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1

Toxicokinetics

Absorption, distribution, metabolism, and excretion of toxins, toxic doses of therapeutic agents, and/or their metabolites.

2

Toxicodynamics

Describes the harmful effects of the toxins or toxic doses to vital organ functions. (what the drug does at the receptor level)

3

DEFG of toxicology

Decontamination
Targeted Elimination
Focused Therapy
"Get toxicologist's help"

4

Anticholinergic Toxicity

*Decreased PANS*
myadriasis, blurred vision, fever, flushed dry skin, AMS, seizures, urine retention/constipation, hypertension, tachycardia

5

Anticholinergics

Antihistamine (diphenhydramine)
Anticholinergic (atropine)
Antipsychotic (haloperidol)
Antidepressants (TCAs)
Environmental (Jimson Weed, Gyromitra)

6

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

7

Cholinergic Toxicity

*Increased PANS activity*
muscarinic, nicotinic, and CNS effect

8

Cholinergics

Organophosphates (pesticides)
Carbamates (physostigmine)
Iatrogenic (edrophonium)
Nerve gas (VX)
Mushroom species

9

Muscarinic Toxidrome

Diarrhea, diaphoresis, urination, miosis, bradycardia, bronchorrhea, bronchospasm, emesis, lacrimation, salivation

10

Nicotinic Toxidrome

Myadriasis, Tachycardia, weakness, Hypertension, Fasciculations

11

CNS Cholinergic Tox

Agitation, seizures, coma

12

Cholinergic Tox treatment

Atropine, Pralidoxime, BZDs

13

Atropine

Cholinergic tox treatment
1-2 mg IV every 5-10 mins, short acting
May need infusion

14

Pralidoxime

VX gas antidote
1-2 grams infused over 30 mins

15

Diazepam

Benzodiazepine - cholinergic tox treatment
Helps CNS effects

16

Adrenergic Toxidrome

*Increases SANS*
CNS: AMS, increase temp, seizures
Myadriasis, increased BP and HR, diaphoresis, nausea, vomiting, urine retention

17

Adrenergic treatment

BZDs, temperature regulation, fluid administration, BP management (verapamil IV, NTG) maybe labetalol - NO BETA only BLOCKERS

18

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

19

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!

20

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

21

Toxic Alcohols

Methanol, ethylene glycol, ethanol, propylene glycol = hyperosmolality AND metabolic acidosis
Isopropranol only = hyperosmolality
HD used as treatment

22

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

23

Protamine

Heparin OD treatment
Slightly basic pH, large dose will result in paradoxical bleeding and CV changes

24

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

25

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

26

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

27

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

28

Antiplatelet Agents

Aspirin (ASA), ticlopidine, clopidogrel, prasugrel, ticagrelor

29

Glycoprotein IIb/IIIa inhibitors

Abciximab, Tirofiban, Eptifibatide

30

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

31

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

32

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

33

Direct Thrombin inhibitors

Argatroban, Bivalirudin, Dabigatran

34

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

35

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

36

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

37

Xa Inhibitors

Enoxaparin, Rivaroxaban, Apixaban

38

Enoxaparin

Xa inhibitor

39

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

40

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

41

Fonsaparinux

Synthetic Anticoagulant

42

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

43

Phytonadione

Vitamin K clotting agonist
Warfarin OD treatment (?)

44

aminocaproic acid

Lysine derivative
Inhibitor of fibrinolysis

45

Tranexamic acid

Lysine derivative
Inhibitor of fibrinolysis

46

Thrombolytics

Streptokinase, Alteplase, Tenecteplase, Reteplase
USE: Coronary thrombosis, PE, DVT, AMI, Stroke

47

Streptokinase

Thrombolytic
derived from B-hemolytic streptococcus bacteria (antigenic activity)
MOA: inhibits thrombin, promotes conversion of plasminogen to plasmin
Indication: AMI, stroke, and PE

48

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.

49

Reteplase

Thrombolytic
MOA: synthetic agent, inhibits thrombin, activates conversion of plasminogen to plasmin = clot lysis
Indication: AMI, stroke, and PE
More use in cardiology

50

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

51

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)

52

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

53

Rapid Preparation Insulin

Drugs: Lispro, Aspart, glulisine
MOA: rapid onset of action/control, but do not last long. ~4 hrs, control for meal time

54

Short Preparation Insulin

Regular insulin
MOA: onset of 30 mins, SQ administration or IV

55

Intermediate preparation Insulin

Neutral Protamine Hagedorn (NPD) or Isophae
MOA: onset ~2 hrs, duration of 4-12 hrs

56

Long preparation insulin

Drug: Glargine and Detemir
MOA: Slow onset (1 hr), and lasts 12-24 hrs

57

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)

58

Glyburide

Sulfonylureas Oral insulin therapy

59

Glipizide

Sulfonylureas Oral insulin therapy

60

Glimepiride

Sulfonylureas Oral insulin therapy

61

Insulin Secretagogues

Meglitinide class: repaglinide
D-Phenylalanine: Nateglinide
Metabolized in liver

62

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

63

Nateglinide

Insulin secretagogue, D-Phenylalanine
MOA: Similar to sulfonylureas, and no sulfur allergy
Metabolized via 2C9 and 3A4

64

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

65

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)

66

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

67

Pioglitazone

Thiazolidinedione
*Benefits cholesterol profile with long term therapy

68

Rosiglitazone

Thiazolidinedione
*increased risk of cardiac events

69

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

70

Miglitol

Alpha-Glucosidase Inhibitor
MOA: inhibits intestinal alpha-glucosidase thereby slowing the absorption of starches and disaccarhides
Tox: GI
taken prior to meal

71

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

72

Incretin therapy

Exenatide
Sitagliptin

73

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!

74

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

75

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

76

Colestipol

Bile Acid Resin
Analog to Cholestyramine

77

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

78

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.

79

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

80

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

81

Dinoprostone

Prostaglandin (PGE2)
USE: to induce labor, 2nd trimester abortion

82

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

83

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

84

Latanoprost

Prostaglandin(PGF2)
USE: topically for the treatment of glaucoma
*Topical only due to bronchoconstrictive properties

85

Epoprostenol

Prostacyclin (PGI2)
USE: Rapid reversal of pulmonary hypertension

86

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

87

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

88

Non selective COX NSAIDs

Aspirin, Ibuprofen, Indomethacin, Ketoprofen, Naproxen, Ketorolac, Sulindac

89

COX-2 selective drugs

Rofecoxib, Celecoxib, Valdecoxib

90

DMARDS

Methotrexate, Leflunomide, Gold salts, Sulfasalazine, Hydroxy-chloroquine

91

Anti TNF

Infliximab, Adalimumad, Etanercept

92

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

93

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

94

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

95

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

96

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

97

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

98

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

99

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

100

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

101

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

102

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

103

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

104

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

105

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

106

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

107

Hydroxy-chloroquine

DMARD

108

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

109

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),

110

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

111

COX-1

PGH synthase I
found in blood vessels, GI, mucosa
Constitutive - prostaglandins have a role in normal physiological function

112

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

113

Glucocorticoids drugs

Hydrocortisone, cortisone, prednisone, methylprednisolone, Triamcinolone, Dexamethasone, Betamethasone

114

Mineralcorticoid drugs

Aldosterone, Fludrocortisone

115

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

116

Metyrapone

MOA: inhibits 11B-hydroxylation, interferes with cortisol and corticosterone synthesis
USE: Cushing's treatment

117

Trilostane

MOA: Inhibits 3B-dehydrogenase
USE: cushing's treatment

118

Sympathomimetic

Epinephrine, isoproterenol, metaproterenol, albuterol, terbutaline, salmeterol

119

Mast cell stabalizer

Cromolyn sodium, nedocromil

120

Corticosteroids (asthma)

Hydrocortisone, prednisone, methylprednisolone, beclomethacone, triamcinolone, fluticasone

121

Xanthine

Theophylline, aminophylline,

122

Antimuscarinic

Ipratropium, tiotropium

123

Leukotriene modifiers

Zafirlukast, montelukast, zileuton

124

IGE antibody

Oalizumab

125

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

126

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

127

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

128

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

129

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

130

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

131

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

132

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

133

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

134

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

135

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

136

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,

137

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

138

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

139

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

140

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)