binds collagen via von Willebrand factor
- Platelets “degranulate” releasing ADP
- ADP binds type 2 purinergic receptors (P2Y12) => intracellular release of Ca+2 via IP3 by activation of Gaq
- Ca2+ activates GP IIb/IIIa receptor complex, which binds fibrinogen => platelet aggregation
- Clopidogrel and prasugrel alkylate P2Y12 receptor irreversibly, which inhibits P2Y12 preventing platelet aggregation
- Ticagrelor is competitive antagonist of P2Y12 receptor
What is ticagrelor usually given w/?
ASA
What are the functions of H1 receptors around the body?
- Lungs/GI – smooth muscle contraction
- CNS – sleep wake regulation, vomiting
- Vasculature – increase vascular permeability
- Systemic – allergic response
What are the cellular effects of H1 receptors?
- Increase phospholipase C, IP3, DAG, and intracellular [Ca2+]
- Decrease K+ outflow
- Result = excitation
H1 receptors are G alpha ___
q
H2 receptors are G alpha __
s
H3 receptor are G alpha __
i
What are the functions of H2 receptors around the body?
- GI parietal cells – increase acid secretion
- CNS – memory
- Heart – increase force and heart rate (very minor)
What are the cellular effects of H2 receptors?
- Increase adenylate cyclase and cAMP
- Result = excitation
What are the functions of H3 receptors?
In CNS, auto-receptor, presynaptic inhibition, and blocks histamine release
What are the cellular effects of H3 receptors?
- Decrease cAMP and intracellular [Ca2+]
- Increase K+ outflow
- Result = inhibition
What is the function of histamine release?
To fight off parasitic infections
Which receptors primarily mediate the allergic histamine response?
H1 receptors
Which cells release histamine and in response to what?
Mast cells, in response to binding of allergens to IgE antibodies on mast cell surface
What effects are caused by histamine after it is released?
- Increased nasal secretion and vascular permeability
- Nasal congestion
- Clear rhinorrhea (won’t be clear in a sinus infection)
- Sneezing, itching, conjunctivitis
- Postnasal drip => coughing
- Wheals and flares (bumps w/ surrounding redness)
What is delayed-type hypersensitivity?
- Mediated by CD8 cells
- Manifests as a rash
- Takes 48h post-contact to develop
- Ex: exposure to poison ivy
- Treated w/ glucocorticoids; cannot be treated w/ antihistamines
What is anaphylactic shock?
- Causes life threatening bronchoconstriction w/ inability to breathe = medical emergency
- Treated w/ adrenaline
What is the predominant form of histamine?
Nt-tautomer (mono-cation form at physiological pH 7.4; charged N is needed for interaction w/ negatively charged aa in H1 and H2 receptors)
What are antihistamines?
H1 receptor antagonists
What are the 2 classes of H1 antagonists?
1) First gen or classical antihistamines - have affinity for many other receptor groups producing additional pharmacological effects and side effects
2) Second gen or “non-sedating” antihistamines - more specific for H1 receptors and have less side effects
Why do second gen antihistamines cause less sedation?
Less hydrophobic and can’t cross BBB
What are uses of first gen antihistamines?
- Tx of allergic response caused by release of histamine from mast cells
- Common cold (usually used for drowsiness)
- Hypnotics (ie for sleeping)
- Motion sickness
What are side effects of first gen antihistamines?
- Antimuscarinic and alpha adrenergic antagonist activity
- Sedation, dizziness
What are the 5 types of first gen antihistamines?
- Ethanolamines
- Ethylenediamines
- Piperazines
- Alkylamines
- Phenothiazines
What are the different dosings of diphenhydramine used for?
- 25 mg for antihistamine
- 50 mg for sleep aid
What are side effects of diphenhydramine and dimenhydrinate?
- Antiemetic activity
- Antimuscarinic
- Sedation
- Alpha adrenergic antagonist activity
Does dimenhydrinate or diphenhydramine have greater activity?
Same
What is significant about the 8-chlorotheophylline on dimenhydrinate?
CNS stimulant like caffeine, so thought to counteract sedation of diphenhydramine (potent sedation results in an overall net mild sedation)
What can increase affinity for H1 receptors?
N (sp2 hybridized) as part of an aromatic ring
For histamine antagonists, do 2 pyridine groups increase potency over 1 pyridine and 1 benzyl?
No b/c one pyridine ring is already in the histamine imidazole binding site
What is an advantage to ethylenediamines over other first gen antihistamines?
Exhibit similar sedation, but generally have less antimuscarinic side effects
What can decrease the pKa of a nitrogen?
Attach it directly to an aromatic ring
What are piperazines used for?
- Prevention and tx of motion sickness
- Nausea and vomiting in general
Which first gen antihistamines produce less sedation?
Alkylamines
What effect do phenothiazines have on other analgesic and sedative drugs?
Increase their sedating effects
Why do second gen antihistamines have long duration of action?
Form active metabolites w/ similar receptor binding profiles
Why do second gen antihistamines have lower affinity for muscarinic and adrenergic receptors?
Affinity is reduced by the large polar or charged alkyl groups linked to the piperidine/piperazine rings
What is the most sedating second gen antihistamine?
Cetirizine
How are antihistamines metabolized?
Aromatic hydroxylation, N-oxydation, or N-dealkylation by CYP P450, except once by MAO
What do PPIs act as?
Pro-drugs; only activated by acid secreted by parietal cells
What are PPIs used for?
H. pylori eradication w/ antibiotics
Are PPIs or H2 antagonists more effective for GERD?
PPIs
What do PPIs do?
Inhibit transmembrane H+/K+ ATPase
What is the rate of onset PPIs determined by?
- pKa1 (nitrogen of pyridine ring)
- pKa2 (nitrogen of benzimidaole ring)
Do all PPIs have the same mechanism?
Yes
Where can uncharged omeprazole travel?
Into parietal cell from blood and then into gastric lumen where pH = 1-2
Why can’t the predominant form of omeprazole cross the membrane into parietal cells?
Has a positive charge
What is the first step to make active omeprazole?
- Undergoes a series of rearrangement steps leading to the active form (uncharged)
- *Can only happen in gastric lumen next to parietal cell and in close proximity to the H+/K+ ATPase; cannot happen in blood!
Where does the active sulfenamide form of PPI occur?
In the low pH area immediately next to H+/K+ ATPase, so is the only protein that is alkylated
What is the active sulfenamide form of PPIs?
Unstable form that is very reactive and can react w/ any exposed Cys SH on a protein (but doesn’t b/c is only produced in low pH)
Ionized form of omeprazole displaces the equilibrium to the ___ side
Luminal
PPI’s w/ a higher pKa1 will have a ____ onset of action
Faster
What do ED pyridine ring substituents do to PPIs?
Increase alkalinity of the nitrogen and make it a better nucleophile
Which substituents will increase rate of reaction most for PPIs?
Para substituents that are ED by resonance
What does pKa1 determine?
The extent of ionization on the pyridine nitrogen (pKa1) dictates how much of the drug is sequestered at the site of action, which determines speed of onset
What does pKa2 determine?
The rate of conversion of PPIs to the active sulfenamide
A higher pKa2 means ____ protonation of the benzimidazole group and ___ onset
Faster; faster
Which PPI converts to the protonated sulfenamide that slowest?
Pantoprazole
What is significant about disulfide bonds in alkylated H+/K+ ATPase formed w/ PPIs?
Can exchange w/ endogenous sulfhydryl containing compounds such as GSH, Cys, and homocysteine (GSH most common)
When is the alkylated H+/K+ ATPase inactive?
When disulfide forms w/ particular cysteines
When is the H+/K+ ATPase active?
If GSH or another -SH compound removes the PPI
What is significant about GSH w/ respect to PPIs?
Can remove PPI from H+/K+ ATPase, forming GS-S-PPI, restoring activity of H+/K+ ATPase
What determines the duration of action from the point of recovery of acid secretion?
Cysteines in PPI’s and H+/K+ ATPase
Which cysteines are in the proton transport domain of the H+/K+ ATPase?
Cys 321, 813, and 822
What effect does disulfide formation w/ cys 892 have?
No effect on H+/K+ ATPase b/c not in the proton transport domain
Alkylation of cys ___ cannot be reversed by GSH
822
Which PPI has the longest half life for recovery of acid secretion and why?
- Pantoprazole
- Binds to Cys 822, which is is difficult for GSH to cleave the PPI-enzyme disulfide bond to free the enzyme
Which Cys is most easily reversed by GSH?
Cys 321
All PPIs bind to Cys ___
813
Which enantiomer of PPIs is less susceptible to metabolism by CYP 3A4?
(S)-enantiomer
Which PPI is only the (S)-enantiomer and what does this mean for kinetics?
- Omeprazole = racemic mixture
- Esomeprazole = (S)-enantiomer (has decreased metabolism, which means increased bioavailability and increased circulating drug)
What types of salts of PPIs are easier to form and why?
Na and Mg salts b/c PPIs are more stable in high pH environment (pH 7-10)
Why are PPIs unstable in low pH?
- If taken orally, PPIs will form active sulfenamide form in acid environment of stomach, and would alkylate any protein w/ exposed Cys or decompose rapidly
- B/c there are many other proteins to alkylate and b/c the H+/K+ ATPase is not necessarily in close proximity, PPIs cannot act “topically” in the stomach but must be absorbed
How do PPIs reach parietal cells if they are sensitive to low pH?
- Formulated w/ enteric coating that protects drug from gastric acid and drug is only released when it reaches the intestine
- Drug remains mostly unionized after release and is only protonated/activated at proton pump acid secretory site
What should PPIs not be taken w/ and why?
- Antacids
- May allow release of PPIs in the stomach
How are liquid formulations of PPIs made?
1) Suspension of delayed release granules
2) Can mix omeprazole powder (or crushed tablets) in a 8.4% sodium bicarbonate solution
What is a good predictor of the duration of activity for PPIs?
Half life for acid recovery better than half life of PPI
How is omeprazole metabolized?
- Hydroxylation by CYP 2C19
- O-demethylation by CYP 2C19
- Sulfone metabolite by CYP 3A4 (all PPIs do this)
Which drugs do PPIs interact w/?
- Azole antifungals (inhibit metabolism of PPIs and PPIs decrease absorption of ketoconazole)
- Macrolide antibiotics (inhibit PPI metabolism)
- Warfarin (PPIs increase warfarin effects)
- Digoxin
- BZDs (PPIs increase plasma levels of BZDs)
What are PPIs used for?
- GERD tx
- Combined w/ NSAIDs to prevent NSAID-associated ulceration of GI
- Part of “triple therapy” for treatment of ulcers caused by H. pylori
What effect does ACh have w/ respect to gastric acid?
Increase mucosal defences and increase HCl
What does gastrin do?
Increases HCl
Is histamine the only signal that increases production of gastric acid?
No
What is the effect of prostaglandins w/ respect to gastric acid and which prostaglandins have this effect?
- Increase mucosal defences and decrease HCl
- PGE2 and PGI2
What are the important cells of the stomach and what does each do?
- Superficial epithelial cells – produce mucus
- Chief cells – produce digestive enzymes
- Parietal cells – produce HCl
- G cells – produce gastrin
- Enterochromaffin-like cells – release histamine (this only happens in the GI)
What occurs when histamine enters the H2 ligand binding site?
- H-bond interactions btwn NH and Asp as well as btwn N and Thr
- Ionic bond interactions btwn Asp and NH3+
What change can be made when histamine enters the H2 ligand binding site if you want an antagonist?
Don’t want an ionic bond interaction
____ within the H2 receptor is critical for formation of the ligand receptor complex
Tautomerism
Which tautomer of histamine is required for initial binding to the H2 receptor?
Nt tautomer
What effect does increased Nt tautomer have?
Increased affinity for H2 receptor over H1
Which characteristics of histamine produce affinity for the H2 receptor?
- 4-methyl group retains H2 affinity while nearly eliminating H1 affinity
- 2 nitrogen’s in the 1 and 3 positions adjacent to the point of attachment of the amino ethyl group (side chain) produces some affinity for H2
Which characteristics of histamine produce affinity for the H1 receptor?
- 2-methyl group retains some H1 affinity while nearly eliminating H2 affinity b/c produces 50:50 ratio of Nt:N-pi tautomers
- N in the aromatic ring immediately adjacent to side chain needed for affinity for H1
- 2 methyl groups on the R2 N retain the most affinity for H1 receptors (3 methyl groups, making a quaternary amine, eliminate affinity for H1 and H2 receptors)
What makes guanylhistamine a partial H2 agonist?
Can bind to 2 sites w/in the H2 receptor, an agonist and antagonist site
What is the difference btwn a positive charged guanidine group on histamine vs. a neutral uncharged guanidine group on histamine w/ respect to agonists and antagonists?
- Positive charged guanidine would always be a partial agonist b/c it would bind to the agonist binding site
- Neutral uncharged guanidine would be capable of forming H-bond w/ antagonist binding site but would be incapable of forming an ion pair w/ agonist binding site, making it a pure antagonist
What effect does side chain length have on H2 antagonism?
Increasing side chain length increases binding w/ antagonist bind site, producing a pure antagonist
How can you improve potency of an H2 antagonist?
Add CH3 group to position 4, which increase proportion of Nt tautomer and increases H2 affinity
What can be added to a molecule to decrease the pKa of a guanidine group?
CN (triple bond) b/c it is strongly EW
What is cimetidine used for? Why isn’t it available OTC in Canada?
- Tx of GERD b/c inexpensive
- Has many drug interactions b/c of imidazole ring and subsequent CYP inhibition
What is the effect of cimetidine’s CYP inhibition?
Inhibits CYP enzymes, so drugs that are metabolized by CYP have delayed elimination and increased serum concentration
What are the major drug interactions w/ cimetidine?
- Carbamazepine
- Pentoxifylline
- Phenytoin
- Propafenone
- Theophylline
- Warfarin
What are some side effects of cimetidine?
- Anti-androgenic activity leading to gyneomastia
- Diarrhea, dizziness, rash (also w/ other H2 antagonists)
How is cimetidine metabolized?
- Aliphatic hydroxylation by CYP P450
- S-oxidation by CYP P450
What are the uses and side effects of ranitidine, famotidine, and nizatidine?
- Used as a cheap alternative to PPI’s for tx of GERD, though not as effective as PPI’s
- Diarrhea and dizziness are chief side effects
How is ranitidine metabolized?
- S-oxidation by CYP
- N-oxidation by CYP
- N-dealkylation by CYP
Which is the most potent and polar H2 antagonist?
Famotidine
What effects do NO2 and sulfonamide have on the planar, polar, neutral H-bonding group of H2 antagonists?
Both reduce pKa of planar, polar, neutral H-bonding group
Are H2 antagonists ever used over PPI’s?
Nope, PPI’s are first line and H2 antagonists are second line
