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58 Cards in this Set
- Front
- Back
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Ion channels
To inhibit depolarization |
- block sodium channels = decreased sodium conductance
- block calcium channels = decreased calcium conductance - open potassium cannels = increased potassium conductance - open chloride channels = increased chloride conductance |
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Drugs acting through sodium channels
nicotinic type I receptors = autonomic ganglia |
agonists = ACh and nicotine (enhance Na conductance)
antagonists (ganglionic blocking drugs) = trimethaphan, hexamethonium |
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Drugs acting through sodium channels
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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Drugs acting through sodium channels
sodium channels of cardiac fast fibers = atria, ventricles |
class IA drugs = procainamide, disopyramide, quinidine
class IB drugs = lidocaine - only affects ventricles |
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Drugs acting through sodium channels
sodium channels in CNS |
the antiepileptic drugs phenytoin, carbamazepine, &
valproate inhibit the spread of electrical signals by prolonging the state of inactivation of the sodium channel |
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Drugs acting through sodium channels
Na+ channels in sensory nerve fibers |
= 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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Drugs acting through sodium channels
Sodium channels coupled to 5-HT3 receptors in CTZ |
induce nausea/emesis,
blocked by ondansetron |
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Ca++ channel blockers
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= nifedipine, diltiazem & verapamil = block L-type channels
in heart and vascular smooth muscle (VSM) |
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Ca++ channels in SM of GI
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SM of GI tract blocked by Al, Fe, diltiazem and verapamil
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Ca++ channels in SM of uterus
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SM of uterus blocked by Mg++
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T-type Ca++ channels in CNS
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Ca++ channels in CNS blocked by ethosuximide
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Glutamate stimulation of NMDA receptors coupled to Ca++ channels
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Ketamine and phencyclidine (“angel dust”) block NMDA receptors and prevent the
excitatory effects of glutamate to cause “dissociative” anesthesia and hallucinations. Felbamate prevents seizures by blocking NMDA receptors. |
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Internal Ca++ channels of SR
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Ca++ channels of SR blocked by dantrolene which prevents the release of
“trigger” Ca++ = DOC for tx of neuroleptic malignant syndrome and anesthesia- induced malignant hyperthermia (hyperpyrexia); dantrolene also used to prevent spasticity caused by neuro diseases, but causes generalized muscle weakness bx it relaxes all skeletal muscle, not just the spastic muscle. |
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Drugs acting through potassium channels = hyperpolarization = inhibition
Muscarinic receptors at the SA node - coupled to a K-channel via a 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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Drugs acting through potassium channels = hyperpolarization = inhibition
5-HT1A-receptors in the CNS |
buspirone is a partial agonist = antianxiety
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Drugs acting through potassium channels = hyperpolarization = inhibition
Vascular smooth muscle |
arterial vasodilators (hydralazine, minoxidil, diazoxide)
activate ATP-modulated K-channels = hyperpolarization = relaxation = vasodilation |
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Drugs acting through potassium channels = hyperpolarization = inhibition
Fast cardiac fibers - antiarrhythmic drugs |
Class IA = procainamide, disopyramide & quinidine prolong repolarization (APD &
ERP increased); only quinidine actually widens the QRS and ↑ the Q-T interval Class IB = lidocaine accelerates repolarization (APD decreased) Amiodarone and sotalol – delay ventricular repolarization via block of K+ channels; APD, ERP and Q-T interval increase Terfenadine blocks K+-channels and delays repolarization in the ventricles, but 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 Cisapride also causes torsades by partially inhibiting the K-repolarization current. |
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Drugs acting through potassium channels = hyperpolarization = inhibition
pancreatic β-islet cells - the orally active hypoglycemic |
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 Diazoxide opens ATP-regulated K+-channels to prevent depolarization and thus inhibit insulin secretion Thiazide diuretic drugs and furosemide also inhibit insulin secretion, but the MOA is unknown |
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Drugs acting through potassium channels = hyperpolarization = inhibition
GABAB-receptors coupled to K+-channels in the CNS; agonist |
baclofen
Baclofen enhances GABA-mediated K+ conductance to hyperpolarize presynaptic terminals and thus reduce the release of an excitatory NT glutamate in the spinal cord. Baclofen used to tx spasticity ass w cerebral palsy, multiple sclerosis and stroke. Baclofen is as effective as BZ’s, but causes less sedation. Baclofen also causes less of a decrease in muscle strength than does dantrolene |
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Drugs acting through potassium channels = hyperpolarization = inhibition
Opiates |
Opiates (morphine) hyperpolarize neurons via mu receptors
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Drugs acting through potassium channels = hyperpolarization = inhibition
D2-receptors in the anterior pituitary |
dopamine, bromocriptine and pergolide
hyperpolarize cells to prevent prolactin release (NB: in other parts of the brain DA inhibits adenyl cyclase or calcium conductance) |
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Drugs acting through potassium channels = hyperpolarization = inhibition
α2-adrenoceptors in the medulla |
clonidine hyperpolarizes to inhibit peripheral
sympathetic outflow |
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Chloride channels
GABAa-receptors = hyperpolarization = inhibition |
Effect of GABA enhanced by: ethanol, propofol, volatile anesthetic agents, BZ’s
(increased frequency of channel opening) and barbiturates (increased duration of channel opening) Valproate increases [GABA] by increasing glutamic acid dehydrogenase and inhibiting GABA transaminase Gabapentin releases GABA from its neurons. |
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Chloride channels
Glycine receptors on Renshaw cells (spinal interneurons) |
Glycine released from Renshaw cells inhibits α-motor neurons; strychnine blocks
glycine receptors in the spinal cord = no α-motor neuron inhibition = convulsions |
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Cyclic AMP (CAMP) - receptors coupled to adenyl cyclase via a G-protein
β1-adrenoceptors |
β1-adrenoceptors
heart =↑ heart rate, contractility & impulse conduction;↓ APD and ERP adipocyte = lipolysis = increased plasma free fatty acids renal JG cells = increased renin release |
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Cyclic AMP (CAMP) β2-adrenoceptors
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β2-adrenoceptors
lungs = (bronchial SM) = relaxation = bronchodilation = increased FEV1 vascular smooth muscle = 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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Cyclic AMP (CAMP) D1-dopamine receptors
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D1-dopamine receptors
vasodilation in the kidney, blocked by D1- D2-receptor blockers like haloperidol |
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Cyclic AMP (CAMP) H2-histamine receptors
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H2-histamine receptors
relaxation of VSM (direct and through NO) causes vasodilation increased gastric acid secretion from oxynitic cells |
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Cyclic AMP (CAMP)
PGI2 (prostacyclin) and PGE receptors |
PGI2 (prostacyclin) and PGE receptors
relaxation of vascular smooth muscle = vasodilation decreased platelet aggregation |
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Cyclic AMP (CAMP) - V2-AVP receptors (renal collecting duct)
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V2-AVP receptors (renal collecting duct) = AVP (ADH) increases water reabsorption
This cyclase inhibited by PGE’s, atrial natriuretic factor, lithium and demeclocycline Antidiuretic effect of AVP potentiated by chlopropramide and carbamazepine. |
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Cyclic AMP (CAMP) - 5-HT1-receptors
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5-HT1-receptors
relaxation of vascular smooth muscle causes sustained vasodilation |
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Cyclic AMP (CAMP) - hormones
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hormones = ACTH, FSH, LH, glucagon, PTH activate adenyl cyclases
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Cyclic AMP (CAMP) -phosphodiesterase inhibitors
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phosphodiesterase inhibitors
theophylline, aminophylline = bronchodilation = tx of neonatal apnea papaverine = relaxation of s.m. in the corpus cavernosa = penile erection dipyridamole = decreased platelet aggregation when used with aspirin amrinone and milrinone = increased cardiac dp/dt (tx of terminal CHF) |
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Signal transduction via cyclic GMP (CGMP) - THINK antianginal drugs!
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Nitric oxide (NO) is produced tonically by the vascular endothelial cells.
nitrate vasodilators (nitroglycerin) and Na nitroprusside are converted to NO which activates guanyl cyclase: CGMP relaxes arterial/venous VSM (a kinase dephosphorylates the MLC’s) and inhibits platelet aggregation. Atrial natriuretic factor (ANF) also ↓ BP by activation of guanyl cyclase and ↑ [CGMP] sildenafil causes erection by inhibiting the type V PDEase which degrades CGMP |
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IP3 and DAG
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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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Receptors of VSM or SM
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1. muscarinic receptors = sphincter muscle of iris, SM of bronchioles, bronchial
glands, SM of GI tract and gall bladder, detrusor muscle of urinary bladder, pancreatic acini and α-islet cells (glucagon); salivary glands, lacrimal glands, nasopharyngeal glands 2. α1-adrenoceptors = radial muscle of eye, vascular SM, trigone and internal sphincter of GU tract, SM of urethra/prostate, pilomotor muscles, salivary glands 3. Ang II receptors -=VSM 4. TXA2 receptors = VSM 5. V1-AVP receptors = VSM 6. H1-histamine receptors = vascular endothelial cells, SM of bronchioles and GI tract 7. 5-HT2-receptors = VSM 8. PGE receptors = SM of uterus and GI tract 9. Li+ inhibits the recycling of PIP2 and thus interrupts the IP3 signaling pathway |
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Alteration of ion transport by drugs
Cardiac glycosides= digoxin & digitoxin |
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 |
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Alteration of ion transport by drugs - Gastric H+-K+ ATPase (proton pump)
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(proton pump) - inhibited by omeprazole
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Alteration of ion transport by drugs- Na+: K+:2Cl- symporter in ascending limb of Henle’s loop
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ascending limb of Henle’s loop is blocked by furosemide
and ethacrynic acid. |
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Alteration of ion transport by drugs - Na+: Cl- symporter in renal DT
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renal DT - inhibited by thiazide diuretic drugs
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Alteration of ion transport by drugs - Na+ channels in principal cells of LDT/CD
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principal cells of LDT/CD - blocked by amiloride and triamterene
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Alteration of ion transport by drugs- H+ ion secretion in renal PT and DT
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renal PT and DT -↓ by acetazolamide bx it inhibits CA
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Alteration of ion transport by drugs - H+ ion secretion from LDT/CD
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LDT/CD - blocked by amiloride and triamterene
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Changes in DNA transcription thyroxine
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↑ β-receptors & mitochondrial E’s for oxidative phosphorylation (ATP)
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Changes in DNA transcription aldosterone
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↑ basolateral ATPase, Na+ channels and 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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Changes in DNA transcription glucocorticoids
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cortisone, hydrocortisone, prednisone, prednisolone,
beclomethasone, triamcinolone - increased transcription of the genes for lipocortin (inhibits PLA2), the inhibitor of NFΚB and enzymes (E's) for gluconeogenesis - ↓ transcription of genes for COX-2; IL-1 & IL-6 in monocytes & macrophages; gene for NFΚB, and E’s for glycogen storage (except glycogen synthetase) |
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Changes in DNA transcription cyclosporine
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decreased transcription of gene for IL-2 in helper T-cells
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Changes in DNA transcription androgens
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increased erythropoesis and hepatic synthesis of C1-esterase inhibitor
of complement |
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Changes in DNA transcription estrogens
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- increased hepatic protein synthesis = transcortin (CBG), thyroxine-
binding globulin (TBG), angiotensinogen (renin substrate), transferrin, fibrinogen and clotting factors 2, 7, 9 and 10. |
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Changes in DNA transcription NSAID’s
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NSAID’s prevent the activation of nuclear factor kappa-B: this action prevents the
increased expression of the genes which code for many inflammatory mediators. |
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Idiosyncratic drug reactions Plasma pseudocholinesterase deficiency
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the NMB caused by succinylcholine last
hours instead of minutes. |
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Idiosyncratic drug reactions Barbiturates
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produce excitation and anxiety instead of sedation in older patients.
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Idiosyncratic drug reactions The older antihistamines
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(e.g. diphenhydramine) cause excitation instead of sedation
in very young children and older patients. |
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Idiosyncratic drug reactions Aspirin and other NSAID's
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precipitate an anaphylactic-like reactions (a.k.a. aspirin
hypersensitivity) in patients with nasal polyps. Blockade of PG synthesis by the NSAID shunts all the arachidonic acid to leukotriene synthesis → LT's cause rhinoconjunctivitis, angioedema and urticaria. |
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Idiosyncratic drug reactions Glucose-6-phosphate dehydrogenase deficiency
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hemolytic anemia is produced by
primaquine, isoniazid, sulfonamides, nitrofurantoin or eating fava beans |
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Idiosyncratic drug reactions . SHIP drugs exhibit toxicity in slow acetylators
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a. sulfapyridine (contained in the drug sulfasalazine) =hemolytic and aplastic
anemia, hepatic damage. b. hydralazine = SLE-like syndrome c. isoniazid = hepatic damage, peripheral neuropathy - tx neuropathy w pyridoxal phosphate (vitamin B6) d. procainamide = SLE-like syndrome |
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Idiosyncratic drug reactions Malignant hyperthermia (hyperpyrexia)
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a gene defect prevents Ca++ from being
sequestered correctly in the sarcoplasmic reticulum (SR) of skeletal muscle. - anesthesia with a volatile anesthetic agent (e.g., halothane) plus the administration of succinylcholine causes the massive release of Ca++ = masseter muscle spasm - S/S = ↑ B, HR, & muscle contraction w hyperthermia, lactic acidosis and cardiac dysrhythmias - tx w dantrolene sodium which prevents the release of Ca++ from the SR |
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Idiosyncratic drug reactions Neuroleptic malignant syndrome
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etiology NOT related to malignant hyperthermia
= produced by rapid blockade of central DA receptors with the typical antipsychotic drugs like haloperidol - S/S = resembles severe Parkinson's dx w catatonia = EPS, stupor, hyperthermia, ↑ CPK, myoglobinuria, ARF - Tx w dantrolene sodium + bromocriptine (a D2-receptor agonist) |
