Autocoids Flashcards
Histamine storage sites
mast cells, basophils, enterochromaffin-like cells, neurons
H1 receptor location
peripheral nerve endings, CNS, smooth muscle of blood vessels, bronchi, and intestine
H1 receptor type
Gq coupled
H1 receptor activation- effects
vasodilation of small vessels; increased vessel permeability; bronchoconstriction; bronchospasm; urticaria; intestinal smooth muscle contraction
H2 receptor locations
gastric mucosa, heart, mast cells, CNS
H2 receptor type
Gs
H2 receptor activation- effects
Vasodilation of small blood vessels; Increased heart rate: reflex tachycardia and direct stimulation; Gastric acid secretion
H3 receptor locations
autoreceptors on histaminergic neurons in CNS and PNS; Gi-coupled
H3 receptor type
Gi
H4 receptor locations
Eosinophils, neutrophils, CD4 T-cells
H4 receptor type
Gi
Diphenhydramine
First generation H1 inverse agonist
- tx for allergic rhinitis, itching, urticaria, motion sickness, insomnia
- MOA: has antimuscarinic activity–> relieve of motion sickness; sedation via antagonism of CNS receptors; relief of allergy
Cetirizine
second generation H1 inverse agonist
- minimal antimuscarinic activity
- low CNS accumulation because pumped out by P-glycoprotein pump
- 50% metabolized in liver as CYP3A4
- fewer adverse reactions, CNS effects only at high doses
- if CrCL<31 mL/min, do not exceed 5mg dose
Fexofenadine
second generation H1 inverse agonist
- no antimuscarinic activity
- low metabolism, 80% excreted in feces
- low CNS accumulation because pumped out by P-glycoprotein pump
- few adverse reactions
- lower dose for patients with decreased renal function, do not take with fruit juice
Loratadine
second generation H1 inverse agonist
- can be formulated with pseudophedrine
- low CNS accumulation b/c effluxed from CNS by P-glycoprotein pump
- extensive CYP3A4 metabolism–> many drug interactions
- precautions: hepatic disease; if CrCL <30mL/min use loser dose
Cimetidine
H2 antagonist
- H2 inverse agonist, reduces constitutive activity of H2 receptors on parietal cells, decreases acid secretion by 60%
- PO or IV, usually 100-400 mg BID-QID or 800mg HS
- non-selective inhibitor of CYP enzymes–> many drug interactions
- 48% excreted in urine
- adverse effects: headaches, blood dyscrasias
- precautions: hepatic disease, renal insufficiency
Ergotamine
partial agonist or antagonist of 5-HT, DA, and a- adrenergic receptors
- vasoconstriction of arteries and veins
- decreased blood flow to extremities
- oxytotic (uterine contractions, decreased postpartum bleeding)
- adverse effects: ergotism
- contraindications: CV disease, hepatic disease, renal failure, pregnancy- risk category X
Sumatriptan
- Agonist at presynaptic 5-HT1D autoreceptors and 5-HT1B receptors
- SC mode more effective than PO
- metabolism by MAO-A in liver, excretion in feces and urine
- adverse effects: fatal CV events, GI issues, injection site reaction
- Precautions: hepatic disease, renal insufficiency
- contraindications: CV disease, ischemic bowel disease
Serotonin syndrome
caused by excessive serotonin concentration at receptors, may be precipitated by concomitant use of drugs that increase serotonin secretion
management of serotonin syndrome
- remove precipitating drug and supportive care
- control agitation- benzodiazepines
- antagonize 5-HT actions: cyproheptadine (H1, 5-HT2, D3, M1-5 blocker)
- control hypertension and tachycardia: sodium nitroprusside, esmolol
- control hyperthermia: vecuronium, no role for antipyretics
Lipoxin receptor (ALX)
GI smooth muscle: relaxation; bronchial smooht muscle: relaxation; vascular smooth muscle: vasodilation; immune: inhibition
Prostaglandin E2 receptor (EP)
GI smooth muscle: increased motility; GI secretion: decreased acid/increased bicarb; penis: relaxation, erection; bronchial smooth muscle: relaxation, bronchodilation; uterus: tone, contractions; vascular smooth muscle: vasodilation, hypotension; immune: activation; platelets: decreased aggregation; kidney: increased renin release, vasodilation, increased GFR; nervous: increased body temp., hyperalgesia
Prostacyclin receptor (IP)
bronchial smooht muscle: relaxation, bronchodilation; vascular smooth muscle: vasodilation, hypotension; platelets: decreased aggreation; kidney: increased renin release, vasodilation, increased GFR
Thromboxane receptor (TXA2)
bronchial smooth muscle: contraction, bronchoconstriction; vascular smooth muscle: vasoconstriction, hypertension; platelets: increased aggreagation
Prostaglandin D2 receptor (DP)
kidney: increased renin release, vasodilation, increased GFR. Smooth muscle contraction, inhibit platelet aggregation
Prostaglandin F receptor (FP)
GI smooth muscle: increased motility; bronchial smooth muscle: contraction, bronchoconstriction; uterus: uterine tone, contractions; vascular smooth muscle: vasoconstriction, hypertension
Leukotriene B4 receptor (BLT)
Immune: activation
Leukotriene receptor CysLT
Bronchial smooth muscle: contraction, bronchoconstriction; vascular smooth muscle: vasoconstriction, hypertension; immune: activation; kidney: vasoconstriction, decreased GFR
Hydrocortisone
Steroidal anti-inflammatory drug
- anti-inflammatory, represses COX-2, decrased cytokine production, decreased endogenous inflammatory mediators, apoptosis of eosinophils
- contraindications: abrupt discontinuation, Cushings
Prednisone
Steroidal anti-inflammatory drug
- similar mechanism as hydrocortisone
- prodrug of prednisolone
- TX for autoimmune, transplant, asthma, IBS, RA
- half life 18-36 hours
fluticasone
Medium potency steroid
- TX for dermatoses, prophylaxis for asthma
- similar mechanisms as hydrocortisone
- metabolism by CYP3A4
- inhaled form can cause oropharyngeal candidiasis
Betamethasone
Steroid with anti-inflammatory potency 25-40; no mineralcorticoid potency; long duration
Dexamethasone
Steroid with anti-inflammatory potency 30; no mineralcorticoid potency; long duration
Fluprednisolone
Steroid with anti-inflammatory potency 15; no mineralcorticoid potency; intermediate duration
Triamcinolone
Steroid with anti-inflammatory potency 5; no mineralcorticoid potency; intermediate duration
Methylprednisolone
Steroid with anti-inflammatory potency 4; minimal mineralcorticoid potency; short-intermediate duration
Fludricortisone
Steroid with anti-inflammatory potency 10 but used mostly for mineralcorticoid replacement (potency 250); intermediate duration
General properties of NSAIDs
anti-inflammatory, antipyretic, analgesic (Not for neurologic pain); used for joint pain, muscle aches, rheumatoid arthritis, osteoarthritis, fever, dysmenorrhea, gout, prophylaxis of polyps and colon cancer
NSAID mechanisms of action
- inhibition of cyclooxygenase resulting in decreased prostaglandin synthesis
- all have risk of CV and GI adverse effects
- all are roughly equally efficacious
Aspirin
- Irreversible/ covalent COX inhibitor with 5x selectivity for COX1 over COX2
- thrombosis prevention- antiplatelet activity is long lasting because platelets cannot regenerate inactivated COX
- metabolized in liver to salicylic acid and excreted in urine
- aspirin triad
- can lead to Reye’s in children
Ketorolac
- NSAID: Competitive inhibitor of COX enzymes with 100x preference for COX-1 over COX-2
- used for short term postsurgical pain that requires major analgesia
- Parenteral dose followed by 10mg PO QID. 90% excreted in urine with 40% metabolized in liver
- contraindications: salicylate sensitivity; aspirin triad; CrCL< 30 ml/min
Indomethacin
- NSAID: Competitive inhibitor of COX enzymes with 5x preference fo COX-1 over COX-2
- used in premature infants to accelerate closure of patent ductus arteriosus
- usually 3 doses given 12 hours apart for PDA; metabolized in liver and undergoes enterohepatic recirculation; 60% recovered in urine and 30% recovered in feces
- precaution: seizure, psychiatric disease, Parkinsons, Pregnancy category D or B depending on trimester
- contraindications: salicylate sensitivity; aspirin triad
Naproxen
- Competitive inhibitor of COX enzymes with 5x preference fo COX-1 over COX-2
- Used mostly for analgesic and antipyretic properties than anti-inflammatory
- largely bioavailabe; extensive hepatic metabolism and conjucation; 95% excreted in urine
- adverse events: GI and derm
- contraindications: salicylate sensitivity; aspirin triad
Ibuprofen
- Competitive inhibitor of COX enzymes with 2x preference for COX-1 vs COX-2
- excreted in urine, 50-60% as metabolites
- CNS, GI, rash, tinnitis, blurred vision
Meloxicam
- Competitive inhibitor of COX enzymes with 10x preference for COX-2 over COX-1
- indicated for rheumatoid arthritis, osteoarthritis. Highly potent. COX-2 selective
- Dose 7.5-10mg QD; highly bound to serum albumin, 70% metabolized by CYP2C9 and CYP3A4; excretion through urine and feces
Celecoxib (Celebrex)
- Competitive inhibitor of COX enzymes, 10-20-fold selective for COX-2 vs. COX-1
- First FDA-approved selective COX-2 inhibitor; 97% metabolized in liver by CYP2C9
Diclofenac
- Competitive inhibitor of COX enzymes, 10-20-fold selective for COX-2 vs. COX-1
- Metabolized in liver by CYP2C9 followed by glucuronidation or sulfation; excretion is 65% renal/ 35% biliary
- adverse events: GI, eleveated liver function tests, renal- decreased blood flow, decreased GFR
Acetaminophen
- NOT an NSAID
- Competitive inhibitor of COX enzymes in the CNS but not in periphery; binds to cannabanoids in spinal cord
- In the liver, 85-90% is metabolized but 10-15% is converted via CYP2E1, 1A2, or 3A4 to a hepatotoxic metabolite, 85% renally excreted
- adverse effect: Rash, pruritis, urticaria, GI at high doses, heptatoxicity treated with N-acetyl cysteine; renal tubule necrosis at high doses
- precautions: alcoholism, hepatic disease, renal disease, tobacco smoking, salicylate sensitivity
Alprostadil
- prostanoid, agonist at EP receptors, increases cAMP and causes vasodilation
- In men: used for erectile dysfunction in men who cannot tolerate nitro- compunds. In neonates: used to maintain patency of ductus arteriosus until surgery
- Very potent, in men comes in powder form and reconstituted for injection; 81% albumin bound; metabolized by one pass through lungs, duration of action is 12-70 min
Latanaprost
- prostanoid used to treat glaucoma
- Selective FP receptor agonist that reduces intraocular pressure by increasing the outflow of aqueous humor, decrease by 6-9 mmHg
- Dosed by drops in eye, reduction in IOP begins within 3-4 hours and maximum effect in 8-12 hours; hydrolyzed by esterases in the cornea to biologically active acid
- adverse effects: blurred vision, burning, itching, increased iris pigmentation, eyelash changes
- do not use if active intraocular inflammation
Misoprostol
- Synthetic prostaglandin analog; agonist at EP receptors on parietal cells and uterine cells. GI: deceased cAMP, decreased acid secretion. Uterine: increased contractions, cervical dilation
- used to prevent gastric ulcers (less effective than H2 antagonists); used to induce labor or abortion
- In medical abortions given 48 hours following mifepristone, rapidly absorbed with peak levels after 9-15 minutes. Half life 20-40 minutes.
Zileuton
- Leukotriene inhibitor, specific 5-LOX inhibitor–> decreased leukotriene formation.
- Causes inhibition of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, decreased capillary permeability, leukotriene-induced smooth muscle contraction
- 600 mg QID, rapidly absorbed with half life of 2.5 hours, apparent Vd of 1.2 L/kg, 93% bound to plasma proteins, substrate for CYP1A2, CYP2C9, CYP3A4
- check LFTs before beginning treatment, do not use in active liver disease
Zafirlukast
- Peptide leukotriene receptor antagonist at G coupled CysLT receptors in muscles, mast cells, neutrophils.
- used in prophylactic treatment of chronic asthma by inhibiting bronchoconstriction, edema, mucus secretion
- 20 mg BID, rapidly absorbed with peak plasma concentration in 3 hours, food increases bioavailability, 99% bound to plasma protein with 8 hour plasma half life, metabolized by CYP3A4 and CYP3C9, most excreted in feces
Montelukast
- Antagonist at G coupled CysLT receptors in airway muscle, mast cells, neutrophils
- used in prophylactic treatment of chronic asthma by inhibiting bronchoconstriction, edema, mucus secretion and for allergic rhinitis
- given PO, 10 mg QD, rapidly absorbed, 99% bound to plasma protein, extensive hepatic metabolism with CYP3A4 and CYP2C9, excreted almost exclusively in bile
- very similar to Zafirlukast but lower dose only once daily so more convenient for patients
