Pharm2Exam2 Flashcards
Toxicokinetics
Absorption, distribution, metabolism, and excretion of toxins, toxic doses of therapeutic agents, and/or their metabolites.
Toxicodynamics
Describes the harmful effects of the toxins or toxic doses to vital organ functions. (what the drug does at the receptor level)
DEFG of toxicology
Decontamination
Targeted Elimination
Focused Therapy
“Get toxicologist’s help”
Anticholinergic Toxicity
Decreased PANS
myadriasis, blurred vision, fever, flushed dry skin, AMS, seizures, urine retention/constipation, hypertension, tachycardia
Anticholinergics
Antihistamine (diphenhydramine) Anticholinergic (atropine) Antipsychotic (haloperidol) Antidepressants (TCAs) Environmental (Jimson Weed, Gyromitra)
Physostigmine
Treatment for anticholinergic toxicity
Reversible AChE antagonist
Increases cleavage of ACh at the neuromuscular junction
Used IF: no co-ingestions (TCAs), no seizures, significant AMS, need CV monitoring, may need infusion
Cholinergic Toxicity
Increased PANS activity
muscarinic, nicotinic, and CNS effect
Cholinergics
Organophosphates (pesticides) Carbamates (physostigmine) Iatrogenic (edrophonium) Nerve gas (VX) Mushroom species
Muscarinic Toxidrome
Diarrhea, diaphoresis, urination, miosis, bradycardia, bronchorrhea, bronchospasm, emesis, lacrimation, salivation
Nicotinic Toxidrome
Myadriasis, Tachycardia, weakness, Hypertension, Fasciculations
CNS Cholinergic Tox
Agitation, seizures, coma
Cholinergic Tox treatment
Atropine, Pralidoxime, BZDs
Atropine
Cholinergic tox treatment
1-2 mg IV every 5-10 mins, short acting
May need infusion
Pralidoxime
VX gas antidote
1-2 grams infused over 30 mins
Diazepam
Benzodiazepine - cholinergic tox treatment
Helps CNS effects
Adrenergic Toxidrome
Increases SANS
CNS: AMS, increase temp, seizures
Myadriasis, increased BP and HR, diaphoresis, nausea, vomiting, urine retention
Adrenergic treatment
BZDs, temperature regulation, fluid administration, BP management (verapamil IV, NTG) maybe labetalol - NO BETA only BLOCKERS
BB/CCB toxicity
Myocardium transitions from FFA to glucose substrate = anaerobic metabolism
hypoglycemia
BB: blockade of both B1 and B2 receptors, high dose = blockade of Na channels, decreased entry of Ca and decrease cAMP release, decreased BP and HR
CCB: Decrease SA/AV conduction, reduced CO and BP
Salicylate (ASA) TOX
Antiplatelet Agent
MOA: irreversibly binds COX-1 and inhibits prostaglandin synthesis. uncoupling of oxidative phosphorylation (aerobic metabolism) and disruption of cellular metabolism.
SEs: gastric bleeding, ulcers
Metabolized into salicylic acid and acetic acid metabolites
*triad of hyperventilation and dizziness, GI upset (vomiting), tinnitus
Treatment: gastric decontamination (activated charcoal), LOW Vd, Hemodialysis!
Acetamenophine (APAP)
active metabolite = N-acetyl-p-benzoquinone
Glutathione required to detoxify NAPQI from liver, glutathione depletion = CYP2E1 saturation and tox
Treatment = N-acetylcystine (NAC) usually IV
MOA tox: covalent binding of protein adducts, Kupffer cells and formation of IL, damage is mainly irreversible
Toxic Alcohols
Methanol, ethylene glycol, ethanol, propylene glycol = hyperosmolality AND metabolic acidosis
Isopropranol only = hyperosmolality
HD used as treatment
Unfractionated Heparin
MOA: short half life (2 hours), administered SQ or IV.
Frequent monitoring with activated partial thrombinplastin time (aPTT) UFH tox reversed with Protamine
Protamine
Heparin OD treatment
Slightly basic pH, large dose will result in paradoxical bleeding and CV changes
Ticlopidine
Antiplatelet Agent
ADP antagonist
*not as commonly used
MOA: interferes with the binding of ADP to its receptor on platelets and therefore inhibits the activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen and bind to each other.
Results in reduced platelet aggregation
Use: Alternative to aspirin in TIA, post-MI, and unstable angina, post-coronary artery stent procedure
Side Effects: GI bleed, neutropenia *RARE side effect of thrombocytopenia
Clopidogrel
Antiplatelet Agent
ADP antagonist
MOA: interferes with the binding of ADP to its receptor on platelets and therefore inhibits the activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen and bind to each other.
Results in reduced platelet aggregation
Use: Alternative to aspirin in TIA, post-MI, and unstable angina, post-coronary artery stent procedure
Side Effects: GI bleed, neutropenia
Prasugrel
Antiplatelet Agent
ADP antagonist
MOA: interferes with the binding of ADP to its receptor on platelets and therefore inhibits the activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen and bind to each other.
Results in reduced platelet aggregation
Use: Alternative to aspirin in TIA, post-MI, and unstable angina, post-coronary artery stent procedure
Side Effects: GI bleed, neutropenia
Ticagrelor
Antiplatelet Agent
ADP antagonist
MOA: interferes with the binding of ADP to its receptor on platelets and therefore inhibits the activation of GP IIb/IIIa receptors required for platelets to bind to fibrinogen and bind to each other.
Results in reduced platelet aggregation
Use: Alternative to aspirin in TIA, post-MI, and unstable angina, post-coronary artery stent procedure
Side Effects: GI bleed, neutropenia
Antiplatelet Agents
Aspirin (ASA), ticlopidine, clopidogrel, prasugrel, ticagrelor
Glycoprotein IIb/IIIa inhibitors
Abciximab, Tirofiban, Eptifibatide
Abciximab
GP IIb/IIIa inhibitor
MOA: monoclonal antibody against GP IIb/IIIa receptors on platelets. Prevents the binding of fibrinogen and other adhesive molecules to GP IIb/IIIa = prevention of platelet aggregation. IV administered
Indication: in patients undergoing percutaneous coronary intervention, unstable angina, and post MI
SEs: Bleeding and thrombocytopenia
*Long acting 18-24 hrs
*Hepatic metabolism no dose adjustment for renal dysfunation
Tirofiban
GP IIb/IIIa inhibitor
Indication: in patients undergoing percutaneous coronary intervention, unstable angina, and post MI
SEs: Bleeding and thrombocytopenia
*Short acting 6-12 hrs
*IV and infusion, requires dose adjustment for renal dysfunction
Eptifibatide
GP IIb/IIIa inhibitor
Indication: in patients undergoing percutaneous coronary intervention, unstable angina, and post MI
SEs: Bleeding and thrombocytopenia
*Short acting 6-12 hrs
*IV and infusion, require dose adjustment for renal dysfunction
Direct Thrombin inhibitors
Argatroban, Bivalirudin, Dabigatran
Argatroban
Direct Thrombin Inhibitors
MOA: synthetic manufactured, IV infusion. Half life 0.5-1 hr
Use: patient that do not react to UFH or ADR
SEs: bleeding dependent of dose
*need dose adjust for hepatic dysfunction
*dose titrated to aPTT monitoring
Bivalirudin
Direct Thrombin Inhibitor
MOA: synthetic manufactured, IV infusion, bolus. Half life 25 min. cleared hepatic and some renal
Use: patient that do not react to UFH or ADR, ACS treatment via PCI
SEs: bleeding dependent of dose
*Monitored via ACT
Dabigatran
Direct Thrombin Inhibitor
Novel oral agent
MOA: pro-drug, no need for extensive monitoring and low drug interactions. Target is thrombin inhibition. Low bioavailability, 1/2 life 14-17 hrs, mainly renal clearance
USE: evaluating outpatient use in DVT and PE
Xa Inhibitors
Enoxaparin, Rivaroxaban, Apixaban
Enoxaparin
Xa inhibitor
Rivaroxaban
Xa inhibitor
MOA: inhibit factor Xa, high bioavailability, half life 7-11 hrs, no monitoring required, hepatic and renal clearance
USE: outpatient treatment of DVT and PE
*may have drug ixn with CYP450 3A4 and P-gp
Apixaban
Xa inhibitor
MOA: inhibit factor Xa, medium bioavailability, half life 12 hrs, no monitoring required, mainly hepatic clearance
USE: outpatient treatment of DVT and PE
*May have drug interaction with CYP450 3A4
Fonsaparinux
Synthetic Anticoagulant
Warfarin
Anticoagulant
MOA: inhibition of hepatic-vitamin K dependent clotting factors (II, VII, IX, and X), long acting therapy, primarily protein bound, liver metabolism (CYP2C9 and CYP3A4). S-isomer is more potent and is 2C9, R is 3A4. Crosses placenta CONTRAINDICATED IN PREGNANCY
*Monitored with prothrombin time (PT) and international normalized ratio (INR)
indications: Long-term outpatient anticoagulation for DVT, PE, stroke, AF, and inherited clotting disorders (Protein C and S deficiencies)
AEs/SEs: bleeding, GI bleed, skin necrosis, multiple drug interactions, teratogenic
*Toxicity reverse with vitamin K and blood products
Drug ixn: Acidic molecule so oral cholestyramine can decrease absorption, protein binding drugs can displace (ASA, sulfonamides, and phenytoin) increasing active drug, inducers and inhibitors of CYP2C9 and 3A4 will alter drug concentrations
Phytonadione
Vitamin K clotting agonist
Warfarin OD treatment (?)
aminocaproic acid
Lysine derivative
Inhibitor of fibrinolysis
Tranexamic acid
Lysine derivative
Inhibitor of fibrinolysis
Thrombolytics
Streptokinase, Alteplase, Tenecteplase, Reteplase
USE: Coronary thrombosis, PE, DVT, AMI, Stroke
Streptokinase
Thrombolytic
derived from B-hemolytic streptococcus bacteria (antigenic activity)
MOA: inhibits thrombin, promotes conversion of plasminogen to plasmin
Indication: AMI, stroke, and PE
Alteplase (tPA)
Thrombolytic
Often used in non-hemorrhagic strokes but time of administration is key
MOA: inhibits thrombin, promotes conversion of plasminogen to plasmin = clot lysis Selectively activates plasminogen that is bound to fibrin (selective clot lysis)
Indication: AMI, stroke, and PE (time critical)
*Less hemorrhagic episodes than other thrombolytics due to specificity.
Reteplase
Thrombolytic
MOA: synthetic agent, inhibits thrombin, activates conversion of plasminogen to plasmin = clot lysis
Indication: AMI, stroke, and PE
More use in cardiology
Tenecteplase
Thrombolytic
MOA: Synthetic agent, activates plasminogen to plasmin = clot lysis
Indication: mainly AMI, can be used for stroke and PE too more use in cardiology
Heparin Immune Mediated Thrombocytopenia (HIT)
More severe thrombocytopenia
MOA: antigen-antibody reaction, onset 7-14 days, diagnostic testing, PLT less than 150,000 or >50% decrease from baseline
*Needs additional therapy: DTI (short-term), Warfarin (home)
Heparin Associated Thrombocytopenia (HAT)
MOA: onset less that 7 days, temporary, requires supportive care but no additional therapy, may continue heparin therapy and monitor PLT
Rapid Preparation Insulin
Drugs: Lispro, Aspart, glulisine
MOA: rapid onset of action/control, but do not last long. ~4 hrs, control for meal time
Short Preparation Insulin
Regular insulin
MOA: onset of 30 mins, SQ administration or IV
Intermediate preparation Insulin
Neutral Protamine Hagedorn (NPD) or Isophae
MOA: onset ~2 hrs, duration of 4-12 hrs
Long preparation insulin
Drug: Glargine and Detemir
MOA: Slow onset (1 hr), and lasts 12-24 hrs
Sulfonylureas
2nd gen: Glyburide, Glipizide, Glimepiride
MOA: alteration of the K dependent channel to result in increased depolarization. This = indirect increase in Ca entry into the cell and insulin release.
Toxicity: Hypoglycemia and increased drug activity due to secondary organ dysfunction (liver or kidney)
Glyburide
Sulfonylureas Oral insulin therapy
Glipizide
Sulfonylureas Oral insulin therapy
Glimepiride
Sulfonylureas Oral insulin therapy
Insulin Secretagogues
Meglitinide class: repaglinide
D-Phenylalanine: Nateglinide
Metabolized in liver
Repaglinide
Insulin Secretagogue, Meglitinide class MOA: similar to sulfonylureas but with faster onset (60 mins) and metabolism via 3A4 Absent of sulfur structure so can be utilized in patients with sulfur allergy
Nateglinide
Insulin secretagogue, D-Phenylalanine
MOA: Similar to sulfonylureas, and no sulfur allergy
Metabolized via 2C9 and 3A4
Metformin
Biguanide Oral insulin agent
MOA: reduce hepatic glucose production via activation of an enzyme AMP - activated protein kinase (AMPK)
Tox: GI (N/V, abdominal pain), lactic acidosis**,
CONTRAINDICATED IN PATIENT WITH LIVER OR RENAL DISEASE
Thiazolidinediones
Pioglitazone
Rosiglitazone
MOA: regulation of peroxisome proliferator-activated receptor-gamma (PPAR-g) which regulated muscle, fat, and muscle tissue expression. (targets mostly adipose cells in diabetics)
Benefits of cholesterol profile (pioglitazone)
Tox: lower risk of hypoglycemic episodes, but increase cardiac events (rosiglitazone)
Alpha-glucosidase inhibitors
Acarbose, Miglitol
MOA: inhibition of intestinal alpha-glucosidase thereby delaying the absorption of starch and disaccarhides. taken prior to meals.
Tox: GI (diarrhea, abdominal pain, flatulence)
Caution in renal impairment
Pioglitazone
Thiazolidinedione
*Benefits cholesterol profile with long term therapy
Rosiglitazone
Thiazolidinedione
*increased risk of cardiac events
Acarbose
Alpha-glucosidase inhibitor
MOA: inhibits the function of intestinal alpha-glucosidase thereby delaying absorption of starches and disaccarhides
Taken prior to meal
Tox: GI, caution in renal impairment
Miglitol
Alpha-Glucosidase Inhibitor
MOA: inhibits intestinal alpha-glucosidase thereby slowing the absorption of starches and disaccarhides
Tox: GI
taken prior to meal
Amylin analog
Pramlintide
MOA: Suppression of glucagon release, delayed gastric emptying, and CNS anorectic effects
USE: patient taking insulin that need addition therapy adjunct
Injectable, to be given right before meal
Tox: Hypoglycemia
Incretin therapy
Exenatide
Sitagliptin
Exenatide
Incretin therapy oral insulin therapy MOA: is an analog of glucagon-polypeptide 1 [GLP-1] USE: Injectable adjunct therapy for T2D *Dose adjust for renal dysfunction TOX: GI!
Stiagliptin
Incretin therapy oral insulin agent
MOA: is an inhibitor of dipeptidyl peptidase-4 (DDP-4) which will increase levels on GLP-1 and GIP
USE: Oral prep given to T2D, 1x/day
Cholestyramine
Bile Acid Resin
MOA: Effects cholesterol absorption. Anion exchange resins bind negatively charged bile salts in the small intestine, loss of bile leads to compensatory increase in hepatic LDL receptors = reduced plasma cholesterol. HMG CoA reductase activity is increased which reduces cholesterol loss (temporarily), Triglyceride synthesis enhanced (temporarily), Temporary increase in VLDL then eliminated.
AEs: temp increase in TGs, bad taste, inconvenient to swallow, abdominal bloating, constipation/steatorrhea, anal leakage, anal fissures, impairment of other drug absorption, decrease in fat soluble vitamin absorption
*poor compliance due to bloating and steatorrhea
Colestipol
Bile Acid Resin
Analog to Cholestyramine
Zetia
Transport inhibitor
MOA: Effects Cholesterol Absorption. Acts as a transport inhibitor, blocking the absorption of cholesterol by the brush border cells of the intestine
USE: minor decrease in LDL, smaller decrease in TGs, and almost no effect on HDL
AEs: Not recommended for those with moderate-severe hepatic insufficiency, drug ixn with cyclosporine, can cause increase in transanimase liver enzymes with statins
*Often used as combination therapy with statins
Statins
HMG CoA Reductase Inhibitors
MOA: interfere with cholesterol synthesis. clearance by liver. Inhibit the enzyme HMG CoA Reductase which catalyzes the conversion of Acetyl CoA to melvonic acid a key step in cholesterol synthesis
*Some upregulation of HMG CoA reductase levels but does not overcome effect.
Results in liver LDL receptor upregulation and decrease in LDL plasma levels. May also be anti-inflammatory by reducing c reactive protein.
USE: Most potent LDL lowering drugs and most preferred.
AEs: Check liver enzymes before and after starting treatment. Myopathy is a major concern and Rhabdomyolysis, transaminase hepatitis
Contraindicated in renal failure and with cyclosporine, microlide antibiotic, antifungal agent, or other CYP450 inhibitor useage.
Nicotinic Acid (Niacin)
Acid form drug
MOA: higher doses have hypolipidemic effect, eliminated via kidneys. Inhibition of VLDL secretion. Increased clearance of VLDL = decreased TGs and increase in HDL.
USE: Most effective agent used for the increase of HDL levels (15-35%)
AEs: Intense flushing and pruritis, nausea/abdominal pain, hyperuricemia, hyperglycemia (decreased glucose tolerance shows Acanthosis Nigricans), Hepatotoxicity (increased transaminase and ALT, flu-like fatigue
Clofibrate (Gemfibrozil)
Fibric acid derivative
MOA: well absorbed, 95% protein bound and can displace Warfarin. Decreases fatty acid synthesis, and lipoprotein lipase-enhanced hydrolysis, stimulates synthesis of apoA-1 (gemfibrozil)
USE: decreases TGs and increases HDL, lower LDL effect *Most effective for TGs
AEs: Dyspepsia, Gallstones, Myopathy- when used with statins enhanced risk for rhabdomyolysis!
*Not commonly used for this reason
Dinoprostone
Prostaglandin (PGE2)
USE: to induce labor, 2nd trimester abortion
Misoprostol
Prostaglandin (PGE1)
USE: used to decrease gastric ulceration, can prevent or reverse gastric SEs due to NSAIDs
*also abortifacient properties
Contraindicated in pregnancy
Commonly combined with NSAIDs to reduce GI side effects
Alprostadil
Prostaglandin (PGE1)
MOA: improves blood flow at in peripheral vascular disease (vasodilator), platelet anti-aggregant
USE: can be used as direct injection for male impotence (ED), and can maintain open ductus arteriosus
Latanoprost
Prostaglandin(PGF2)
USE: topically for the treatment of glaucoma
*Topical only due to bronchoconstrictive properties
Epoprostenol
Prostacyclin (PGI2)
USE: Rapid reversal of pulmonary hypertension
Aspirin (ASA) General
NSAID prototypical
MOA: non-selective COX-1 and COX-2 inhibitor, acetylates COX on a serine resulting in an irreversible inhibition (important in platelets because they cannot regenerate COX). Readily metabolized into salicylic acid which reversibly inhibits COX. Mainly metabolized in liver
USE: Analgesic - mild to moderate musculo-skeletal pain and post-op pain, Antipyretic (adults only), Polyarthritic conditions*, Prevention of MI, unstable angina, and TIA (antiplatelet)
*Not recommended in children (Reye’s syndrome)
SEs: GI upset (burping, cramps, nausea, ulceration, pH burning), PGI2 and PGE2 inhibition (decreases gastric mucus production) = upset
*Ok in pregnancy, but avoid in last trimester
Acetaminophen (APAP)
COX inhibitor, not NSAID!
MOA: Is a weak inhibitor of COX in the presence of peroxides which accumulate during inflammation, therefore lacks anti-inflammatory properties. Is good for analgesia and antipyretic
USE: pain without inflammation, those who can’t take aspirin (ulcers/GI, hematologic issues, sensitivity to NSAIDs)
SEs: little CV effects, respiratory, GI, or platelet function. Tox: Dose dependent hepatic toxicity (glutathione) GSH depletion = metabolite build up and hepatocyte damage.
*Tox treatment: n-acetylcysteine (time dependent)
*Tox increases with alcohol use in conjunction and excessive fasting
Non selective COX NSAIDs
Aspirin, Ibuprofen, Indomethacin, Ketoprofen, Naproxen, Ketorolac, Sulindac
COX-2 selective drugs
Rofecoxib, Celecoxib, Valdecoxib
DMARDS
Methotrexate, Leflunomide, Gold salts, Sulfasalazine, Hydroxy-chloroquine
Anti TNF
Infliximab, Adalimumad, Etanercept
Rituximab
Anti CD 20
MOA: monoclonal antibody that targets CD20 antigen on the surface of B cells.
USE: RA (for people that do not respond to anti-TNF therapy, B cell lymphomas
SEs: similar to Infliximab: cytokine release syndrome (headache, fever, chills) -rare, lupus like syndrome (discontinue), infections (contraindicated in TB), myalgia or back pain
*Expensive usually 3rd line
Anakinra
IL-1 receptor blocker
MOA: IL-1 blocker, onset 4-6 weeks, less efficient than TNF blocker, but may retard bone erosion
USE: moderate to severe RA
SE: injection site issues, infection (Rare), neutropenia
Ibuprofen
Non-selective COX inhibitor, NSAID
MOA: non-selective, propionic acid metabolite
USE: primary dysmenorrhea, minor aches/pains, fever, tooth ache, backache, minor arthritic pain
SEs: GI (less severe than aspirin), dose dependent, minor inhibition of platelet coagulation, N/V, some renal toxicity
TOX: amblyopia, other ocular disturbances
Indomethacin
Non-selective COX inhibitor, NSAID
MOA: non-selective, acetic acid metabolite
USE: closure of patent ductus arteriosus, not often used for pain - more for inflammation
SEs: GI (less severe than aspirin), dose dependent, minor inhibition of platelet coagulation, N/V, some renal toxicity
TOX: amblyopia, other ocular disturbances
*Acute renal toxicity
Ketoprofen
Non-selective COX inhibitor, NSAID
MOA: non-selective, propionic acid metabolite
USE: primary dysmenorrhea
SEs: GI (less severe than aspirin), dose dependent, minor inhibition of platelet coagulation, N/V, some renal toxicity
TOX: amblyopia, other ocular disturbances
Naproxen
Non-selective COX inhibitor, NSAID
MOA: propionic acid metabolite
USE: dysmenorrhea,
SEs: GI (less severe than aspirin), can increase BP! dose dependent, minor inhibition of platelet coagulation, N/V, some renal toxicity
TOX: amblyopia, other ocular disturbances
Ketorolac
Non-selective COX inhibitor, NSAID
MOA: acetic acid metabolite,
USE: moderate to severe pain management, NOT RA/OA
SEs: GI (less severe than aspirin), dose dependent, minor inhibition of platelet coagulation, N/V, some renal toxicity
TOX: amblyopia, other ocular disturbances
*can cause renal failure
Sulindac
Non-selective COX inhibitor, NSAID
MOA: acetic acid metabolite
USE: not for pain, used in inflammation
SEs: GI (less severe than aspirin), dose dependent, minor inhibition of platelet coagulation, N/V, some renal toxicity
TOX: amblyopia, other ocular disturbances
*only non-selective with NO renal effects
Rofecoxib
COX-2 Selective inhibitor drug
MOA: high COX-2 selectivity, not more effective analgesia or anti-inflammatory
USE: OA/RA treatment, acute pain and dysmenorrhea
SE: reduced GI/platelet effects, abdominal pain, diarrhea, nausea, headache, upper respiratory
*Cardiotoxic! decreases release of anti-thrombotic PGI2, so COX-1 mediated thromboxane A2 takes over and is pro-thrombotic
Celecoxib
COX-2 Selective inhibitor drug
MOA: significant COX-2 selectivity, not more effective analgesia or anti-inflammatory
USE: OA/RA treatment, acute pain and dysmenorrhea
SE: reduced GI/platelet effects, abdominal pain, diarrhea, nausea, headache, upper respiratory
*Cardiotoxic! decreases release of anti-thrombotic PGI2, so COX-1 mediated thromboxane A2 takes over and is pro-thrombotic
Valdecoxib
COX-2 Selective inhibitor drug
MOA: high COX-2 selectivity, not more effective analgesia or anti-inflammatory
USE: OA/RA treatment, acute pain and dysmenorrhea
SE: reduced GI/platelet effects, abdominal pain, diarrhea, nausea, headache, upper respiratory
*Cardiotoxic! decreases release of anti-thrombotic PGI2, so COX-1 mediated thromboxane A2 takes over and is pro-thrombotic
Methotrexate (MTX)
DMARD
MOA: immunosuppressive, in higher doses inhibits dihydrofolate reductase. Doses used here may inhibit adenosine and TNF-alpha
USE: RA
SEs: stomatitis, nausea, GI, thrombocytopenia, pulmonary fibrosis, hepatotoxicity
*Contraindicated in pregnancy, LIVER tox, immunodeficiency
Leflunomide
DMARD
MOA: Inhibits synthesis of uridine phosphate (1 month)
USE: RA
SEs: hepatotoxicity, immunesuppression, alopecia, diarrhea, hypertension, respiratory infections
*Contraindicated in pregnancy - teratogenic
*Works better with MTX
Gold Salts
DMARD
MOA: Taken up by macrophages, inhibits phagocytosis and decreases rheumatoid factor, decreased IgG (injection at joint)
SEs: Stomatitis, rashes (discontinue), renal toxicity, immunosuppression
*long onset, oral and IM as well
Sulfasalazine
DMARD
MOA: Sulfa drug, RA treatment MOA not known. Impairs secretion of myofibroblasts that prevent the breakdown of scar tissue
USE: RA
SEs: Stomatitis, nausea, GI, rare thrombocytopenia, decrease WBC
Hydroxy-chloroquine
DMARD
Infliximab
Anti TNF
MAO: monoclonal antibody to TNF-alpha, binds to TNF and clears from the joint and blood stream. Prevents TNF from binding to its cellular receptor: there is reduced activation/infiltration of inflammatory cells. Reduces clinical symptoms and slows/stops progression
USE: RA and Crohn’s
*Co-treat with methotrexate to reduce Ab formation
SEs: cytokine release syndrome (headache, fever, chills) -rare, lupus like syndrome (discontinue), infections (contraindicated in TB), myalgia or back pain
Adalimumab
Anti TNF
MOA: monoclonal antibody to TNF-alpha, binds to TNF and clears from the joint and blood stream. Prevents TNF from binding to its cellular receptor: there is reduced activation/infiltration of inflammatory cells. Reduces clinical symptoms and slows/stops progression. Completely human Ab
Less likely to develop Ab response
USE: RA
SEs: injection site reactions, infection (TB),
Etanercept
Anti TNF
MOA: soluble dimeric form of the p75 TNF receptor, binds TNF and prevents from binding cellular receptors
USE: RA, ankylosing spondylitis, psoriatic arthritis
SEs: sepsis/infection (deadly), injection site issues, and abdominal pain
COX-1
PGH synthase I
found in blood vessels, GI, mucosa
Constitutive - prostaglandins have a role in normal physiological function
COX-2
PGH synthase II
Found in macrophages, Mast cells, and other cells associated with the immune or inflammatory response.
Inducible - up regulated in inflammation
Glucocorticoids drugs
Hydrocortisone, cortisone, prednisone, methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone
Mineralcorticoid drugs
Aldosterone, Fludrocortisone
Glutocorticoids general
MOA: Stimulates synthesis of lipocortin which inhibits phospholipase A2 - reduces arachidonic acid production (starting point for prostaglandin and leukotriene synthesis)
Effect: increased apoptosis of lymphocytes (reduced activation of NF-kB), inhibits cytokine production, inhibits activation of neutrophils and leukocytes - decreased ICAM, selectins, and integrins, stabalizes leukocyte lysosomal membranes, reduces capillary permeability and edema, antagonism to histamine and edema
USE: Rheumatoid and collagen diseases, allergic - angioedema, serum sickness, contact dermatitis, hypersensitivity, UC, corticoid replacement
SEs: few side effects, but short term activity, hypertension, lethargy, amenorrhea, “steroid diabetes”, Cushing’s syndrome, growth suppression, muscle wasting, N/V, osteoporosis, cataracts, Na retention, Ca and K loss, increased RBCs, WBC increase, CNS
Metyrapone
MOA: inhibits 11B-hydroxylation, interferes with cortisol and corticosterone synthesis
USE: Cushing’s treatment
Trilostane
MOA: Inhibits 3B-dehydrogenase
USE: cushing’s treatment
Sympathomimetic
Epinephrine, isoproterenol, metaproterenol, albuterol, terbutaline, salmeterol
Mast cell stabalizer
Cromolyn sodium, nedocromil
Corticosteroids (asthma)
Hydrocortisone, prednisone, methylprednisolone, beclomethacone, triamcinolone, fluticasone
Xanthine
Theophylline, aminophylline,
Antimuscarinic
Ipratropium, tiotropium
Leukotriene modifiers
Zafirlukast, montelukast, zileuton
IGE antibody
Oalizumab
Epinephrine
Emergency bronchodilator
MOA: a1, b1, b2 non-selective, relaxes bronchial smooth muscles, increased mucus clearance, prevent mast cell mediator release
USE: emergency relief of bronchospasm in acute asthma or anaphylaxis
SEs: muscle tremors, tachycardia, palpitations due to cardiac stim, peripheral vasodilation (hypotension), tolerance developed of long term use, metabolic effects (increase FFA, glucose, lactate after large dose)
*inhalation = minimal SEs
Metaproterenol
Inhaled bronchodilator of choice
MOA: b2 agonist (3-4hr) Relaxes bronchial smooth muscles, increased mucus clearance, prevents mast cell mediator release
USE: episodic relief of bronchospasm, rapid short acting
SEs: muscle tremors, tachycardia, palpitations due to cardiac stim, peripheral vasodilation (hypotension), tolerance developed of long term use, metabolic effects (increase FFA, glucose, lactate after large dose)
*inhalation = minimal SEs
Albuterol
Inhaled bronchodilator of choice
MOA: b2 agonist (3-4hr) Relaxes bronchial smooth muscles, increased mucus clearance, prevents mast cell mediator release
USE: episodic relief of bronchospasm, rapid short acting
SEs: muscle tremors, tachycardia, palpitations due to cardiac stim, peripheral vasodilation (hypotension), tolerance developed of long term use, metabolic effects (increase FFA, glucose, lactate after large dose)
*inhalation = minimal SEs
Terbutaline
Inhaled bronchodilator of choice
MOA: b2 agonist (3-4hr) Relaxes bronchial smooth muscles, increased mucus clearance, prevents mast cell mediator release
USE: episodic relief of bronchospasm, rapid short acting
SEs: muscle tremors, tachycardia, palpitations due to cardiac stim, peripheral vasodilation (hypotension), tolerance developed of long term use, metabolic effects (increase FFA, glucose, lactate after large dose)
*inhalation = minimal SEs
Salmeterol
Long Acting Beta2-agonist
MOA: b2 agonist, long duration (12-24hrs) long onset (2 hrs)
USE: Suppression of night time asthma
*Does NOT replace a rescue inhaler (long onset)
SEs: muscle tremors, tachycardia, palpitations due to cardiac stim, peripheral vasodilation (hypotension), tolerance developed of long term use, metabolic effects (increase FFA, glucose, lactate after large dose)
*inhalation = minimal SEs
Isoproterenol
Sympathomimetic asthma drug
MOA: b1 and b2 non-selective agonist, inhaled
short acting (60-90mins)
Use: asthma
SE: cardiac due to b1, muscle tremors, tachycardia, palpitations, peripheral vasodilation, direct stim of b1 cardiac receptors, tolerance over time, metabolic
Cromolyn Sodium
Mast cell stabilizer (asthma)
MOA: Inhibition of mast cell degranulation by stimuli (including cell bound IgE), alter function of delayed Chloride channel in cell membranes inhibiting activation. Suppresses activation of chemoattractant peptides on PMN, eosinophils, and monocytes, reverses elevated receptor expression on leukocytes. No bronchodilator or antihistamine activity.
USE: Prophylactic treatment of asthma (mild to moderate) especially allergic asthma, allergic rhinitis. Often used prior to challenge (exercise, allergen, cold) Long term treatment. Prevents early and late response to allergen - decreases bronchial response
*Coadministered with b2 agonist (albuterol) to assure access of cromolyn to airways
SE: very few (likely due to low absorption rate), often used in childhood asthma *not as often used due to greater effect of leukotriene inhibitors
Nedocromil
Mast cell stabilizer (asthma)
MOA: Inhibition of mast cell degranulation by stimuli (including cell bound IgE), alter function of delayed Chloride channel in cell membranes inhibiting activation. Suppresses activation of chemoattractant peptides on PMN, eosinophils, and monocytes, reverses elevated receptor expression on leukocytes. No bronchodilator or antihistamine activity.
USE: Prophylactic treatment of asthma (mild to moderate) especially allergic asthma, allergic rhinitis. Often used prior to challenge (exercise, allergen, cold) Long term treatment. Prevents early and late response to allergen - decreases bronchial response
*Coadministered with b2 agonist (albuterol) to assure access of cromolyn to airways
SE: very few (likely due to low absorption rate), often used in childhood asthma *not as often used due to greater effect of leukotriene inhibitors
Corticosteroids (asthma general)
Anti-inflammatory agents (asthma)
Systemic: prednisone - po, methylpednisolone - inj
MOA: potent anti-inflammatory, inhaled is less absorbed = fewer SEs. Reduces number and activity of inflammatory cells in the airway, inhibits release of arachidonic acid metabolites in airway, prevent vascular permeability, suppresses IgE binding, decreases severity of disease and increases bronchodilator effect
*Not bronchodilator
USE: Patients who require b2 agonist use more than 4x per week, suppresses late response
Systemic use for short term “burst” in persistent severe asthma
Inhaled: long term use, suppression, control, and reversal of inflammation, reduces need for oral corticosteroids
*Often used with LABA
SE: inhaled= dysphonia, Oropharyngeal candidiasis,
systemic=short term: reversible glucose metabolism abnormalities, increased appetite, fluid retention, weight gain, mood alteration, hypertension, peptic ulcer, rare necrosis of femur
long term: adrenal axis suppression, growth suppression, hypertension, diabetes, osteoporosis, infection
Theophylline
Xanthine
MOA: inhibition of phosphodiesterases, increases cellular cAMP, adenosine receptor antagonism, blocks adenosine receptor which mediates bronchoconstriction, bronchodilation independent -mainly blocks constriction
6-12hrs PO
USE: reverses and block bronchoconstriction, less potent than b2 agonist, additive effect with b2 agonist (bronchodilation) *often coadministered
sustained release for night time asthma
SE: VERY NARROW THERAPEUTIC INDEX, TI=1.3! significant SE with plasma over 20 mg/L, low dose to reach required plasma levels
Low: headache, N/V, restlessness, increased acid secretion, diuresis
High: convulsions, arrhythmias
Aminophylline
Xanthine
MOA: inhibition of phosphodiesterases, increases cellular cAMP, adenosine receptor antagonism, blocks adenosine receptor which mediates bronchoconstriction, bronchodilation independent -mainly blocks constriction
6-12hrs IV
USE: reverses and block bronchoconstriction, less potent than b2 agonist, additive effect with b2 agonist (bronchodilation) *often coadministered
sustained release for night time asthma
SE: VERY NARROW THERAPEUTIC INDEX, TI=1.3! significant SE with plasma over 20 mg/L, low dose to reach required plasma levels
Low: headache, N/V, restlessness, increased acid secretion, diuresis
High: convulsions, arrhythmias
Ipratropium
Antimuscarinic MOA: muscarinic antagonist, parasympathetic pathway (can induce bronchospasms) USE: combined therapy with b2 agonist *drug of choice for COPD SEs: few side effects,
Zafirlukast
Leukotriene Modifiers
MOA: selective leukotriene receptor (LKT4) antagonist, 12 hr PO
USE: alternative to low dose inhaled corticosteroids, cromolyn or medocromil, beneficial in allergen related asthma
SEs: diarrhea, dizziness, cough, headache, N/V, difficulty sleeping (mild or rare) uncommon: earache, fever, sore throat, muscle weakness, mood change, hallucination, suicide ideation, other neuropsychiatric events
Zileuton
Leukotriene Modifier
MOA: 5 lipoxygenase inhibitor, decreases leukotriene synthesis, 6 hrs PO
USE: alternative to low dose inhaled corticosteroids, cromolyn or medocromil, beneficial in allergen related asthma
SEs: diarrhea, dizziness, cough, headache, N/V, difficulty sleeping (mild or rare) uncommon: earache, fever, sore throat, muscle weakness, mood change, hallucination, suicide ideation, other neuropsychiatric events
Montelukast
Leukotriene Modifier
MOA: N/A - inhaled
USE: alternative to low dose inhaled corticosteroids, cromolyn or medocromil, beneficial in allergen related asthma
SEs: diarrhea, dizziness, cough, headache, N/V, difficulty sleeping (mild or rare) uncommon: earache, fever, sore throat, muscle weakness, mood change, hallucination, suicide ideation, other neuropsychiatric events
Omalizumab
Anti IgE antibody (asthma)
MOA: antibody that binds to IgE in circulation and prevents its binding to cellular receptors. Does not activate IgE already on cells, 2x SQ
USE: chronic severe asthma not controlled by other medications (b2 agonists, corticosteroids, LABA, etc), most effective for precipitated allergen or seasonal asthma, reduces frequency and severity of attacks
*Very expensive, last line treatment for severe persistent asthmatics
SEs: injection site, anaphylaxis (rare)
