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40 Cards in this Set
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- Back
DESMOPRESSIN (DDAVP®)
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Releases stores of vWF into blood from “Weibel-Palade bodies” in
endothelial cells • vWF then leads to rapid elevation of factor VIII − Used to treat bleeding episodes and prior to surgery for prophylaxis of bleeding − Stores become depleted → Not for chronic treatment |
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ASPIRIN
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NSAIDs inhibit COX-1 and thromboxane synthesis by platelets and, hence,
inhibit platelet aggregation. • Aspirin is unique in that it is an irreversible inhibitor of platelet COX-1 at relatively low doses Treatment of suspected acute MI • Prophylaxis of primary (discussed above) and subsequent MI and ischemic strokes in patients at high risk, e.g. − those who have already suffered MI or stroke − stable angina, TIAs (mini-strokes), but not helpful for IC − those who have undergone bypass surgery or angioplasty • Aspirin should be avoided in patients with 1) Active peptic ulcer 2) Hepatic or renal disease 3) Disorders of blood coagulation |
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TICLOPIDINE (Ticlid®)
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Irreversibly block ADP-induced platelet aggregation.
• Ticlopidine and clopidogrel are taken orally • There is 1-2 day lag in the onset of action Due to bone marrow toxicity, drug label has a “Black Box Warning” and it is recommended that use of ticlopidine should be limited to patients who cannot tolerate aspirin. Problems are usually seen in first 3 months − Neutropenia - incidence ~2% − Thrombotic thrombocytopenic purpura (TTP) and aplastic anemia also occur - Incidence ~0.02% • USES − Thrombosis prophylaxis patients who have had a stroke or are at risk and those that have coronary artery stents inserted |
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CLOPIDOGREL (Plavix®)
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Irreversibly block ADP-induced platelet aggregation.
• Clopidogrel is a newer closely related drug, which has less frequent side effects than ticlopidine and appears to be slightly more effective than aspirin − Clopidogrel long-term (1-2 yr) treatment seems O.K. − Bone marrow toxicity (neutropenia), incidence 0.04% |
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ABCIXIMAB (ReoPro®)
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Abciximab is a mouse/human chimeric Fab fragment of an antibody to the
fibrin receptor integrin GpIIb/IIIa. − Blocks Irreversibly − Decreases death + MI associated with angioplasty from 10% → 5% • USES: Prophylaxis of thrombosis during percutaneous coronary interventions |
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DIPYRIDAMOLE (Persantine®)
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Inhibition of endothelial and platelet cAMP phosphodiesterases promotes
vasodilation and inhibits platelet aggregation. • ACTIONS − Coronary vasodilator and antiplatelet, precise mechanism uncertain − Blocks adenosine deaminase – elevates adenosine − Blocks phosphodiesterase – elevates cAMP |
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CILOSTAZOL (Pletal®)
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Inhibition of endothelial and platelet cAMP phosphodiesterases promotes
vasodilation and inhibits platelet aggregation. • Oral inhibitor of PDE III – raises cAMP • Femoral vascular beds particularly sensitive − Approved for treatment of intermittent claudication Antiplatelet Drugs 10/28/2008 17 • Side Effects − Increases heart rate and contractility – via cAMP elevation − Contraindicated in CHF patients (Chronic use of inotropic drugs, other than digoxin, is associated with increased mortality) |
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PROSTACYCLIN (PGI2, EPOPROSTENOL, Flolan®)
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PGI2 raises platelet cAMP and lowers platelet Ca2+ thereby inhibiting the release
reaction and platelet aggregation. Due to its short (2-3 min) half-life (see Eicosanoid notes) and the requirement for parenteral administration by continuous IV infusion, usefulness is limited. • Primarily used for treatment of primary pulmonary hypertension and pulmonary hypertension associated with scleroderma. Benefits arise from both dilation of pulmonary blood vessels and its inhibition of platelet aggregation and thrombosis. − Major side effect is a decrease in BP. • Can be used as an anticoagulant in place of heparin during extracorporeal circulation of blood, e.g. hemodialysis |
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HEPARIN
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Heparin accelerates the inactivation of thrombin, factor Xa and other proteases by
the endogenous plasma protein antithrombin III. Thus, provided the blood contains adequate antithrombin III heparin works in vitro and in vivo. |
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FONDAPARINUX (Pentasaccharide, Arixtra®, 2001)
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• Synthetic pentasaccharide containing only the antithrombin III binding
sequence • Stimulates inactivation of factors Xa (and IXa), but has no effect on thrombin • Clinical trials suggest it may be more effective than enoxaparin in prophylaxis of DVT associated with hip and knee replacement surgery • Half-life 17-21 hours |
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PROTAMINE SULFATE
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• Neutralizes heparin
• Protamine Sulfate (1 mg/100 u UH or 1mg/mg LMWH) is administered by IV infusion over a 10 min period • MECHANISM − Protamine is a strongly basic (positively charged), low mol. Wt. protein isolated from fish sperm, which combines with negatively-charged heparin to form an inactive salt. − Note that protamine is less effective in neutralizing LMWHs, producing a maximum effect of 60% − Protamine Sulfate itself has weak anticoagulant activity (binds to thrombin) and has a longer half-life than heparin. It should not, therefore be administered in excess. |
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enoxaparin (Lovenox®)
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Low Molecular Weight
Heparins (LMWH), LMWHs bind much less strongly to a variety of proteins. This leads to • Greater SC bioavailability • Longer and dose-independent half-life, • Lower incidence of thrombocytopenia • Less bleeding • Lower risk of osteoporosis • More effective in prevention and treatment of DVT and MI Net result: LMWHs permit 1-2 dose per day SC with no lab (or little) monitoring, but need to be careful in patients with renal problems or who are unusually large or small. LMWHs can also be self-administered by patient at home. |
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HIRUDINS
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Hirudin is a direct inhibitor thrombin obtained from the medicinal leech (Hirudo
medicinalis). Since thrombin is a powerful inducer of platelet aggregation, hirudin is potentially useful as an antiplatelet drug. • MECHANISM: It is a 65 amino acid protein, which binds to the “substrate” binding site and active site of thrombin but not the fibrin binding site. Hence, it can block fibrin-bound thrombin in the clot itself. (Remember, most of the proteases are protected from inhibition by antithrombin while they are bound within the clot). • Must be administered IV or SC |
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LEPIRUDIN
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recombinant proteins almost identical to hirudin
Lepirudin, IV infusion for treatment of HIT type II Administered by continuous IV infusion. Half-life 1.3 hr, excreted by the kidneys. Antibodies generated against lepirudin are seen in 40% of patients and may increase the anticoagulant effect by delaying renal excretion. Allergic and hypersensitivity reactions including anaphylactic shock have been reported. |
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WARFARIN
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NO EFFECT on coagulation factors or their precursors in vitro, i.e. indirect action
• Effects in vivo are only seen after a lag of 36-72 hrs. Note, however, that the t1/2 is long (37 ±15hrs) therefore steady state plasma concentrations will not be achieved for 7-10 days • Blocks γ-carboxylation of glutamate residues of newly synthesized factors II, VII, IX, X as well as protein C and protein S. • Normal levels of non-carboxylated factors are still found in the blood • The lag results from the time required for the natural decay of the normal factors and, thus, reflects the half-lives of factors IMPORTANT: Since the desired anticoagulant/antithrombotic effects are associated with depletion of factors II and X, loading doses should NOT be given, since this could deplete protein C below a safe level before prothrombin levels are affected |
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phytonadione
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VITAMIN K1
Administration of vitamin K increases active factors within 6-12 hours (oral) |
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STREPTOKINASE
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SK is a nonenzymatic protein (MW 47,000) activator of plasminogen
produced by type C β-hemolytic streptococci. • Mechanism: SK forms a complex with free Pg causing a conformational change that exposes its proteolytic activity. This complex then activates free Pg to plasmin (see Fig. 19). This therapy works because the streptokinaseplasminogen complex is resistant to inhibition by α2-antiplasmin. |
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ε-aminocaproic acid (EACA)
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Plasmin Inhibitor
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ALTEPLASE
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TISSUE PLASMINOGEN ACTIVATOR
This is the “natural” endothelial activator of Pg produced by recombinant DNA techniques. It is cleaved by plasmin to a two chain form without change in activity. • Supposed Advantages: Activation of Pg is limited to the surface of fibrin on the thrombus. No antibodies present/produced. • Disadvantages: Cost = $2,800. Half-life 5 min and 8 min for single and twochain forms respectively. • Usage: continuous IV infusion e.g. For treatment of MI: 15mg bolus followed by 0.75mg/kg (max 50mg) over 30 min then 0.5mg/kg over 60 min. For stroke: 0.9mg/kg (max 90mg) 10% as bolus followed by remainder over 60 min. |
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acetylcholine
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• Agonist at all muscarinic and nicotinic receptors, therefore not
selective - many effects • Quaternary compound - limited CNS distribution • Ester bond is hydrolyzed by esterases in gut and very rapidly by AChE and BChE in the blood stream - very short half-life • Virtually no therapeutic uses |
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pilocarpine
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cholinergic agonist
topical use for glaucoma selective for muscarinic actions. NOT a quaternary ammonium compounds - permanent charge. |
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bethanecol
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cholinergic agonist
selective for muscarinic actions quaternary ammonium compounds - permanent charge. Bethanechol is sometimes given orally or subcutaneously to treat urinary retention resulting from general anesthetic or diabetic neuropathy of the bladder, or to treat gastrointestinal atony (lack of muscular tone). |
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nicotine
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uses: insecticides, psychoactive drug
Various preparations available (gum, patch, inhalant). Use and abuse patterns related to time-action characteristics. Tertiary ammonium, lipophilic drug easily crosses mucosal membranes, blood-brain barrier, skin, etc. Agonist at NMJ, autonomic ganglia/adrenal medulla, and in CNS. |
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muscarine
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cholinergic agonist
of interest in relation to mushroom poisoning, and as prototype muscarinic agonist |
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edrophonium
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a simple
alcohol cholinesterase inhibitor Readily reversible inhibition of acetylcholine hydrolysis. Duration of action typically 5 - 15 minutes. Quaternary ammonium - no CNS actions Uses Diagnosis of myasthenia gravis Assess effects of longer acting anticholinesterases: If dose is too low, edrophonium will increase strength If dose is too high, edrophonium will decrease strength [i.e., depolarization block had occurred] |
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pyridostigmine
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anticholinesterase
Treatment of myasthenia gravis Duration of action largely determined by rate of enzyme regeneration. Pyridostigmine is the slowest of these examples. |
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physostigmine
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anticholinesterase
tertiary N physostigmine can cross the bloodbrain barrier, but the others do not. |
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Malathion
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organophosphate
Hydrophobic, lipophilic drugs that can be absorbed through skin. |
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(diisopropylfluorophosphate, DFP)
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organophosphate
Hydrophobic, lipophilic drugs that can be absorbed through skin. |
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pralidoxime
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for organophosphate poisoning, to help regenerate
cholinesterase Quaternary - Pralidoxime does not enter CNS Must be injected - usually by IV infusion High doses can block NMJ NOT effective after “aging” of the enzyme-inhibitor complex. |
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neostigmine
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anticholinesterase
myasthenia gravis |
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echothiophate
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anticholinesterase
topical for glaucoma |
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atropine
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competitive antagonist at muscarinic cholinergic receptors.
No significant action at nicotinic receptors. no fixed charge, distributes to CNS. should not be used in men with prostatic hypertrophy, or people with glaucoma. |
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scopolamine
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MUSCARINIC ANTAGONIST
compared to atropine, relatively greater CNS effects. Scopolamine distributes readily to CNS, some absorbed through skin. CNS effects - sedation; amnesia; dreamless-sleep. Especially with high doses or in presence of pain, restlessness, excitement, hallucinations, delirium. Effective for motion-induced nausea (motion sickness), some effectiveness against post-operative nausea |
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ipratropium
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MUSCARINIC ANTAGONIST
Quaternary compound - will not cross the blood-brain barrier. Used for certain respiratory diseases such as COPD (chronic obstructive pulmonary disease), asthma . Used by inhalation - helps achieve some selectivity. Desired effects - bronchodilation, inhibition of secretion. Adverse effects - dry mouth, etc. |
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tolterodine
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MUSCARINIC ANTAGONIST
Somewhat selective for M3 receptors. Relaxes the detrusor muscle in bladder. Relatively small effect on salivary and other glands. Used for overactive bladder, urinary frequency, urgency, incontinence. |
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Atropine poisoning
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All the effects previously noted are prominent -
“Dry as a bone, blind as a bat, red as a beet, mad as a hatter”. There is difficulty with thermoregulation. Especially with infants and younger children, hyperthermia may be quite prominent, and may lead to death. The elderly tend to be relatively more sensitive to the CNS effects - hallucinations, confusion. Many drugs have, as adverse effects, atropine-like effects. For some, the prominent signs of intoxication are the same as atropine. |
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Tubocurarine (curare)
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Rapid onset after i.v. injection.
Weakness progressing to flaccid paralysis. Small muscles involved in finely-controlled movements (such as eye muscles) are most sensitive, large muscles are less sensitive. Intercostals and diaphragm are least sensitive. Curare is partly excreted unchanged, and partly as metabolites. Compared to many newer drugs, curare has a relatively long duration of action. Curare is not 100% selective; it has some effect to inhibit transmission at autonomic ganglia. Curare can cause release of histamine from mast cells. competitive antagonists at the nicotinic receptor. Produce a non-depolarizing block |
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Mivacurium
Pancuronium Atracurium |
Competitive antagonists at nicotinic receptors of the skeletal neuromuscular
junction ALL of these are quaternary. Limited volume of distribution, and NO CNS EFFECTS. Thus, another drug must be given to depress consciousness. All the newer drugs are more selective than tubocurarine. Several (like vecuronium) are biotransformed more than tubocurarine, and have shorter halflives. Break-down products of some have neuromuscular blocking actions of their own. Atracurium breaks down spontaneously. One product (laudanosine) can cause seizures. Mivacurium is very short-acting – hydrolyzed by plasma esterase |
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succinylcholine
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Succinylcholine acts as an agonist at the nicotinic receptors of the NMJ.
Unlike acetylcholine, it is not hydrolyzed by acetylcholinesterase. It produces a depolarizing block - same as occurs with excess ACh or nicotine Succinylcholine action is intensified by anticholinesterase drugs (in contrast to their effect on non-depolarizing blockers). K+ may be released and cause serious hyperkalemia. Succinylcholine may produce malignant hyperthermia. |