Term
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Definition
Mechanism: inhibition of phospholipase A2-> ultimately inhibits the release of arachidonic acid from membrane phospholipids.
Agent: Glycocorticoids*(e.g.prednisone, prednisolone, desamethasone)
Main therapy in autoimmune and inflammatory diseases
Induce secretion of lipocortines interfer with the action of phospholipase A2 to release arachidonic acid
Induce secretion of annexins (annexines derived peptides) act at GPCR on leukocytes to block pro-inflammatory responses
Inhibits the action of COX2 and formation of prostanglandines
Repressing COX2 gene and enzyme expression
Repressing the cytokine expression that activate COX2
Limiting arachidonic acid by indirectly blocking phospholipase A2 |
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Term
| prednisone, prednisolone, desamethasone |
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Definition
Glycocorticoids
Main therapy in autoimmune and inflammatory diseases
Induce secretion of lipocortines interfer with the action of phospholipase A2 to release arachidonic acid
Induce secretion of annexins (annexines derived peptides) act at GPCR on leukocytes to block pro-inflammatory responses
Inhibits the action of COX2 and formation of prostanglandines
Repressing COX2 gene and enzyme expression
Repressing the cytokine expression that activate COX2
Limiting arachidonic acid by indirectly blocking phospholipase A2 |
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Term
| Withdrawal from glucocorticoid treatment |
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Definition
During long-term therapy-high plasma glucocorticoids (cortisol) levels suppress CRH/ACTH atrophy of the adrenal cortex
Abrupt cession of the therapy can lead to acute adrenal insufficiency
Long time required to reactivate the hypothalamic-pituitary-adrenal axis
Exacerbation inflammatory response due to disinhibition of immune system |
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Term
| CYCLOOXYGENASE INHIBITORS |
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Definition
Traditional nonselective inhibitors: NSAIDs
Anti-inflammatory, antipyretic, and analgesic properties
Inhibition of COX-mediated generation of proinflammatory eicosanoids, and limit inflammation, fever (inhibit PGE2) and pain
All NSAIDs (except for aspirin) act as reversible, competitive inhibitors of COX1 and COX2 |
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Term
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Definition
the hydrophobic channel of the cyclooxygenase protein where the substrate binds (arachidonic acid)
Block the conversion of arachidonic acid->PGE2
Due to the differences in the substrate binding site and tissue distribution NSAIDs block COX1/COX2 to different degree. |
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Term
| Long term NSAIDs therapy adverse effects |
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Definition
induced gastropathy and Pertubed regulation of blood flow to kidney
Elimination of cytoprotective roles of COX-1 eicosanoids products
NSAIDs-induced gastropathy
Gastrotoxicity, subepithelial damage and hemorrhage, ulceration, gastic mucosal necrosis
Pertubed regulation of blood flow to kidney
Decreased GFR, renal ischemia, interstitial nephritis and renal failure
PK properties: near complete absorption from the gut, binding to plasma protein, efficient renal excretion
Short half life (<6 hr) and long half life (>10 hr, naproxen, salicylate) |
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Term
| Structural Classes of NSAIDs |
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Definition
NSAIDs are hydrophobic molecules, with a carboxylic acid group.
NSAIDs are categorized by class depending on one or more of the key moieties in the structure.
The moiety is common to members of each class (box).
The structure helps to determine the pharmacokinetic properties of each particular NSAID.
Note: Acetaminophen is not NSAID, it has weak anti-inflammatory properties; like NSAIDs, it has analgesic and antipyretic effects. |
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Term
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Definition
Aspirin (acetylsalicylic acid) is widely use to treate mild-to-moderate pain, headache, myalgia, and arthralgia
Aspirin acts in an irreversible manner by acetylating the active binding site in both COX1 and COX2 |
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Term
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Definition
prevent the formation of COX1 derived prostangladines, thromboxanes (TxA2) and prostacyclines (PGI2)
Daily low-dose aspirin is used as an antithrombogenic agent for both prophylaxis and post-event management (acute coronary disease, ischemic stroke)
A single administration of aspirin, decreases the levels of TxA2 shifting the TxA2-PGI2 axis towards PGI2-mediated vasodilation, platelet inhibition, and antithrombogenesis |
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Term
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Definition
prevents generation of prostaglandins
Aspirin-modified COX2 enzyme maintain part of its catalytic activity
Arachidonic acid 15-HETE 15-epi-lipoxin
Aspirin-triggered lipoxins (ATLs) mimic the function of lipoxins as anti-inflammatory agents. |
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Term
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Definition
| gastropathy and nephropathy: gastrointenstinal ulceration and hemorrhage, nephrotoxicity and hepatic injury |
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Term
| Aspirin induced airway hyperreactivity |
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Definition
| asthmatics- exposure to aspirin leads to ocular and nasal congestion, airway obstruction |
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Term
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Definition
| hepatic encephalopathy and liver steatosis in young children. Aspirin is not administered to children, acetaminophen is used instead |
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Term
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Definition
| potent analgesic used in rheumatoid arthritis, osteoarthritis, gout |
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Term
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Definition
| long plasma half life, higher potency and directly inhibits leukocyte function. Causes less adverse effects than aspirin |
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Term
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Definition
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Term
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Definition
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Term
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Definition
direct inhibitor of neutrophil motility and inhibits the vasodilatory eicosanoids PGE2 and PGI2
The acetic acid NSAIDs are mostly used to relieve symptoms in the long-term treatment of rheumatoid arthritis, osteoarthritis. Use of acetic acid NSAID cause gastrointestinal ulceration. |
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
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Definition
Has analgesic and antipyretic effects with no anti-inflammatory effecs
Weak inhibition of cyclooxygenase
Acetaminophen therapy can be valuable in patients (children), that are in risk for the adverse effects of aspirin.
Adverse effect: hepatotoxicity |
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Term
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Definition
FDA approved drug
Anti-inflammatory, antipyretic, analgesic properties
No anti-platelet action
Risk for increased thrombogenicity due to prolonged inhibition of vascular COX-2 within endothelial cells, leading to PGI2
Celecoxib decreases the activity of PPAR, TF involved in growth regulation – prevent development of colon cancer
Coxib are approved for treatment of osteoarthritis, RA, acute pain in adults
COX- 2 SELECTIVE
INHIBITORS |
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Term
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Definition
Coxib are approved for treatment of osteoarthritis, RA, acute pain in adults
COX- 2 SELECTIVE
INHIBITORS |
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Term
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Definition
Coxib are approved for treatment of osteoarthritis, RA, acute pain in aduCOX- 2 SELECTIVE
INHIBITORS
lts |
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Term
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Definition
COX- 2 SELECTIVE
INHIBITORS |
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Term
COX- 2 SELECTIVE
INHIBITORS |
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Definition
Adverse effects: dose- and duration- dependent cardiovascular thrombotic events (myocardial infarction and stroke)
Celecoxib also increases the risk of hypertension, edema, and heart failure at high doses
Celecoxib is contraindicated in the treatment of pain associated with coronary artery bypass surgery
Prescribing analgesic therapy with a coxib primary consideration is if anti-inflammatory agent is necessary
Primarily analgesic: acetaminophen in combination with adjunct analgesics or adjunct therapies
Need for anti-inflammatory therapy (+ risk factor for gastrophathy) : coxib or a combination regimen with NSAIDs+ proton pump inhibitor |
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Term
| Cytokine inhibition; Anti-TNF Agents |
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Definition
TNF and IL-1 enhance prostaglandin production and up-regulate COX-2
Antibody based TNF antagonists:
Etanercept
Infliximab
Adalimumab
Golimumab
Certolizumab
TNF antagonists approved for treatment of RA, psoriatic arthritis, juevenile idopathic arthritis, Crohn’s disease
Adverse effects: increased risk of serious infection, incl extrapulmonary tuberculosis, fungal infections, hepatitis B
Small risk of lymphoma, demyelinating disease, heart diseses |
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Term
| Leukotriene Pathway Inhibitors |
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Definition
Leukotriene inhibition is an attractive therapy
Inhibition of 5-LOX has the potential to major therapeutic for disease such as asthma, inflammatory bowel disease and RA
Zileuton- the only clinically used inhibitor: asthma induced by cold, drugs, and allergens
Induces bronchodilation, improves asthma symptoms ,long-lasting effects in pulmonary function test
Adverse effects/PK effects: liver toxicity, low bioavailability, low potency |
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Term
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Definition
Interfering with FLAP-an alternative approach to the selective inhibition of 5-LOX
FLAP inhibitors prevent and reverse LOX binding to FLAP and block the arachidonic acid binding site
Not currently available for clinic use |
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Term
| Lipoxin, ATL, resolvins stable analogues |
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Definition
Stable analogues of these compounds represent new methods to treatment, endogenous anti-inflammatory and pro-resolution pathways
Endogenous regulators- selective actions with less adverse effects
Stable analogues of lipoxins and ATLs are currently being developed |
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Term
| Histamine Synthesis and Degradation |
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Definition
Synthesis occurs in mast cells and basophils, but also in gastric mucosa cells and neurons of CNS
Slow turn over pool: mast cells and basophils-release of histamine. Several weeks are required to replenish the stores.
Rapid turn over pool: in gastric ECL cell and CNS- production and release of histamine is dependent on physiological stimuli |
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Term
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Definition
| mast cells and basophils-release of histamine. Several weeks are required to replenish the stores. |
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Term
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Definition
| in gastric ECL cell and CNS- production and release of histamine is dependent on physiological stimuli |
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Term
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Definition
Smooth muscle, vascular endothelium, afferent nerve terminals, heart, GI tract and CNS
Smooth mucle: dilation of terminal arterioles/ postcapillary venules BUT contraction of veins.
The vasodilatory effect of histamine is most prominent on the vasculature. E.g. during infection or injury- erythema!
Histamine causes bronchoconstriction of human respiratory system
Constriction of vascular endothelial cells- edema!
Pheripheral sensory nerve terminal respond to histamine- itch and pain
Combine action of histamine on vascular smooth muscle, vascular endothelial cells and peripheral nerves – wheal and flare! |
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Term
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Definition
Histamine actions are mediated by binding of histamine to its receptor/subtypes: H1-H4
H1: mediate inflammatory and allergic reactions
Tissue responses include edema, bronchoconstriction, sensitization of afferent nerve terminal
H2: mediate gastric acid secretion
pump mediated delivery of protons into the gastric fluid
H3: limit the synthesis/release of histamine (and other neurotransmitters)
H4: mediate histamine-induced leukotriene B4 production, chemotaxis of various cells |
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Term
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Definition
mediate inflammatory and allergic reactions
Tissue responses include edema, bronchoconstriction, sensitization of afferent nerve terminal |
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Term
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Definition
mediate gastric acid secretion
pump mediated delivery of protons into the gastric fluid |
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Term
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Definition
| limit the synthesis/release of histamine (and other neurotransmitters) |
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Term
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Definition
| mediate histamine-induced leukotriene B4 production, chemotaxis of various cells |
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Term
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Definition
allergen (pollen) crosses the nasal epithelium, upon encountering sensitized mast cells and cross links IgE/Fc receptors -> mast cell degranulation/histamine release
H1 receptor activation cause blood vessel dilation and increases vascular permeability leading to edema.
Swelling of mucosa is responsible for nasal congestion
Itching, sneezing, runny nose/tearing result from histamine release and other inflammatory mediators (PGs, LTB)-> hypersecretion and irritiation |
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Term
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Definition
Systemic mast cell degranulation
Resulting systemic vasodilation, and extravasation of plasma cause severe hypotension.
Systemic histamine release cause bronchoconstriction and epiglottal swelling
Epinephrine administration |
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Term
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Definition
Inverse agonists (rather than competitive antagonists)
H1 receptors coexist in two conformational states—the inactive and active conformational equilibrium
Histamine acts as an agonist for the active conformation of the H1 receptor and shifts the equilibrium toward the active conformation.
Antihistamines act as inverse agonists that bind and stabilize the inactive conformation of the H1 receptor, thereby shifting the equilibrium toward the inactive receptor state.
PK : Oral antihistamines are well absorbed from GI tract, peak plasma concentration in 2-3hr.
Most H1 antihistamines are metabolize in the liver-> consideration must be taken in patients with liver disease
As inhibitors of cytochrome P450 system, antihistamines may effect metabolism of other drugs
CNS toxicity; High lipophilicity of first generation H1- antihistamines, readily penetrate BBB antagonize the histamine effects in CNS
Sedation
Second generation:ionized at physiological pH and do not enter BBB preferred for long term treatment, limited sedative effect
Cardiac toxicity; specially in patients with pre-exsisting cardiac dysfunction. Early second generation antihistamines prolong QT interval that leads to ventricular arrhythmias
Anticholinergic effects; more prominent in the first generation compounds include pupillary dilation, dry eyes, dry mouth, urine retantion.
Elderly individuals may demonstrate sensitivity to the anticholinergic and sedative effects of first generation antihistamines. Hypotension (blockade of a-adrenergic)
Young children are also susceptible to adverse effects related to antihistamine use.
FDA advises against use of antihistamines for children < 2 yrs.
Rare overdose of first generation antihistamines can cause severe CNS depression presenting as somnolence, ataxia and coma |
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Term
| Structure of First-Generation H1-Antihistamines |
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Definition
The general structure of the first-generation H1-antihistamines consists of a substituted ethylamine backbone with two terminal aromatic rings. Each of the six subclasses (denoted by blue boxes) is a variation on this general structure.
First-generation H1-antihistamines are neutral compounds at physiologic pH, readily cross BBB.
In contrast, second-generation H1-antihistamines are ionized at physiologic pH and do not appreciably cross BBB.
This difference in blood–brain barrier penetration between first- and second-generation H1-antihistamines underlies the differential adverse effect profiles, specifically CNS depression and dry mouth. |
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Term
| H1 -antihistamines indications |
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Definition
Used in allergy, itching, nausea, motion sickness and insomnia.
Limited role in treatment of asthma or anaphylactic reactions
Allergy disordes: relieve symptoms of rhinitis, conjunctivitis, urticaria and pruritus.
H1-antihistamines block increased capillary permeability- more effective when used as prophylactic
Anti-inflammatory properties are attribute to suppression of NFB pathway, chemotaxis and adhesion molecule expression
Second generation antihistamines are preferred for long term clinical use due to low adverse effect profile
Topical nasal antihistamines have shown to be beneficial specially combine with intranasal corticoids
Generalized itching: Potent antipruritic agents: hydroxyzine/ doxepin
Doxepin, tricyclic antidepresant, cause confusion and disorientation in non depressed patients
Topical H1-antihsitamines have a more rapid onset of action and require multiple administration
Nausea and Motion sickness: First generation H1 –antihistamine (diphenhydramine) are used for motion sickness, chemotherapy-, migraine- related nausea.
Inhibit histaminergic signals from the vomiting center in the medulla (antiemetic agents).
Insomnia: First –generation H1-antihistamines (diphenhydramine) have prominent CNS depressive effects, and are used to treat insomnia.
Adverse effects: sedation, reduction of alertness and psychomotor performance
Contraindicated in individuals required to maintain alertness
Limited use: Asthma and anaphylaxis
H1- antihistamine have limited efficacy in bronchial asthma and should not be used as monotherapy.
They are ineffective for systemic anaphylaxis – epinephrine remains the treatment of choice |
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Term
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Definition
Oral antihistamines are well absorbed from GI tract, peak plasma concentration in 2-3hr.
Most H1 antihistamines are metabolize in the liver-> consideration must be taken in patients with liver disease
As inhibitors of cytochrome P450 system, antihistamines may effect metabolism of other drugs |
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Term
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Definition
relieve symptoms of rhinitis, conjunctivitis, urticaria and pruritus.
H1-antihistamines block increased capillary permeability- more effective when used as prophylactic
Anti-inflammatory properties are attribute to suppression of NFB pathway, chemotaxis and adhesion molecule expression
Second generation antihistamines are preferred for long term clinical use due to low adverse effect profile
Topical nasal antihistamines have shown to be beneficial specially combine with intranasal corticoids |
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Term
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Definition
Potent antipruritic agents: hydroxyzine/ doxepin
Doxepin, tricyclic antidepresant, cause confusion and disorientation in non depressed patients
Topical H1-antihsitamines have a more rapid onset of action and require multiple administration |
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Term
| Nausea and Motion sickness |
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Definition
First generation H1 –antihistamine (diphenhydramine) are used for motion sickness, chemotherapy-, migraine- related nausea.
Inhibit histaminergic signals from the vomiting center in the medulla (antiemetic agents). |
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Term
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Definition
First –generation H1-antihistamines (diphenhydramine) have prominent CNS depressive effects, and are used to treat insomnia.
Adverse effects: sedation, reduction of alertness and psychomotor performance
Contraindicated in individuals required to maintain alertness |
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Term
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Definition
H1- antihistamine have limited efficacy in bronchial asthma and should not be used as monotherapy.
They are ineffective for systemic anaphylaxis – epinephrine remains the treatment of choice |
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Term
| H1-Antihistamines ADVERSE EFFECTS |
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Definition
CNS toxicity; High lipophilicity of first generation H1- antihistamines, readily penetrate BBB antagonize the histamine effects in CNS
Sedation
Second generation:ionized at physiological pH and do not enter BBB preferred for long term treatment, limited sedative effect
Cardiac toxicity; specially in patients with pre-exsisting cardiac dysfunction. Early second generation antihistamines prolong QT interval that leads to ventricular arrhythmias
Anticholinergic effects; more prominent in the first generation compounds include pupillary dilation, dry eyes, dry mouth, urine retantion.
Elderly individuals may demonstrate sensitivity to the anticholinergic and sedative effects of first generation antihistamines. Hypotension (blockade of a-adrenergic)
Young children are also susceptible to adverse effects related to antihistamine use.
FDA advises against use of antihistamines for children < 2 yrs.
Rare overdose of first generation antihistamines can cause severe CNS depression presenting as somnolence, ataxia and coma |
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Term
| How might COX-2 inhibition contribute to thrombotic events in cardiovascular toxicity? |
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Definition
| COX-2 inhibition prevents endothelial production of PGI2, but not platelet production of TXA2 |
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Term
| Aspirin is often used in low doses to prevent platelet aggregation by inhibiting the synthesis of which substance? |
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Definition
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Term
| Which of the following is correct about acetaminophen |
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Definition
| It is a strong analgesic and antipyretic NSAID |
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Term
| Glucocorticoids beneficial effects are due to production of… |
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Definition
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Term
| Why does diphenhydramine cause drowsiness? |
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Definition
| Antagonize the effect of histamine in the CNS |
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Term
| Which of the following agents will work the most rapidly to prevent young patients severe adverse effects/ death |
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Definition
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Term
| What is the etiology of anaphylaxis? |
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Definition
| A systemic release of histamine |
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