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AdPhTest3
antiepileptics, dantrolene, diuretics, serotonin, renin, kinins, NSAIDS, prostag
| Question | Answer |
|---|---|
| AEDs (anti-epileptic drugs) | Sodium channel blockers – Calcium current inhibitors – GABA enhancers – Glutamate blockers – Carbonic anhydrase inhibitors – Hormones – Drugs with unknown MOAs |
| Sodium Channel Blockers | phenytoin, cabemazepine, oxcarbazepine, zonisamide (all four of these have calcium channel blocking capacities also); lamotrigene (also gabanergic) |
| Sodium Channels Have how many states? | 3 - resting (allows passage of sodium), active (allows increasd influx of sodium), inactive ( does not allow sodium into cell). |
| Presynaptic and postsynaptic Na channel blockade | Stabilizes neuronal membranes – Blocks & prevents posttetanic potentiation – Limits development of maximal seizure activity – Reduces spread of seizures |
| AEDs with selective Na Channel Blockade | Carbamazepine • Oxcarbazepine • Fosphenytoin |
| Carbamazepine (CBZ) | Trade names—Tegretol, Carbatrol • major first-line AED for partial seizures and generalized tonic-clonic seizures, induces its own metabolism. |
| Carbamazepine (metabolism) | induces its own metabolism, causing an increase in clearance and a decrease in levels, the serum half-life decreases by 50% during the first few weeks of treatment – Dosage increase is necessary 2 to 4 weeks after initiation of therapy |
| CBZ Effects | can produce dose-related adverse effects, which include dizziness, diplopia, nausea, ataxia, and blurred vision • Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens-Johnson syndrome |
| CBZ Effects contin | Asymptomatic elevation of liver enzymes is observed commonly during the course of therapy in 5-10% of patients • High plasma levels exert arginine vasporessin hormone- like action – Hyponatremia can occur |
| CBZ - what drugs inhibit metabolism | macrolide antibiotics (erythromycin and clarithromycin), isoniazid, chloramphenicol, calcium channel blockers, cimetidine, and propoxyphene, inhibit the hepatic enzyme cytochrome P- 4503A4 (CYP3A4), |
| CBZ - what drugs induce metabolism | Grapefruit juice and St. John's wort are inducers of CYP3A4 and can decrease CBZ levels • CBZ accelerates metabolism of oral contraceptives – Most women require increase in daily dose of estrogen |
| Calcium Channels in brain (how many types) | there are 3 known forms of calcium channels – L, N, and T–Small channels and inactivated quickly • Influx of Ca currents in the resting state produces a partial depolarization of the membrane ,helps action potential after rapid depolarization of the ce |
| Calcium Channels | Function as"pacemakers" of normal rhythmic brain activity •true particularly of the thalamus.T-calcium channels have been known to play a role in the 3 per second spike/wave discharges of absence seizures |
| Calcium Channel (t-calicum channel dugs) | AEDs that inhibit these T-calcium channels are particularly useful for controlling absence seizures • Ethosuximide or valproate |
| GABA-A receptors/channels | GABA binds to GABA-A receptor – Passage of chloride into the cell is facilitated • Influx of chloride increases negativity of cell – A more negative resting membrane potential – Cell now has more difficulty reaching the action potential |
| GABA-A receptors/channels What enzyme makes GABA | GABA is produced by decarboxylation of glutamate – This is mediated by the enzyme glutamic acid decarboxylase (GAD) – Some AEDs act as modulators of the enzyme • Enhances production of GABA and down-regulates glutamate |
| A Calcium Channel Blocker | ethosuximide |
| GABAa agonists | benzos, barbs, progesterone, ganaloxone |
| Gaba uptake inhibitor | tiagabine |
| Gaba - transaminase inhibitor | vigabatrine |
| GAD modulation | gabapentin (a sodium blocker also), valproate |
| Gaba prodrug | progabide |
| Glutamate receptors have 3 main subtypes | NMDA, metabotropic, non-NMDA (AMPA,kainate) |
| Phenytoin | Works at Na and CA channels. Unpleasant side effects: gingival hyperplasia, coarsening of womens facial features.Affects vestibular and cerebellar:ataxia,nystagmus,diplopia,vertigo. Peripheral neuropathies,Prego no:hydantoin syndrome(wide eyes,finger,jaw) |
| Phenytoin other side effects | insulin inhibition:glucosuria, hyperglycemia.induces oxidative metabolism:bigger doses of NDNMBA required. |
| Lamotrigine | chemically unrelated to any of the other AEDs • major mechanism of action is blocking voltage-dependent sodium-channel conductance • inhibit depolarization of the glutaminergic presynaptic membrane, thus inhibiting release of glutamate |
| Lamotrigine side effects | produces few CNS side effects.Rash is the main concern associated with this drug occurs in 5% of patients and is associated with rapid titration.preferred choices in treating elderly patients.preferred treatments during pregnancy. |
| Valproate | mechanism of action is uncertain.up GABA function,yet only at high concentrations.may up the synthesis of GABA by stimulating GAD.also produces selective modulation of voltage-gated sodium currents during sustained, rapid, repetitive neuronal firing |
| Gabapentin | similar to that of GABA.evidence shown that GBP has,in fact,little or no action on the GABA receptor.It enhances the enzyme GAD,but does so weakly.At this time,the exact mechanism by which GBP increases the intracellular concentration of GABA is unknown |
| Gabapentin side effects | no drug interactions,lack of plasma protein binding,and renal excretion make GBP particularly useful in patients with renal or hepatic disease or complex drug regimens.relatively well tolerated.No adverse effects have been reported |
| Malignant Hyperthermia | Inherited autosomal dominant condition.Children and siblings of MH patient have 50% chance of MH.Believe there is defect in the skeletal muscleryanodine receptor gene.This receptor controls release calcium from sarcoplasmic reticulum into sarcoplasm |
| Malignant Hyperthermia-What happens | Calcium from SR d/t open DHT.Continuous interaction in the excitation‐ contraction mechanism of Actin and myosinHypermetabolism occurs |
| Malignant hyperthermia effects | Increased O2 consumptionAnaerobic metabolismIncreasedCO2andLactic acid.HypercarbiaHyperthermiaDepleted ATPstoresAcidosisHyperkalemiaRhabdomyolysis |
| Signs of MH | EarliestMostSensitiveAndSpecificSignUnexplainedElevationETCO2CombinedWithSuddenUnexplainedTachycardia. |
| Other signs of MH | TachypneaInSpontaneouslyBreathingPatient.MuscleRigidityIsNotAConsistentPresentation.WillBeUnresponsiveToNDNMBA.SevereMetabolicAndRespiratoryAcidosis.HyperkalemiaPeakedTwavesonEKG.DiaphoreticMottledSkinHyperthermiaIsLateSign |
| MH- if untreated | Rhabdomyolysis and muscle death • Contributes further to hyperkalemia • Myoglobinuriaacute renal failure – Cola‐colored urine DIC,CHF,compartment syndrome,pulmonary&cerebral edema, bowel ischemia,MSOF, death |
| Dantrolene | binds to ryanodine receptor-blocks release of Ca++from SR. Allows reuptake of CA++ back into SR. Very Alkaline (9.5). Caustic to veins. Mannitol added to make more isotonic. Elemination 1/2 time 12 hours. x |
| Dantrolene side effects | Skeletal muscle weakness, local phlebitits, nausea, diarrhea, blurred vision, can cause hepatitis. Avoid use with ca+ channel blockers-hyperkalemia,heart depress, cardiac arrest, incrased NMB effect |
| New uses for dantrolene | neuroleptic malignant syndrome, ecstacy induced hyperthermia, fatal hyperthermia and muscle breakdown in new onset diabetes in young people, Heat stroke |
| Dantrolene dosage | oral prophylaxis - 5mg/kg 3 to 4 divided doses every 6 hours. Last dose should be 4 hours prior. IV prophylaxis - 2.5mg/kg over 10-30 minutes just be fore induction. Repeat 1/2 dose after 6 hours. |
| Dantrolene dosage for crisis | 2.5mg/kg; repeat 2mg.kg q 5 minutes until MH reversed. often reoccurence about 6 hours after crisis (continue treatment). Dantrolene vial 20mg vial in 60ML preervative free water. Vials shaken for 2-3miutes to dissolve - add 3 grams of mannitol; use 6hrs |
| Thiazides—Clinical uses | Essential HTN • Edema including that associated with heart failure – However, when clinical goal is managing edema, a loop diuretic is almost always used instead of a thiazide |
| Thiazide clinical uses continued | NephrogenicDI-SymptomaticManagement-CanDecreaseButNotNormalizeTheIncreasedDaily UOP-impairAbilityToFormDiluteUrine Idiopathic hypercalciuria Meniere’sDiseaseAdjunct to Na restrictionToReduceIntraauralPressureDecreaseSomeOfTheSymptomsAssociated /c diseas |
| Thiazides--Actions | Early distal convoluted tubule&cortical portion of ascending loop of Henle.Inhibits Na reabsorption.ModestUpNaandH2Oexcretion.Major(-)along withNaIsCl Urine Na up-Lots of soluteRelatively little water.K+ secretion into renal tubulesUsually no changes pH. |
| Thiazides—Potential Side Effects | HYPOnatremia– Thiazide diuretics most common cause of drug- induced hyponatremia – Occurs because amount of extra Na+ lost >> the amount of extra H2O loss • HYPOkalemia •Hypomagnesemia • Hypokalemic hypochloremic metabolic alkalosis |
| Thiazides—Potential Side Effects continued | Hypokalemiaandhypomagnesemia – ¤ risk of cardiac arrhythmias • Otherproblemsrelatedtohypokalemia – Skeletal muscle weakness – GI ileus – Nephropathy – ¤’d risk of dig toxicity – Potentiation of non-depolarizing neuromuscular blockade |
| Thiazides—Potential Side Effects again | HYPERglycemia-notA renalMechanismPossibly R/T drug-inducedInhibitionInsulinReleaseFromPancreas&BlockadeOfPeripheralUtilizationOfGlucose.HYPERcalcemia (downRenalCaExcretion).AllergicreactionsSulfonamideCrossSensitivityDueToSulfaRelatedStructureOfTheseDrugs |
| Loop Diuretics edema, chronic or acute | Edema,chronicoracute – Improves pulmonary edema • Causes acute peripheral vasodilation‡‹’d preload • Occursbeforetheonsetofdiuresis |
| Loop Diuretics - Intracranialhypertension | Systemic diuresis – ‹’s CSF production—interferes with Na ion transport in glial tissue – No alteration in CBF or plasma osmolarity |
| Loop Diuretics - hyper calcemia | Inhibits paracellular uptake of calcium |
| Loop Diuretics--Actions | Site of action is primarily in medullary portion of ascending limb of loop of Henle • Inhibits reabsorption of Na+ and Cl- by inhibition of Na+/K+/2Cl- cotransport mechanism – ‹’s intracellular Na+ concentration |
| Loop Diuretics-Action Cnotin | cant concentrate urine-opposite of thiazides • Has a “steep” dose-response relationship – Very rapid response – Typically ~ 8Xup of baseline UOP>>what can be achieved with thiazides (or any other oral diuretic class) |
| Loop Diuretics--Actions again | Furosemide¤’s prostaglandins’ renal effects – Renal vasodilation improving RBF • RBF redistributed from inner to outer renal cortex which contributes to diuretic action • This effect inhibited by NSAIDS |
| Loop Diuretics—Potential Side Effects | Excessive Na and H2O loss (equal amounts) • Hypovolemia and hypotension HYPOkalemia – loss of K and Cl is significant – ¤’d risk of dig toxicity – Enhances effects of non-depolarizing NMBAs – HYPOcalcemia • Renal excretion of calcium¤’d by loop diureti |
| Loop Diuretics—Potential Side Effects continued | Hypokalemic, Hypochloremic Metabolic Alkalosis – Requires prompt intervention – Circulating fluid volume shrinkage and its consequences (e.g.¤Hct, hypotension)‡ hypotension – Significant renal Cl- loss leaves net excess of HCO3 in blood hence alkalosis |
| Loop Diuretics—Potential Side Effects again | FurosemideCanPotentiateNDNMBAS.MayActOnPresynapticNerveTerminalsInhibitingProductionOfcAMPWhichLeadsToInhibitionOfAcetylcholineRelease.Allergicreactions(CrossSensitivityWithSulfomanides.Less likely with ethacrynic acid b/c it lacks a sulfonamide nucleus |
| Loop Diuretics—Potential Side Effects again again | Ototoxicityrisk – Rare complication – Prolonged use increases plasma concentrations of drug – Rapid administration of high doses – Presence of renal insufficiency • Possiblemechanism – drug- induced changes in electrolyte composition of endolymph |
| Osmotic diuretics—Clinical uses | Treatment of¤’d ICP and¤’d intraocular pressure • “forced” diuresis to maintain renal function in face of renal failure and increasing excretion of some toxins (drug overdoses) |
| Osmotic Diuretics-Actions | NonMetabolizedLowMolecularWeightSugar IV infusion-Freely filtered,NotReabsorbed,IncreasesPlasmaOsmolality,ThenUrineOsmolality-OsmoticallyReducesWaterReabsorptionInDistalNephron/collectingDucts.PrimarySite– Proximal tubule – Thin descending loop of Henle |
| Osmotic Diuretics—Side effects | Pulmonary edema can develop in patients with poor left ventricular function or prior history of CHF • Hypovolemia • hypokalemia |
| Potassium-sparing Diuretics | Two classes – Renal epithelial Na+ channel inhibitors • Amiloride and triamterene – Aldosterone inhibitors • Spironolactone |
| Potassium-sparing Diuretics—Na Channel Inhibitors | ActMainlyInDCTandEarlyCD.<TheActionOfNa-KExchanger.>NaExcretionAnd<’dKexcretion • AccomplishedbydrugblockingtheluminalNa+ channels in PCells – Effect independent of any actions involving aldosterone • Onlymodestdiureticeffect |
| Potassium-sparing Diuretics—Na Channel Inhibitors—Potential Side Effects | hyperkalemia |
| Potassium-sparing Aldosterone Inhibitor | Blocks aldosterone receptors • Inhibits reabsorption of Na+ and Cl- • Only effective if aldosterone is present • Most serious side effect is hyperkalemia • Can also cause hyperkalemic, hyperchloremic acidosis |
| Carbonic Anhydrase Inhibitors— Clinical Uses | Not used for its diuretic properties • Glaucoma –‹’s carbonic anhydrase in the eye‡‹ aqueous humor formation • “Altitude sickness” – ‘alkaline diuresis’ helps correct altitude- induced respiratory alkalosis |
| Carbonic Anhydrase Inhibitors— Clinical Uses continued | Adjunctive treatment of some drug overdoses – e.g. alkalinizing the urine‡¤renal clearance of salicylate (aspirin) and phenobarbital – Given orally or parenterally along with fluids and supplemental HCO3 to maintain alkaline diuresis and urine productio |
| Carbonic Anhydrase Inhibitors— Actions | Inhibits carbonic anhydrase enzyme – Prevents reabsorption of NaHCO3 • Diuresis with‹’d excretion of H+ and¤’d loss of HCO3 |
| Carbonic Anhydrase Inhibitors— Actions Continued | Effects on urine, blood pH balance – Modest<Na+ reabsorption (>excretion)=modest diuresis – > HCO3 excretion alkalinizes urine=metabolic acidosis –metabolic acidosis with continued use leads to refractoriness to further diuresis K+ wasting agents |
| Carbonic Anhydrase Inhibitors— Potential Side Effects | Hypokalemic metabolic acidosis • Allergic reactions – Sulfonamide cross-sensitivity due to sulfa- related structure of these drugs |
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crawfora
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