Drug List Block 2 - Sheet1 Flashcards
1
Q
Synthetic analog of PGE2
Therapeutic uses:
- Cervical ripening
- Terminating early pregnancy/abortion
Mechanism:
1. Activation of collagenase also relaxing cervical smooth muscle EP4 receptor subtype (for cervical ripening)
- Uterine contractions via EP1/3 receptors
SE:
GI related (nausea, vomiting, diarrhea)
Fever
Uterine rupture: contraindicated in women having history fo cesarean section or other uterine surgery
A
Dinoprostone
2
Q
Analog of PGF2alpha
Therapeutic use:
- Termination of pregnancy in 2nd trimester
- Control postpartum hemorrhage that is not responding to conventional treatment methods
Mechanism:
- Stimulates uterine contractility by action at FP receptors
- Postpartum, the drug cause myometrial contractions via FP receptors. This provides hemostasis at the stie of placenta formation
SE: GI related (nausea, vomiting, diarrhea) Fever Uterine rupture (contraindicated in women having history of cesarean section or other uterine surgery) Rare case of bronchoconstrictino
A
Carboprost
3
Q
PGE1 analog
Therapeutic use:
Replacement therapy for prevention of ulcers caused by long term NSAIDS
Mechanism:
Suppresses gastric acid secretion by stimulating EP3 receptors on parietal cells; causes decrease in cAMP
Increase mucin and bicarbonate secretion
Increase mucosal blood flow
SE: Diarrhea-common and contraindicated in pregnancy
*(Misoprostol used with methotrexate or mifepristone for termination of early pregnancy)
A
Misoprostol
4
Q
PGE1
Use:
- Impotence/ED
- Maintenance of patent ductus arteriosus
Mechanism of action
- Increase in cAMP which relaxes smooth muscle fo corpus cavernosum
- cAMP mediated relaxation of ductus arteriosus smooth muscle
SE:
1. Pain at site of injection (reason for intra-urethral formulation)
Priapism: prolonged erection
2. Apnea in 10% of neonates,
A
Alprostadil
5
Q
PGI2 agonist
Therapeutic use: Primary pulmonary hypertension.
Mechanism: cAMP mediated dilation of pulmonary artery vascular smooth muscle
SE: Nausea, vomiting, headache, flushing
A
Epoprostenol
6
Q
Prostaglandin PGF2alpha analog
Uses: glaucoma and eyelash hypotrichosis
Mechanism: Increases outflow of aqueous humor and Increases the percent and duration of hairs in the growth phase.
Pharmacology: administered as opthalmic drops
SE: Eye redness, itching, permanent changes in eye color (increased brown pigment), eyelid skin; may increase length and number of eyelashes
A
Bimatoprost
7
Q
Mechanism: Blocks 11 beta hydroxylation so synthesis is stopped at 11-desoxycortisol. Does not inhibit ACTH release, so plasma ACTH increases stimulating synthesis and excretion of 17-hydroxycorticoids as 11-desoxycortisol.
Used as a diagnostic test
A
Metyrapone
8
Q
Competitive antagonist at progesterone and glucocorticoid receptors
Progesterone antagonist- Termination of pregnancy
Glucocorticoid antagonist- Treat cushing syndrome etc.
A
Mifepristone
9
Q
Competitive antagonists at mineralcorticoid receptor
Uses: diuretics, cardiac fibrosis/hypertrophy, HTN
A
Spironolactone
10
Q
Competitive antagonists at mineralcorticoid receptor
Uses: diuretics, cardiac fibrosis/hypertrophy, HTN
A
Eplerenone
11
Q
Progesterone and Mineralocorticoid and Androgen receptor antagonist
Mineralcorticoid antagonist-diuretic, antagonizes the salt retaining effects of estrogen
Progesterone Agonist- Used with estrogen to suppress ovulation and as hormone replacement therapy in post menopausal women
Androgen receptor antagonist
A
Drospirenone
12
Q
Responses: 1. Lymphocytopenia and monocytopenia, Prevent neutrophil adherence to endothelium, Inhibit action of chemotactic factors
2. Interferes with macrophage antigen processing, blocks the actions of lymphokines, inhibits binding to Fc receptors
Toxicity: 1. Suppression of adrenal-pituitary axis (acute adrenal insufficiency on abrupt withdrawal
2. Cushing’s syndrome
Contraindication: in presence of existing infection
Uses: in combination with other drugs in autoimmune diseases and to prevent graft rejection
A
Prednisolone
13
Q
Mechanism: Metabolized to 6-mercaptopurine, a purine antimetabolite that inhibits purine biosynthesis thereby inhibitng DNA synthesis, inhibits De novo AND salvage pathways.
Pharmacology: Orally active
Used to inhibit rejection of transplanted organs and some autoimmune diseases such as rheumatoid arthritis
SE: Bone marrow depression, GI and hepatic toxicity
A
Azathioprine
14
Q
Mechanism: alkylating agent that cross links DNA to kill replicating and nonreplicating cells.
Pharmacology: Toxic effect more pronounced on B cells so more effective in suppressing humoral immunity.
Orally active.
Use: treatment of autoimmune diseases in combination with other drugs.
NOT EFFECTIVE IN PREVENTING GRAFT REJECTION
SE: Bone marrow depression
A
Cyclophosphamide
15
Q
Mechanism: inhibitor of dihydrofolate reductase, inhibits folate dependent steps in purine synthesis, inhibiting DNA synthesis
Use: treat autoimmune diseases
SE: Hepatic toxicity
A
Methotrexate
16
Q
Mechanism: Lymphocyte selective immunosuppressant by inhibiting IMP dehydrogenase (necessary for de novo purine synthesis w no effect on salvage pathway). Lymphocytes cannot make GMP via salvage. More selective than AZA or methotrexate but equally effective
Pharmacology: Orally active
Used with cyclosporine and corticosteroids to prevent renal allograft rejection (allowing lower dose of cyclosporine)
Use: treat autoimmune diseases– rheumatoid arthritis and refractory psoriasis
Contraindications: Active GI disease, reduced renal function and infections. Also pregnancy (loss and congenital malformations)
SE: infection, leukopenia, anemia
A
Mycophenolate Mofetil
17
Q
Mechanism: binds to cellular receptor Cyclophilin and inhibits calcineurin (a calcium dependent phosphatase), blocking activation of transcription factor NFAT necessary for IL 2 production. Blocks T cell helper function.
Pharmacology: Orally active
Use: Prevent rejection of transplanted organs. some autoimmune diseases. more effective than other agents used with fewer side effects
SE: nephrotoxicity. Hepatotoxicity
A
Cyclosporine
18
Q
Mechanism: binds FK binding protein a cyclophilin related protein, same mechanism as cyclosporine. Spectrum is same but 50-100 more potent
SE: less nephro and hepatotoxicity
A
Tacrolimus
19
Q
Mechanism: Inhibits T cell activaiton and proliferation downstream of IL-2. Binds FKBP-12, binds and inhibits mTOR (not calcineurin), this mTOR is a kinase involved in cell cycle progression blocking G1->S transition
Use: Same as cyclosporine. Coating of cardiac stents.
A
Sirolimus
20
Q
Mechanism: Irreversible inhibitor of cyclooxygenase 1 and 2.
Uses: Cancer? CV disease (low dose) Fever, pain, (intermediate dose) Chronic inflammatory disease/rheumatoid arthritis (high dose)
SE: Typical NSAIDs side effects + Salicylism + Reye’s Syndrome
Pharmacology:
Non COX inhibition effects (1. Uric acid excretion 2. CNS 3. Respiration)
- At low dose decrease uric acid secretion. at high dose increase uric acid excretion.
- CNS (b/c crosses BBB) delirium psychoses, nausea, vomiting.
- Respiration (Direct stim of respiratory center to increase RR, leading to respiratory alkalosis, compensated by a renal excretion of bicarbonate.
- Salicylism
- Reye’s syndrome (liver failure and death related to viral epidemics
A
Acetylsalicylic Acid/Aspirin
21
Q
Mechanism: Reversible inhibitor of COX 1 and COX 2. Naproxen has a much longer plasma half life (14 hr vs. 2) than ibuprofen
Uses:
Both: Rheumatoid disorders (including juvenile rheumatoid arthritis), osteoarthritis, mild-to-moderate pain, dysmenorrhea, fever,
Ibuprofen: Inflammatory diseases, IV preparation to induce closure of PDA in premature infants less than 32 wk gestational age when usual treatments ineffective.
Naproxen: manage ankylosing spondylitis, acute gout/bursitis/tendonitis,
SE: Less GI effects than Aspirin
A
Ibuprofen and Naproxen
22
Q
Mechanism: Reversible inhibitor of COX 1 and COX 2
Uses:
gout
preterm labor (investigational)
IV form used for closure of patent ductus arteriosus in neonates,
not routinely used to treat pain or fever.
SE: Frequent adverse rxns, CNS severe frontal headache, better tolerated if given at night
A
Indomethacin
23
Q
Mechanism: Reversible inhibitor of COX 1 and COX 2
Uses:
Alternative for opioid analgesics in treatment of post-operative pain (short term, and much more effective for pain than inflammation)
SE: Serious adverse effects
A
Ketorolac
24
Q
Mechanism: Active metabolite (6methoxy2naphthylacetic acid) is reversible inhibitor of COX2 moreso than COX-1.
Uses:
Osteoarthritis
Rheumatoid arthritis
SE: Well tolerated with less GI effects
A
Nabumetone
25
Mechanism: Reversible inhibitor of COX 1 and COX 2. SUPER LONG HALF LIFE plasma T1/2 50 hours
Uses:
Symptomatic treatment of acute and chronic rheumatoid arthritis and osteoarthritis, advantage in osteoarthritis treatment because of LONG HALF LIFE.
SE: GI toxicity
Piroxicam
26
Mechanism: 5-aminosalicylic acid (mesalamine) active component linked to sulfapyridine (a sulfa antibiotic) by azo bond (which prevents absorption in upper GI tract). NOT CYCLOOXYGENASE INHIBITION. Possibly inhibition of IL-1, TNFalpha, lipoxygenase pathway, scavenging of free radicals oxidants, inhibition of NF-kappaB.
Uses:
Mild or moderately active ulcerative colitis (b/c of mesalamine)
Rheumatoid arthritis and ankylosing spondylitis (b/c of sulfapyridine)
SE:
High % for b/c sulfa moiety
Allergic rxns (rash, fever, hepatitis, pneumonitis, hemolytic anemia, bone marrow suppression)
Decreases number and motility of sperm
Therapeutic application: mild or moderately active ulcerative colitis, rheumatoid arthritis, and ankylosing spondylitis
Sulfasalazine
27
Mechanism: COX-2 selective inhibition. Metabolized by CYP450 2C9
```
Uses:
Rheumatoid arthritis and osteoarthritis
Primary dysmenorrheal
Management of acute pain
reduce # of intestinal polyps in familial adenomatous polyposis (COX2 contributory to certain cancers)
```
SE:
Hypersensitivity
Increase risk in GI irritation, ulceration, bleeding
Increased risk of adverse CV thrombotic events
Anemia (rare)
```
Contraindications:
Sulfonamide toxicity
Prior NSAID hypersensitivity
CV risk factors/disease
GI disease
Coronary artery bypass graft surgery
CYP2C9 deficiency
```
Celecoxib
28
Mechanism: No aff for COX1 or COX2 active site. inhibits reduction of COX to peroxidase form, brain selective? COX3?
Metabolized partially by liver microsomal system (CYP2E1, CYP1A2, CYP3A4), but mostly by glucoronidation and sulfation (95%)
Uses:
Treatment of mild-to-moderate pain and fever; does not have antirheumatic or anti-inflammatory effects
SE:
Well tolerated with little to no GI issues at normal doses. But with excessive use results in hepatic toxicity... evidenced by elevated liver enzymes like aminotransferase.
NAPQI (N-acetyl-p-benzoquinoneimine toxicity if glutathione reduced), covalently binds amino acids in proteins and enzymes.
N-acetylcysteine used to replenish glutathione stores to manage toxicity.
Contraindication:
Ethanol use, as alcohol induces CYP450 (producing NAPQI) and depletes glutathione.
Acetaminophen
29
1st generation with most sedative effect
| Uses: Allergies, Motion sickness, Sleeping, Early stage Parkinson's disease
Diphenhydramine
30
1st generation
| Uses: Allergies, Motion sickness, Vestibular disturbances
Dimenhydrinate
31
1st generation
Chlorpheniramine
32
1st generation
| Uses: Allergies, Motion sickness, Chemotherapy induced nausea and vomiting
Promethazine
33
2nd generation
| NOT metabolized by P450
Fexofenadine
34
2nd generation
| Metabolized by CYP450 to desloratadine
Loratadine
35
2nd generation with most sedative effect
| Active metabolite of hydroxyzine
Cetirizine
36
H2 receptor antagonist
| Has the most potential for adverse effect due to inhibiting P450 metabolism
Cimetidine
37
H2 receptor antagonist
Famotidine
38
H2 receptor antagonist
| Also inhibits P450 metabolism but to less of an extent than Cimetidine
Ranitidine
39
Mechanism: Stabilizes mast cell membrane to prevent release of histamine.
Uses:
Chronic control of asthma and prophylaxis of bronchospasm (allergen or exercise induced). NOT A RESCUE MEDICINE
Nasal formulation for allergies
Opthalmic formulation for conjunctivitis
Oral formulation for systemic mastocytosis (significant increases in mast cell numbers in the skin and internal organs)
Off label uses for food allergy and irritable bowel syndrome
SE: Safe drug/few side effects
Cromolyn sodium
40
Mechanism: IgG monoclonal antibody for which the antigen is the Fc region of the IgE antibody. Forms omalizumab-IgE complexes ergo no affinity for FcRI
Uses: Decreases amount of antigen specific IgE that normally binds to and sensitizes mast cells,
SE: Injection site reaction, anaphylaxis after the first dose and in some cases >1 year after initiation of regular treatment.
Omalizumab
41
5-HT2 receptor agonist. Hallucinogen
lysergic acid diethylamide
42
5-HT1A receptor partial agonist- antianxiety
buspirone
43
Agonist for 5-HT1D receptor on cerebral blood vessels.
Promote vasoconstriction. Treatment of migraine headaches, stops existing ones.
SE: nausea, vomiting, angina, dizziness, flushing
sumatriptan
44
5-HT4 partial agonist. Releases other enteric transmitters. Normalizes impaired intestinal motility, stimulates intestinal secretion
Uses: For irritable bowel syndrome with constipation in women.
SE: Taken off market 2007 due to CV effects, but restored with limited prescribing program
Tegaserod
45
Selective 5-HT2C receptor agonist. activation of receptors in the hypothalamus activate spropiomelanocortin (POMC) production
Uses: Treatment of obesity with BMI greater than 30. Promotes weight loss through satiety
Lorcaserin
46
Serotonin specific reuptake inhibitors (SSRIs), block active reuptake of serotonin. Increases amount of transmitter in synapse.
Uses: Treatment of affective disorders,, OCD, panic attacks.
SE:Sexual dysfunction nausea etc.
fluoxetine
47
Monoamine oxidase inhibitor, block metabolism of serotonin, NE, and DA. Increased synaptic serotonin.
Uses: Treatment of affective disorders and narcolepsy
SE: hypertensive crisis
phenelzine
48
5-HT2 antagonist, also histamine H1 antagonist.
Uses: Treatment of allergies, pruritis, urticaria. Carcinoid.
cyproheptadine
49
5-HT3 antagonist, CNS and GI action
Uses: Treatment of chemotherapy induced nausea and vomiting, post op and x ray therapy induced nausea and vomiting
ondansetron
50
Selective 5-HT3 antagonist
Uses: treat diarrhea predominant IBS in women.
SE: Can produce severe GI adverse effects. A restricted prescribing program must be followed
alosetron
51
Syntheized from serotonin in pineal. Own receptors M1, M2- Gi associated
Uses: Entrains circadian clock, target for insomnia treatment.
Melatonin
52
Vasodilator drugs
Nitroglycerin, Nitroprusside, Hydralazine, Minoxidil, Diazoxide, Ca2+ channel blockers, Verapamil, Diltiazem, Milrinone, Inamrinone, Cilostazol, Sildenafil, Tadalafil, ACE inhibitors, Fenoldopam, Prazosin
53
Bronchodilator drugs:
Albuterol, Pirbuterol, Terbutaline, Salmeterol, Formoterol, Ipratropium, Tiotropium, Theophylline, Aminophylline
54
Mechanism: Generation of nitric oxide, activating guanylate cyclase, increasing cGMP, resulting in relaxation. Venous dominant,
Uses: Heart failure
Effects: hypotension
Nitroglycerin/Isosorbide Dinitrate/Isosorbide-5-mononitrate
55
Mechanism: NO releasing, guanylate cyclase action, increase cGMP, relaxation. Arterial/venous both affected
Use: hypertensive emergencies
SE: hypotension
Nitroprusside
56
Mechanism: Unknown. Direct vasodilator
Uses: Heart failure patients, pill with Isosorbide dinitrate (works on venous circulation), working on arterial circulation. Severe/emergencies hypertension.
Hydralazine
57
Mechanism: K+ATP channel opening. Works on arterial circulation. Direct vasodilator
Uses: Severe hypertension and hair growth for males.
SE: Fluid retention (so use with diuretics)
Minoxidil
58
Mechanism: K+ channel opener, efflux of K+ leads to hyperpolarization, closing Ca2+ channel, preventing contraction
Uses: in hypertensive emergencies (and hypoglycemia) and in hypoglycemia
Diazoxide
59
Ca2+ Channel blockers
Examples: Nifedipine, Verapamil, Diltazem
Mechanism: Block the L-type Ca2+ channels. Non selective, and affect arterial circulation, block Ca2+ influx.
Heart vs. Vascular Smooth Muscle: PKA phosphorylates Ca2+ channel causing influx and contraction. Versus. PKA phosphorylates and inactivates MLCK, normally activating by phosphorylation Myosin light chain.
60
PDE3 inhibitors
Milrinone, inamrinone, cilostazol
Intracellular signaling
Used for heart failure (and dilate vacular smooth muscle)
61
PDE5 inhibitors
Sildenafil, tadalafil
Intracellular signaling
Erectile dysfunction
62
Mechanism: Vasodilator on endothelial through action on B2 receptor through release prostaglandins, nitric oxide, and epoxygenase metabolites. Increased by ACE inhibitor. (because ACE breaks down bradykinin). *SO A LITTLE DIFF THAN AT1 RECEPTOR BLOCKER*. Works on both arterial and venous circulation
Bradykinin
63
Mechanism: Dopamine 1 receptor agonist. Arterial and venous circulation
Use: Good for hypertensive crisis. Renal blood flow and Na excretion increased
Fenoldopam
64
Mechanism: Vasodilator that blocks NE acting on Alpha-adrenergic receptors. Arterial and venous circulation
Prazosin
65
Mechanism: Oxytocin antagonist, inhibit uterine contractions
Works through PLC, increasing Ca2+, causing contraction
Use: Preventing pre term labor
Atosiban
66
B2 adrenergic agonists
Bronchodilators
Examples: Albuterol (most widely used), Pirbuterol, terbutaline, Simeterol, Formoterol
Mechanism: Beta 2 agonist causes rise in cAMP/PKA resulting in relaxation. Also acts on Calcium activated potassium channels to cause Potassium efflux and hyperpolarization and relaxation.
SE: Cardiotoxicity-tachycardia (Beta 2 on the cardiac smooth muscle)
67
Anti cholinergic bronchodilator
Bronchodilators
Examples: Ipratropium, tiotropium
Mechanism: Block muscarinic receptors, blocking a contraction pathway. (Acetylcholine acting on M3 receptor typically causes contraction)
Use: Can also be used for inhibiting mucous secretion
68
Methylxanthine
Bronchodilator
Examples:Theophylline, aminophylline
Mechanism: Adenosine receptor antagonism and phosphodiesterase inhibition. Increasing cAMP leading to bronchodilation. Also inhibits Adenosine from causing bronchoconstriction.
Use: Good for mucous clearance, antiinflammatory actions, prevent edema by decreasing permeability.
69
ACE inhibitors
Examples: captopril, enalapril, lisinopril
Improves CHF survival, regardless of BP
Increases Bradykinin levels, resulting in increase in Nitric oxide and Prostaglandins
Decreases MAP when Angiotensin I given
Does not change MAP when Angiotensin II given
Does not change MAP when NE given
Increases decrease in MAP when Brady kinin given (enhances bradykinin response)
Does not change loss in MAP when other vasodilators given
SE: Cough and rash (due to elevation in bradykinin), Taste disturbance, rarely an allergic reaction resulting in angioedema (life threatening, and thus CANNOT USE ACE INHIBITOR. CONTRAINDICATION)
Pharmacology:
Racial differences in antihypertensive response (Blacks less response to ACE inhibition or angiotensin renin system. Thus the first antihypertensive you would prescribe is diuretic. Cauc/asian have same response to either)
70
Renal Vasodilators
Examples: Dopamine, Fenoldopam, Caffiene, Atriopeptins
Mechanism: Selectively dilates renal vasculature that modifies proximal tubular function. Increases RBF with no change to GFR, decreasing filtration fraction, resulting in decreased proximal tubular sodium reabsorption which is compensated by more distal nephron segments limiting diuretic effect
Therapeutic uses: Limited, hypertensive crisis and shock
71
Osmotic Diuretics
Examples: Mannitol
Mechanism: (1. Freely filtered. 2. Not reabsorbed. 3. Metabolically inert)
Given IV, act in tubular lumen as nonreabsorbable solute, Urine volume and Na+ excretion are proportional to osmotic load. Thus increased urinary excretion of sodium, potassium, chloride, water, and mannitol.
Therapeutic uses: Edema, glaucoma, acute renal failure
SE: Related to volume overload and expansion of intravascular fluid volume. Also a rare hypersensitivity
72
Inhibitors of carbonic anhydrase
Examples: Acetazolamide
Mechanism:
Weak diuretic
Inhibited by acidosis-limits clinical use
Filtered and secreted by Organic Acid Transporter, acts from tubular lumen
Inhibits Carbonic anhydrase in the proximal distal tubule (which normally provides H+ ions for bicarbonate reabsorption)
Increases excretion of Na+, K+, bicarbonate, H2O
Alkalinize the urine
```
Therapeutic uses:
Glaucoma
Alkalize the urine for decreasing drug toxicity
Altitude sickness
Anticonvulsant
```
SE: Metabolic acidosis and Hypokalemia
73
Loop diuretics
Examples: Furosemide, Bumetanide, Etharynic acid
Mechanism:
High efficacy (20-30%)
Rapid in onset and short duration of action (20 min)
Na+ K+ 2Cl- Symport inhibitors
Filtered and secreted by the OAT
Acts on the cortical and medullary segments of the ascending limb of the loop of Henle
Increase the excretion of sodium, potassium, chloride, and water
Increases the renal blood flow and GFR
Enhances calcium excretion
Large urine volume
Therapeutic uses:
Edema of cardiac, hepatic, or renal origin,
Acute pulmonary edema
Hypertension
```
SE:
Hypokalemia
Alkalosis
Hypovolemia
Hyperuricemia
Hyperglycemia (furosemide only)
Ototoxicity
```
74
Thiazide diuretics
Examples: Chlorothiazide, Hydrochlorothiazide, Metolazone
```
Mechanism:
Intermediate efficacy
Moderate onset (60 min)
Long duration
Filtered and secreted by the OAT
Inhibits Na-Cl symporter
Acts on cortical segment of distal tubule
Increases excretion of Na+ K+ Cl- H2O
Urine is hypertonic-unable to dilute
Increases K= secretion
Enhances urate reabsorption (PT)
```
Therapeutic uses:
Edema due to CHF
Hypertension
Hypercalcinuria/Ca salt-renal caliculi
```
SE:
Hypokalemia
Alkalosis
Hyperuricemia
Hyperglycemia
Decrease in GFR
```
75
Potassium sparing diuretics
Examples:
Spironolactone, Eplerenone (Aldosterone antagonists): Block aldosterone action on collecting duct
Triamterene, Amiloride (Na+ channel inhibitors): Block Na+ entry into principal cells of the collecting duct
```
Mechanism:
Low efficacy
Weak diuretic
Increases Na+ excretion without K+ loss
Increase Na+ excretion
Decrease K+ excretion
Increase urinary excretion of sodium, chloride, and H2O
```
Therapeutic uses:
Edema
Hypertension
Seldom used alone but with thiazide or loop diuretics to enhance naturesis without potassium loss
Aldosterone antagonism improves survival in heart failure
SE:
Low efficacy
Hyperkalemia if used alone, thus usually used with thiazide
Gynecomastia (spironolactone>>eplerenone)
Triamterene decreases RBF and GFR
Na+ channel inhibitors-mild azotemia
76
Heterogeneous mixture of sulfated polysaccharides
Large and highly negatively charged (must be IV or subcutaneous injection)
DOES NOT: affect synthesis of clotting factors or lyse existing clot
DOES: Prevent further clot formation and further extension of the clot
Cleared and degraded by the reticuloendothelial system (monocytes and macrophages in reticular connective tissue) and liver
Mechanism: Catalyzes antithrombin's inhibition of several coagulation proteases.
Therapeutic use:
Deep venous thrombosis or pulmonary embolism. (USE IV INFUSION FOR INITIAL TREATMENT, also administer warfarin)
Low dose used as prevention in surgical patients
Initial management of unstable angina or acute myocardial infarction
Coronary angioplasty or stent replacement
Surgery requiring cardiopulmonary bypass
In Vitro with: 1. hemodialysis, 2. blood samples drawn for lab, 3. Maintain patency of indwelling arterial catheters
Does not cross placenta, so used in pregnancy for anticoagulation
SE:
Bleeding/hemorrhage (treat with protamine sulfate)
Heparin induced thrombocytopenia (immune response decreasing platelet counts by 50% due to IgG antibodies formed against complex of heparin-platelet factor 4 a chemokine released during platelet activation binding to FcgammaIIa receptors on platelet). Discontinue heparin and use LMWH or lepuridin
CI:
active bleeding
Severe uncontrolled HTN
Recent surgery of eye, brain, spinal cord
Heparin (UFH)
77
Suicide substrate for thrombin, 10a, 9a, 11a, 12a
Because activated coag factors attack specific Arg-Ser peptide bond in the reactive site, becoming trapped and inactivated.
1000 fold increase in rxn rate in presence of heparin. 3x D-glucosamines and 2x uronic acid residues bind to AT making reactive site more accessible to proteases.
Antithrombin function
78
Examples: Enoxaparin/Dalteparin
Fragment of standard MW Heparin.
Administered subcutaneously, with longer half life than heparin so advantage in hospital setting.
Poorly catalyze inhibition of thrombin by ATIII because it can no longer ALSO bind to the thrombin (in addition to the ATIII). You end with somewhat more specificity for 10a,9a,11a,12a.
```
Therapeutic Use:
Acute DVT
Prophylaxis of DVT
Hip replacement surgery, during, and following hospitalization
Acute unstable angina and MI
```
SE:
Risk in patient with renal disease due to renal elimination
Less risk of bleeding compared to heparin
Lower risk of thrombocytopenia compared to heparin
```
CI:
Active bleeding
Severe uncontrolled hypertension
Recent surgery for eye, brain, spinal cord
Renal impairment
```
Low molecular weight heparins (LMWH)
79
LMWH
Enoxaparin/Dalteparin
80
Direct thrombin inhibitor
Mechanism: Inactivates thrombin by blocking the substrate binding site 1:1 complex. Bind to both the catalytic site and exosite 1
IV administration (as compared to dabigatron, which is oral)
Renal excretion
Therapeutic use: alternative to heparin in patients with heparin-induced thrombocytopenia
Lepirudin/Bivalirudin
81
Direct Factor 10a inhibitor
Synthetic pentasaccharide
```
Subcutaneous administration (as compared to rivaroxaban, which is oral)
Renal excretion
```
Therapeutic use:
Prevention of DVT in patients undergoing surgery
Treatment of acute PE
Treatment of acute DVT w/o PE
Fondaparinux
82
Heparin antagonist Low MW, + charged.
1:1 binding with heparin
SE:
Weak anticoagulant properties in high doses or when alone
Anaphylactic reaction from fish hypersensitivity and previous exposure from insulin products
Severe pulmonary hypertension
Therapeutic use:
Heparin overdose with acute bleeding that cannot be controlled by stopping heparin
Reverse heparin following cardiopulmonary bypass
Protamin sulfate
83
Oral anticoagulant
Structural analog of Vitamin K. 3 types, racemic/S/R...
Administered as racemic but S is more active form.
Metabolized differently KNOW MORE FOR S: (S uses CYP2C9) (R uses CYP1A1, 1A2, 3A4)
Mechanism: (Moreso S-warfarin) Blocks VKORC1 (vitamin K reductase), preventing the recycling of oxidized Vitamin K (epoxide) to the reduced form (hydroquinone). This results in preventing the gamma-carboxylation of several glutamate residues in
prothrombin, 7,9,10, and endogenous anticoagulalant proteins C and S.
This is a competitive inhibition because Vit K administation will displace warfarin.
Therapeutic effect not seen for several hours to days
Peak plasma at 24 hours
```
CI:
same as heparin, also
CYP2C9 polymorphisms
Genetic variations in VKORC1
Pregnancy/teratogenic, boen metabolism is vit k dependent
Liver, kidney disease, vit k deficiency
```
Adverse reactions that are rare
Purple toe syndrome
Skin necrosis/gangrene
Warfarin
84
PT, prothrombin time
1. Blood sample collected with citrate to inactivate calcium and prevent clotting
2. Add thromboplastin, a saline extract of brain containing tissue factor and phospholipids
NORMAL CLOTTING in 12-14 seconds
Tests extrinsic and common pathway.
*There is a variability in thromboplastin, so ratio of patient PT to a control PT is obtained by standard method using WHO primary standard thromboplastin. So you actually measure INR
Normal INR between 0.8-1.2
Warfarin is therapeutic when PT betwen 15-26
INR usually 2-3
*Therapeutic effect of warfarin delayed because... blocks synthesis of clotting factors. The circulating factors are not inhibited by warfarin. so These active factors are still aorund while no longer able to synthesize any more active factors
How to test for warfarin function
85
If INR at therapeutic 2-3: Stop drug
If INR>5: give Vitamin K
For immediate reversal: transfusion with fresh frozen plasma
How to reverse warfarin
86
1. CYP2C9*2 and *3 have decreased activity so wafarin not inactivated so use less warfarin
2. VKORC1 variants. If produce less, then use less warfarin. If produce more, use more warfarin
Why might the dosage of warfarin be varied among individuals
87
Oral anticoagulant.a direct thrombin inhibitor.
Lepirudin is the IV equivalent
Given as a pro-drug, metabolized to active dabigatran
Mechanism: interacts with active site of thrombin thus potent, reversible, competitive direct thrombin inhibitor that inhibits BOTH FIBRIN-BOUND AND FREE THROMBIN
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Pharmacokinetics:
Predictable
Oral
Rapid onset (2 hours peak plasma)
Short half life (14-17 hr)
Not substrate for CYP450
Excreted by kidney
Must be carefully stored since administered as pro-drug can breakdown if exposed to moisture (30 days of stability)
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P-glycoprotein can limit oral absorption of drugs by transporting them back into GI.
SE:
Less for bleeding compared to warfarin
No antidote!! Depends on excretion with plasma halflife of 14 hr
Upset GI
CI:
Renal impairment
Advanced liver disease
Valvular heart disease (bioprosthetic heart valves). More dangerous than with warfarin.
Drug interactions with P-glycoprotein efflux transporters. (If used with P-gp inducer, plasma conc and half life reduced. If used with P-gp inhibitor, increased plasma concentration)
Therapeutic Use:
Patients with nonvalvular atrial fibrillation at risk for stroke or systemic embolism
Prophylaxis in patients with knee or hip replacement
Dabigatran
88
Oral anticoagulant, a direct 10a inhibitor
Fondaparinux is the subcutaneous equivalent
(notice the Xa in the name..)
Good because Xa is primary site of amplification (1000 cul thrombin per 1 cul Xa)
Also good because you wouldn't affect existing thrombin levels
Unlike heparin, capable fo gaining access to clotbound factor 10a. Inhibits both free factor 10a and factor 10a in the prothrombinase complex. This prevents extension of the thrombus by blcoking further generation of thrombin within the clot
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Pharmacokinetics:
1/3 renal eliminated unchanged
2/3 metabolized in liver, half of which renal half of which hepatobiliary route
CYP450 metabolized.
Substrate for P-glycoprotein
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No significant between group difference in risk of major bleeding ALTHOUGH INTRACRANIAL AND FATAL BLEEDING OCCURRED LESS FREQUENTLY WITH RIVAROXABAN GROUP
SE:
Bleeding
Drug interactions with CYP3A4 inhibitors/inducers AND P-glycoprotein inhibitors/inducers
No good monitoring
Therapeutic Use:
Similar to dabigatran
(patients with nonvalvular atrial fibrillaiton at risk for stroke or systemic embolism)
(Prophylaxis in patients with knee or hip replacement)
Rivaroxaban
89
Thrombin bound to fibrin within a thrombus remains enzymatically active and protected from inactivation by antithrombin.
Fibrin-bound thrombin can locally activate platelets and trigger coagulation thereby causing thrombus growth
Importance of free thrombin vs. fibrin-bound thrombin
90
None. little effect on PT or INR
Monitoring of dabigatran and rivaroxaban
91
Aminocaproic acid
Tissue plasminogen activator (t-PA)
Alteplase
Thrombolytic drugs
92
Plasminogen converted to plasmin by cleavage of single peptide bond Arg560-Val561). Generates a towo chain disulfide linked molecule exposing the kringles. N terminus/heavy chain has 5 disulfide bonded loops to bind lysine residues in polymerized fibrin. C terminus/light chain, contains the active catalytic site
t-PA (endogenous) and Alteplase (exogenous) cleaves the ARG-VAL bond to form plasmin from plasminogen
Plasmin is fibrin-specific due to alpha2-antiplasmin
Mechanism for fibrinolysis
93
t-PA recombinant
Activates bound plasminogen several hundred fold more rapidly than free plasminogen
Very short half life, requires IV
Limits systemic lytic state only at low phys concentrations.
SE: Hemorrhage
Therapeutic Uses:
Acute MI (STEMI)
Treatment of pulmonary embolism/DVT
Stroke within first 3 hours
Alteplase
94
Inhibitor of Fibrinolysis
A lysine analog that binds to lysine binding sites on plasminogen and plasmin blocking binding of plasma to fibrin
Reverse states assoc with excessive fibrinolysis
Concentration in urine can be 100x that in plasma; useful for treating urinary tract bleeding
Aminocaproic acid
95
Aspirin
Dipyridamole
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor
Abciximab, Eptifibatide
Antiplatelet drugs
96
GlycoProtein receptor proteins (integrins) binding collagen, vWF causing platelets to adhere to subendothelium: GPIb, GPIa/IIa,
GPIIb/GPIIIa: glycoprotein receptor binding fibrinogen
PAR1/PAR4: protease activated receptors; thrombin (IIa) binds to these receptors
P2Y/P2Y12: purinergic receptors for ADP
Activation of PAR1/PAR4 or P2Y1/P2Y12 receptors: stimulates COX and GPIIb/IIIa: fibriongeon binding results in cross linking of adjacent platelets
COX mediated production of TXA2/PGI2
Important platelet receptors
97
Low dose aspirin. Irreversible inhibitor of COX-1 in platelets, inhibit platelet production of TXA2 preserves PGI2
SE: GI irritation/bleeding
low dose aspirin could haeve potentially adverse effects assoc with aspirin/nsaids like hypersensitivity
Therapeutic uses:
MI prophylaxis
alone or in comb with thrombolytics in acute MI
Acute phase of ischemic stroke
Stroke prophylaxis
Unstable angina/acute coronary syndrome (unexpected chest pain at rest)
Preeclampsia prophylaxis- remains controversial
Aspirin
98
A vasodilator and inhibitor of platelet aggregation
Main mechanism: Inhibition of phosphodiesterase (PDE3 and PDE5), increasing cAMP in platelet, inhibits platelet aggregation
SE: headache/GI upset
Therapeutic use:
Primary prophylaxis of thromboemboli in patients with prosthetic heart valves, given in combination with warfarin
In combination with aspirin for secondary prevention of MI or TIA
Dipyridamole
99
Mechanism:
Act through ADP receptor (P2Y1/P2Y12) receptors to inhibit ADP induced platelet aggregation
2 different GPCR that mediate platelet aggregation
P2Y1 couples to Gq, increases PLC, increases calcium
P2Y12 couples to Gi, decreases AC, decreases cAMP, decreases PKA
IF stimulate ADP receptor=get platelet aggregation
If block ADP receptor=block platelet aggregation
All are irreversible except ticagrelor
Oral drugs
Prasugrel prodrug with 2 step process: esterase mediated hydrolysis, then CYP3A4 and 2B6 to active cmpd
Clopidogrel and Ticlopidine are prodrugs metabolized to active compound by CYP2C19
Advantage of reversible anti platelet drug?
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor Mechanism
100
SE:
Bleeding-all drugs
Ticagrelor specific-dyspnea
Ticlodipine-neutropenia (so used much less often if at all)
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor SIDE EFFECTS
101
* DRUG INTERACTION BETWEEN ASPIRIN AND CLOPIDOGREL
CYP2C19 polymorphisms, poor metabolizers, meaning not as much active drug
also
Patient taking both aspirin and clopidogrel complianing of GI irritation. Prescribed proton pump inhibitor omeprazole which is also a substrate for CYP2C19. Leading to less active metabolite of clopidogrel
Clopidogrel mechanism importance...
102
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Clopidogrel:
Unstable angina
NSTEMI (non-occlusive thrombus) in comb with aspirin
STEMI (occlusive thrombus)
Recent myocardial infarction, stroke
Established peripheral arterial disease
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Prasugrel:
Manage patients undergoing percutaenous coronary intervention (PCI) for UA, NSTEMI, STEMI
Ticagrelor:
Used with aspirin for secondary prevention in patients with UA, NSTEMI, STEMI
To manage patients undergoing PCI a/o coronary artery bypass CABG
Clopidogrel, Ticlopidine, Prasugrel, Ticagrelor THERAPEUTIC INDICATIONS
103
GbIIb/IIIa antagonist, IV preparations
Abciximab: quick onset but delayed clearance. Effective up to 7 days
Eptifibatide: Quick onset, quick offset (normal platelet aggreg within 8 hr of stopping) renal clearance
SE:
Bleeding
Thrombocytopenia, hypotension, bradycardia
Eptifibatide, caution in patients with renal disease
Clinical use:
Abciximab:
Patients undergoing PCI, including angioplasty or stent placement
In comb with aspirin and heparin (or LMWH)
Also used with alteplase for thrombolysis
Eptifibatide:
Patients with unstable angina and myocardial infarction, often with LMWH
Patients undergoing PCI, including angioplasty or stent placement
Abciximab/Eptifbatide pharmacokinetics, SE, Use
104
Fab fragment of the chimeric human murine monoclonal antibody
Prevents binding of fibrinogen, vW factor, and other adhesive molecules
Blocks access of the molecules to the receptor. Not a direct interaction with the binding site of the GPIIa/IIIb receptor. noncompet
Abciximab
105
Cyclic heptapeptide
Derivative of Disintegrins, proteins from snake venoms inhibiting platelet aggregation
Contains KGD (Lys,-Gly, Asp) sequence motif binding specifically to GpIIb-IIIa receptors ont he platelet surface blocking binding of fibrinogen activated platelets
Competitive and reversible inhibitor
Binds specifically to the receptor
Eptifibatide
