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67 Cards in this Set
- Front
- Back
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How do we inhibit depolarization of an ion channel?
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1. block sodium channels = decreased sodium conductance
2. block calcium channels = decreased calcium conductance 3. open potassium channels = increased potassium conductance 4. open chloride channels = increased chloride conductance |
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Where are the sodium channels found that drugs like to affect?
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1. autonomic ganglia --> nicotinic type I receptors
2. skeletal muscle motor endplate --> nicotinic type II receptors 3. cardiac fast fibers in atria and ventricles 4. CNS 5. sensory nerve fibers 6. Na channels coupled to 5-HT3 receptors in CTZ |
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SODIUM CHANNEL: Nicotinic type I receptor
Agonists and antagonists? |
nicotinic type I receptors = autonomic ganglia
AGONISTS ACh and nicotine -- enhance Na conductance ANTAGONISTS trimethaphan, hexamethonium -- ganglionic blocking drugs |
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SODIUM CHANNEL: Nicotinic type II receptors
Agonists and antagonists? |
nicotinic type II receptors = skeletal muscle motor endplate
AGONISTS ACh, nicotine, succinylcholine -- enhance Na conductance ANTAGONISTS d-tubocurarine (d-tc), pancuronium, Mg++ -- the -curiums and -roniums |
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SODIUM CHANNEL: cardiac fast fibers
Drugs that affect them and their classes? |
CLASS IA DRUGS
procainamide disopyramide quinidine CLASS IB DRUGS lidocaine -- only affects ventricles |
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SODIUM CHANNEL: CNS
Which drugs and MOA? |
ANTIEPILEPTICS
phenytoin carbamazepine valproate Inhibit spread of electrical signals by prolonging the state of inactivation of the sodium channel |
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SODIUM CHANNEL: sensory nerve fibers
Which drugs and MOA? |
the cationic form of local anesthetic drugs
-- cocaine -- procaine -- lidocaine Blocks Na+ conductance by binding to a site in the channel on the axoplasmic side (inside cell) |
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SODIUM CHANNEL: coupled to 5-HT3 receptors in CTZ
Effect of receptor binding and antagonist? |
Induces nausea/emesis
Blocked by ONDANSETRON |
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6 different locations Ca channels are antagonized?
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1. block heart and vascular smooth muscle (VSM) L-type channels
2. block channels in SM of GI 3. block channels in SM of uterus 4. block T-type channels in CNS 5. block NMDA receptors coupled to Ca channels 6. block internal Ca channels of SR |
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Drugs which block L-type Ca channels in heart and VSM?
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nifedipine
diltiazem verapamil |
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Drugs which block Ca channels in SM of GI?
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diltiazem
verapamil Al Fe |
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What blocks Ca channels in SM of uterus
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Mg++
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Drug which blocks Ca channels in CNS?
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ethosuximide
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Drug which blocks NMDA receptors coupled to Ca channels?
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KETAMINE
PHENCYCLIDINE ("angel dust") -- prevent excitatory effects of glutamate to cause "dissociative" anesthesia and hallucinations FELBAMATE -- prevents seizures by blocking NMDA receptors |
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Drugs which blocks Ca channels in SR? Use of that drug?
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DANTROLENE
-- prevents release of "trigger" Ca 1. DOC for tx of -- neuroleptic malignant syndrome -- anesthesia induced malignant hyperthermia 2. prevent spasticity caused by neuro diseases byt causes generalized muscle weakness b/c relaxes ALL skeletal muscle, not just spastic muscle |
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9 locations to affect K channels?
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1. Muscarinic receptors at the SA node
2. 5-HT1A-receptors in the CNS 3. Vascular smooth muscle 4. Fast cardiac fibers 5. pancreatic -islet cells 6. GABA-B receptors coupled to K+-channels in the CNS 7. mu receptors 8. D2-receptors in the anterior pituitary 9. alpha2-adrenoceptors in the medulla |
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Muscarinic receptors at the SA node: agonists and antagonists?
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Muscarinic receptors are coupled to a K-channel via G-protein
AGONISTS ACh pilocarpine AChase inhibitors (indirect through increased ACh) ANTAGONISTS atropine et al. pancuronium quinidine TCA’s older antihistamines like diphenhydramine |
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Which drug affects 5-HT1A-receptors in the CNS?
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buspirone is a partial agonist = antianxiety
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Which drugs affect vascular smooth muscle K channels? Their MOA?
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ARTERIAL VASODILATORS
hydralazine minoxidil diazoxide activate ATP-modulated K-channels = hyperpolarization = relaxation = vasodilation |
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Which drugs affect K channels at fast cardiac fibers?
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ANTIARRHYTHMICS
CLASS IA procainamide disopyramide quinidine -- all PROLONG repolarization (APD & ERP increased) -- only quinidine actually widens the QRS and increases the Q-T interval CLASS IB lidocaine -- ACCELERATES repolarization (APD decreased) Amiodarone and sotolol -- DELAY ventric repol by blocking K+ channels -- APD, ERP and Q-T interval increase Terfenadine -- blocks K+ channels and DELAYS repol in ventricles |
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What is special about terfenadine?
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Under normal circumstances terfenadine is completely metabolized by CYP450 to its active metabolite fexofenadine.
The macrolide erythromycin inhibits this CYP450, so terfenadine inhibits repolarization and can increase the Q-T interval enough to cause torsades de pointes = polymorphic ventricular tachycardia CIDAPRIDE also causes torsades by partially inhibiting the K-repolarization current. |
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Which drugs affect K channels at pancreatic beta-islet cells to INCREASE insulin secretion? MOA?
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the orally active hypoglycemics
-- tolbutamide -- chlorpropamide -- glypizide Close K+-channels causing the cell to depolarize -- depolarization opens voltage-sensitive channels -- Ca++ flows in to activate PLC which increases IP3 which release more Ca++ from the SR -- increased free intracellular Ca++ causes insulin secretion |
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Which drugs affect K channels at pancreatic beta-islet cells to DECREASE insulin secretion? MOA?
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DIAZOXIDE opens ATP-regulated K+-channels to prevent depolarization and thus inhibit insulin secretion
THISZIDE DIURETICS and FUROSEMIDE also inhibit insulin secretion, but the MOA is unknown |
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Which drugs affect GABA-B receptors coupled to K+-channels in the CNS? MOA?
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BACLOFEN
-- enhances GABA-mediated K+ conductance to hyperpolarize presynaptic terminals -- thus reduces the release of an excitatory NT glutamate in the spinal cord. |
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Baclofen therapeutic use?
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1. Baclofen used to tx spasticity assoc w/ cerebral palsy, multiple sclerosis and stroke.
2. Baclofen is as effective as BZ’s, but causes less sedation. 3. Baclofen also causes less of a decrease in muscle strength than does dantrolene |
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Which drugs affect K channels at mu receptors? MOA?
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opiates (morphine)
hyperpolarizes neurons via mu receptors |
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Which drugs affect alpha2-adrenoceptors in the medulla? MOA?
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CLONIDINE
-- hyperpol to inhibit peripheral sympathetic outflow |
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2 locations to affect chloride channels?
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1. GABA-A receptors
2. Glycine receptors on Renshaw cells (spinal interneurons) |
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Which drugs enhances GABA-A chlorine channel effect?
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GABA-A receptors = hyperpol = inhibition
1. ethanol 2. propofol 3. volatile anesthetics 4. BZs -- increase freq of channel opening 5. Barbituates -- increase duration of channel opening 6. valproate -- increases [GABA] by increasing glutamic acid dehydrogenase and inhibiting GABA transaminase 7. gabapentin releases GABA from its neurons |
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Which drugs affect glycine receptors on Renshaw cells (spinal interneurons)?
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Glycine released from Renshaw cells normally INHIBITS alpha-motor neurons
STRYCHNINE blocks glycine receptors in the spinal cord -- no alpha motor neuron inhibition --> convulsions |
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Where might we find cAMP receptors coupled to adenyl cyclase via a G-protein?
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1. B1-adrenoceptors
2. B2-adrenoceptors 3. D1-dopamine receptors 4. H2-histamine receptors 5. PGI2(prostacyclin) and PGE receptors 6. V2-AVP receptors 7. 5-HT1 receptors |
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B1-adrenoceptor cAMP denyl cyclase activation causes?
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HEART
-- increased heart rate, contractility & impulse conduction -- decreased APD and ERP ADIPOCYTE -- lipolysis -- increased plasma ffa's RENAL JG CELL -- increased renin release |
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B2-adrenoceptor cAMP denyl cyclase activation causes?
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LUNGS (bronchial SM)
relaxation = bronchodilation = increased FEV1 VSM -- relaxation -- vasodilation of arteries and veins UTERUS -- relaxation (inhibition of parturition) LIVER -- glycogenolysis via protein kinase activation of phosphorylase a MAST CELL -- decreased free intracellular calcium inhibits degranulation |
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D1 dopamine receptor cAMP denyl cyclase activation causes?
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vasodilation in the kidney,
**blocked by D1- D2-receptor blockers like haloperidol |
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H2-histamine receptor cAMP denyl cyclase activation causes?
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1. relaxation of VSM
-- direct and through NO -- causes vasodilation 2. increased gastric acid secretion from oxynitic cells |
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PGI2 (prostacyclin) and PGE receptor cAMP denyl cyclase activation causes?
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1. relaxation of vascular smooth muscle
-- vasodilation 2. decreased platelet aggregation |
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V2-AVP receptor (renal collecting duct)cAMP adenyl cyclase activation causes?
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AVP (ADH) release increases water reabsorption
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V2-AVP receptor inhibited by...?
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-- PGE's
-- atrial natriuretic factor -- lithium -- demeclocycline |
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V2-AVP receptor potentiated by...?
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chlopropramide
carbamazepine |
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5-HT1 receptor cAMP adenyl cyclase activation causes?
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relaxation of vascular smooth muscle
-- causes sustained vasodilation |
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Which hormones activate adenyl cyclases?
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ACTH
FSH LH glucagon PTH |
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What are the phosphodiesterase inhibitors and what are they used for?
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1. theophylline, aminophylline
-- bronchodilation -- tx of neonatal apnea 2. papaverine -- relaxation of s.m. in the corpus cavernosa -- penile erection 3. dipyridamole -- decreased platelet aggregation when used with aspirin 4. amrinone and milrinone -- increased cardiac dp/dt -- tx of terminal CHF |
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What is the effect of NO?
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NO is produced tonically by the vascular endothelial cells
NO activates guanyl cyclase --> cGMP relases arterial/venous VSM (a kinase dephosphorylates the MLCs) and inhibits platelet aggregation |
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Which drugs affect signal transduction via cGMP? MOA?
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THINK ANTIANGINAL DRUGS!!
NITRATE VASODILATORS (nitroglycerin) Na NITROPRUSSIDE -- both can convert to NO ATRIAL NATRIURETIC FACTOR (ANF) -- also decreases BP by activation of guanyl cuclase and increased [cGMP] SILDENAFIL causes erection by inhibiting the type V PDEase which degrades cGMP |
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What is the response to IP3 and DAG release from PIP2?
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IP3 releases Ca++ from the SR
-- Ca++ binds to calmodulin which then activates enzymes (E’s) -- smooth muscle contraction or secretion |
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Where might we find IP3/DAG-mediated responses?
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1. muscarinic receptors
2. alpha1-adrenoceptors 3. Ang II receptors 4. TXA2 receptors 5. V1-AVP receptors 6. H1-histamine receptors 7. 5-HT2-receptors 8. PGE receptors |
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IP3/DAG and muscarinic receptors: What is affected?
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1. sphincter muscle of iris
2. SM of bronchioles 3. bronchial glands 4. SM of GI tract and gall bladder 5. detrusor muscle of urinary bladder 6. pancreatic acini and B-islet cells (glucagon) 7. salivary glands 8. lacrimal glands 9. nasopharyngeal glands |
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IP3/DAG and alpha1-adrenoceptors: What is affected?
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1. radial muscle of eye
2. vascular SM 3. trigone and internal sphincter of GU tract 4. SM of urethra/prostate 5. pilomotor muscles 6. salivary glands |
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IP3/DAG and AngII/TXA2/V1-AVP/5-HT2 receptors: What is affected?
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VSM (vascular smooth muscle)
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IP3/DAG and H1-Histamine receptors: What is affected?
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1. vascular endothelial cells
2. SM of bronchioles and GI tract |
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IP3/DAG and PGE receptors: What is affected?
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SM of uterus and GI tract
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What interrupts the IP3 signaling pathway? How?
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Lithium inhibits the recycling of PIP2, thus interrupting the IP3 signaling pathway
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Alteration of ion transport by drugs: DIGOXIN and DIGITOXIN
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Depolarization allows Ca++ to move into the cell via L-type (voltage-sensitive) Ca++ channels.
-- Some of the Ca++ is pumped into the SR. -- Additional Ca++ is extruded by a Na/Ca antiporter which uses the high outside/low inside Na+ gradient to move Ca++ out against its concentration gradient. -- This outside/inside Na gradient is maintained by the membrane Na/K ATPase. DIGOXIN -- partially blocks the Na/K ATPase -- the outside/inside Na gradient is decreased -- less Ca++ is extruded via Na/Ca exchange -- this excess Ca++ in the cell is stored in the SR -- the next depolariaztion results in a greater release of Ca++ from the SR (thus greater contraction) DIGOXIN and DIGITOXIN are cardiac glycosides |
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Alteration of ion transport by drugs: Gastric H/K ATPase
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This proton pump is INHIBITED by
Omeprazole |
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Alteration of ion transport by drugs: N/K/2Cl symporter
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Symporter is in ascending LofH
-- blocked by FUROSEMIDE and ETHACRYNIC ACID |
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Alteration of ion transport by drugs: Na channels in principal cells of LDT/CD
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blocked by AMILORIDE and TRIAMTERENE
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Alteration of ion transport by drugs: Na/Cl symporter in renal DT
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inhibited by THIAZIDE diuretics
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Alteration of ion transport by drugs: H+ secretion in renal PT and DT
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decreased by ACETAZOLAMIDE b/c it inhibits carbonic anhydrase (CA)
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Alteration of ion transport by drugs: H+ secretion from LDT/CD
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blocked by AMILORIDE and TRIAMTERENE
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List the drugs that can change DNA transcription
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1. throxine
2. aldosterone 3. glucocorticoids 4. cyclosporine 5. androgens 6. estrogens 7. NSAIDS |
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Thyroxine and DNA transcription?
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INCREASES
-- B-receptors -- mitochondrial E's for OxPhos (ATP) |
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Aldosterone and DNA transcription?
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INCREASES
-- basolateral ATPase -- Na+ channels -- E’s for oxidative phosphorylation (ATP) in the LDT/CD INCREASED -- deposition of fibrillar collagen in the extracellular matrix of the heart |
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Glucocorticoids and DNA transcription?
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cortisone, hydrocortisone, prednisone, prednisolone, beclomethasone, triamcinolone
INCREASES -- transcription of the genes for lipocortin (inhibits PLA2) -- the inhibitor of NFKB -- enzymes (E's) for gluconeogenesis DECREASES -- transcription of genes for COX-2 -- IL-1 & IL-6 in monocytes & macrophages -- gene for NFKB -- E’s for glycogen storage (except glycogen synthetase) |
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Cyclosporine and DNA transcription?
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DECREASED
-- transcription of gene for IL-2 in helper T-cells |
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Androgens and DNA transcription?
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INCREASED
-- erythropoesis -- hepatic synthesis of C1-esterase inhibitor of complement |
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Estrogens and DNA transcription?
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INCREASED hepatic protein synthesis:
-- transcortin (CBG) -- thyroxine-binding globulin (TBG) -- angiotensinogen (renin substrate) -- transferrin -- fibrinogen -- clotting factors 2, 7, 9 and 10. |
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NSAIDS and DNA transcription?
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PREVENT activation of nuclear factor kappa-B
-- prevents the increased expression of the genes which code for many inflammatory mediators |
