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166 Cards in this Set
- Front
- Back
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Na channels
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targets for local anesthetics, antiepileptic drugs, antidysrhymics
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Gate Theory
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ion channel exists in one of 3 states:
Resting, Active, Inactive -state depends on membrane potential |
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Ca, Mg ATPase
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-plasma membrane pump (Ca extrusion)
-sarcoplasmic reticulum pump (Ca sequestration) -activated by Ca2+-calmodulin -indirect activation by cGMP, cAMP |
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phospholamban
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important protein in SR for Ca2+ pump activity
-phosphorylated by A-Kinase = dissoc from Ca pump = more Ca sequestered in SR = ↑ contract |
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examples of indirect activation of Ca, Mg ATPase pump
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*phosphorylation of phospholamban by A-Kinase in cardiac SR
*nitrovasodilators ↑ cGMP = ↑ pump out of cell = ↓ contract |
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H, K-ATPase
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target for gastric secretion inhibitors (ex. omeprazole)
-mediates acid secretion from parietal cell |
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omeprazole
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-inactive at neutral pH
-at acid pH6 forms active species which covalently binds to pump |
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Ca Channels
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target for: antihypertensives, antianginals, antidysrhymthmics
two types: L-type (long-lasting) channel and receptor-operated Ca2+ channel |
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L-type Ca2+ channel
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drug receptor sites α1 subunit
-voltage-dependent, inactivates slowly in A state -sites for phosphorylation (ex. NE inotropic via cAMP kinase) |
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prototype blockers of L-type channels
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nifedipine (distinct binding site), verapamil, diltiazem
-either slows recovery or prev. Ca2+ entry during A state |
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receptor-operated Ca2+ channels
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-unknown structure, allows Ca2+ entry with no change in MP
-?modif of L-typ by agonist -?separate channel pop'n ex. isolated blood vessel exp |
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isolated blood vessel experiment
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studied mechanism of receptor-operated Ca2+ channel
-found that even after full depolarization, could further contract w/ NE |
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K+ channels
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-diverse properties and reg.
-targets for oral hypoglycemics, class III antidysrhythmics, vasodilator K+ channel openers -classified based on gating, conductance, pharmacology |
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voltage-gated K+ channel
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ex. phase 3 of action potentials
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ion-gated K+ channel
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ex. Ca2+-activated K+ channels
-vary in conductance, function to terminate excitatory processes caused by ↑ Ca2+ |
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Ligand-gated K+ channel
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ex. atrial hyperpolarization by ACh
ex. ATP-dependent K+ channels (blocked by sunfonylurea-type drugs) |
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ATP-dependent K+ channels
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ligand-gated K+ channel
close when internal [ATP] ↑ = depolarization, Ca2+ entry, ↑ insulin secretion from β cells |
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atrial hyperpolarization by ACh
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ligand-gated K+ channel
ACh activ specific G protein = α subunit of Gpro activates K+ channel = ↑ K+ efflux |
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3 ion channels
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Na+, K+, ,Ca2+
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3 ion pumps
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1. Na, K-ATPase
2. Ca, Mg-ATPase 3. H, K-ATPase |
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Na, K-ATPase
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3 Na in = 2 K out
-target for: digitalis -electrogenic (adds -5mV to resting MP, net charge leaving) -activity varies during AP |
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3 ion exchangers
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1. Na-Ca exchange
2. Na, K, 2Cl cotransport 3. Other Ion transporters in Kidney |
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Na-Ca Exchange
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-electrogenic, 3 Na+ in = 1 Ca out, driving force: Na+ grad
-helps remove Ca from myocytes after card contract -affected by card. glycosides |
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Na, K, 2Cl Cotransport
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target for: loop diuretics
-mediates ion reabsorption in thick ascending limb of loop of Henle |
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Other Ion Transporters in Kidney
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NaH CO3 cotransport
NaCl cotransport (inhib with thiazide diuretics) NaH exchange (proximal tubule) → Na+ gradient driving force |
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local anesthesia
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loss of sensation confined to a discrete area of the body
-block in sensory nerve conduction |
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methods of local anesthesia
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*physical (trauma, hypothermia, anoxia)- potent. irreversible
*chemical (alcohol, phenol) potentially irreversible *drugs (LA) reversible |
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classification of local anesthetics
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*duration of action (short = 1 hour, long = 3 hours)
*structure: esters or amides |
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examples of local anesthetics
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procain, lidocain, mepivacaine, bupivacaine, tetracaine, ropivacaine, cocaine
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pKa of local anesthetics
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*all salts of weak bases
pKa > physiol pH = mainly ioniz. *non ionized crosses nerve memb., ionized binds to receptor |
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mechanisms of local anesthetics
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bind to specific receptor in Na channels
-stabilize channel in "inactivated-closed" state =no depol = no prop of AP |
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onset of action of local anesthetics
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determined by pHa and tissue pH (ie. amount of drug that can cross membrane)
-can be increased by alkalinization |
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potency of local anesthetics
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related to lipid solubility (how readily crosses membrane)
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duration of action of local anesthetics
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determined by protein binding (more bound = longer duration)
-affected by blood flow to area -may be increased with vasoconstrictors |
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absorption of local anesthetics
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-dep on mode of administration (topical vs injection)
-vasodilator activity (lidocaine vs cocaine = VC = arrhythmias) -vasoconstrictor addition |
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distribution of local anesthetics
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highest at site of application
-distributes to all tissues -crosses BBB and placenta |
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metabolism of local anesthetics
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amides: liver enzymatic metabolism
esters: hydrolyzed in plasma |
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toxicity of local anesthetics
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related to: plasma concentration
-drugs (lidocaine vs bupivacine) -pregnancy (lower safety margin, fetal acidosis = higher fetal:mother concentration) |
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types of toxicity for local anesthetics
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*high plasma level (OD, inject)
*allergy: esters <rare amides, more b/c of preservatives *site of injection (inadvertent spinal) |
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prevention of toxicity for local anesthetics
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-limit dose
-minimize aborption (aspirate on syringe, vasoconstrictors) -prophylaxis: benzodiazepine |
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clinical use of local anesthetics
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*skin (EMLA cream), airway
*infiltration *block: peripheral nerve, plexus, intravenous (Bier), central neural (spinal, epid.) |
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components of anaesthesia
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1.hypnosis 2.analgesia 3.amnesia 4. blunted autonomic responses
5. +/- muscle relaxation |
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the ideal anethetic
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rapid induction/recovery, changes in depth
relaxation of muscles, wide safety margin, no tox, cheap, non explosive |
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classification of general anesthetics
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*inhalational
*intravenous |
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inhalational general anesthetics
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-gases: N2O, cycloropane, xenon
-volatile liquids: halothane, isoflurane, sevoflurane, desfluran, ether, methoxyflurane, chloroform |
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intravenous general anesthetics
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-barbituates (sodium propophol)
-benzodiazepines -ketamine -methohexital |
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mechanisms of general anesthetics
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*global depression of CNS and other tissues incl. RAS and macromolecules
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reticular activating system
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centre of consciousness, depressed by general anesthetics
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central role of cell membranes in general anesthetics
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*lipid solubil. (Meyer-Overton)
*critical volume *fluidization *pressure reversal |
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structure of volatile anesthetics
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fluorinated hydrocarbons
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potency of general anesthetics
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Minimum Alveolar Concentration
-determined exp: conc = 50% mice don't react to tail clamp -50% patients: 0.75% halothane, 105% NO |
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signs and stages of general anesthetics
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1. loss of consciousness
2. delerium (↑ BP, HR, tone) 3. surgical (4 planes, ↑ resp depression, ↓ reflexes) 4. resp. paralysis |
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delivery of general anesthetics
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inhale through anesthetic apparatus → airway, lungs → blood uptake → tissue blood flow
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effects common to inhalational anesthetics
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*alter breathing pattern, depress vent response to CO2
*vasodilation, myocardial depr. *skeletal musc relaxation *uterine relaxation |
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halothane
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a general anesthetic
regular potency (in 50% patients) = 0.75% *liver toxicity (hepatitis) from normal dose |
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isoflurane
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inhalational general anesthetic
less cardiac depression than with others |
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desflurane
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inhalational general anesthetic
not used anymore least soluble in blood (fast in/out) |
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sevoflurane
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inhalational general anesthetic
-smooth induction, less irritating to airways -useful in children, rapid emergence |
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nitrous oxide
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"laughing gas", a general anesth
Pros: good analgesic, allows ↓ other agents Cons: weak (no induced unconsc), hypoxia, expands air spaces |
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common problems in general anesthesia
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1. circulatory depression (fluids, vasopressors)
2. resp. depression (airway control, ventilation) 3. awareness (monitor EEGs) |
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malignant hyperthermia
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*condition of hypermetabolism
-↑ intracel Ca2+, ↑↑temp -b/c of inhal agents and succinylcholine; genetic -↑ mortality; tx: dantrolene |
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propofol
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intravenous general anesthetic-most common, good for induction and maintenance; wake up from pleasant/sexual dreams
-anti-nausea |
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sodium thiopental
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barbituate; intravenous general anesthetic
-truth serum |
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ketamine
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intravenous general anesthetic
-dissociative, phencyclidine (PCP) = hallucinations ↑ BP and HR (only one), releases catecholamines |
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midazolam
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a benzodiazepine, intravenous general anesthetic
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ideal general anesthetic agent
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= combination of agents
-reduction of each dos -reduction of toxic effects -synergism |
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angina pectoris
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-sx of ischemic heart disease
-imbalance b/w myocardial oxygen demand (↑) and supply (↓) = severe, sudden chest pain -2 types: typical & variant |
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Typical Angina
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aka Angina of Effort
-↑O2 demand (exercise, cold, emotion, eating) and ↓ supply (atherosclerotic coronary artery disease) = S-T depression (EKG) |
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Variant Angina
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cx: vasospasm of coronary artery, w|w/o atherosclerosis
-chest pain develops at rest |
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Therapeutic Aim for Angina
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*improve balance b/w O2 D and S
-typical: ↑ coronary blood flow, ↓myocardial workload -variant: ↓/prev coronary vasospasm |
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organic nitrates
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rx for angina = relax vasc. SM
esters of nitric acids -can be short acting (nitroglycerine, GTN) or long acting (ISDN) |
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nitroglycerine
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short acting organic nitrate
rx for angina pectoris |
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glyceryl trinitrate
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GTN, short acting organic nitrate
rx for angina pectoris |
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isosorbine dinitrate
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ISDN, long acting organic nitrate
rx for angina pectoris |
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mechanism of action for organic nitrates
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RONO2 = organic nitrate
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Decreased Myocardial Oxygen Requirement Action of ON's
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*venodilation (↓ venous return = ↓ preload = ↓ work = ↓O2 nd)
*arteriolar dilation (↓ periph resist = ↓ afterload = ↓ work) |
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Improved Perfusion of Ischemic Myocardium Action of ON's
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can dilate vasc to healthy areas to force blood to the blocked area (GTN) or divert towards healthy area (coronary steal, dipyridamole)
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Absorption of ON's
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*sublingual
*oral *skin *IV to heart suring failure/buccal/inhalation (rec) |
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sublingual absorption of ON's
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-short duration
-nitroglycerine (GTN) main drug (effects for intense) --peak effcts ~3 min, last for 20-30 min |
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oral absorption of ON's
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common route for ISDN
-extensive first-pass metabolism by glutathione transferase -higher doses than subling. |
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glutathione transferase
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enzyme responsible for first pass metabolism of ISDN
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skin absorption of ON's
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2% GTN ointment = effective long lasting preparation ~4 hrs
-GTN discs/patches: allow gradual absorption over 24 hours (?tolerance problem) |
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adverse effects of ON's
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b/c of vasodilation:
*headache (common and severe) *flushing (head, neck) *dizziness & weakness *methemoglobemia |
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methemoglobemia
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*adverse effect of ON's
-oxidation of heme iron in RBC's by nitrite anion released during metabolism w high infusion rates -tx for cyanide poisoning |
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nitrate tolerance
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only seen with: *chronic oral ISDN: ↓antianginal and hemodynamic effect;
*transdermal GTN patches |
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prevention and mechanism of ON tolerance
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prev by having drug-free period
mech: ↓ vasc biotransformation = altered guanyly cyclase = ↑ phosphodiesterase activity |
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therapeutic uses of organic nitrates
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*termination or preention of individual angina attack (GTN sublingual)
*chronic prophylaxis of angina (ISDN ↓ freq of attacks) |
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Calcium Entry Blockers
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block L-type Ca2+ channels
-mostly dihyropyrimidine compounds -ex. nifedipine, verapamil, diltiazem |
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mechanism of action of Calcium Entry Blockers
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block voltage-dependent calcium channels in vascular smooth muscle and cardiac tissue
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Effects of Calcium Entry Blockers on cardiac function
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*negative inotropic effect
*↓ pacemaker rate at SA node *↓ conduction through AV node |
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Differential Actions of Calcium Entry Blockers (N vs D vs V)
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Nifedipine blocks channels in vascular smooth muscle at much lower doses (card effects not observed) vs Verapamil and Diltiazem potent cardiac effect
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Anti Anginal Effects of Calcium Entry Blockers
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1. arteriolar dilation
2. Prevent/inhib coronary vasospasm *ideal for variant* 3. Cardiac effects of V and D = ↓ work |
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pharmacokinetics of Calcium Entry Blockers
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-all well absorbed orally
-bioavail 20-50% b/c first pass -plasma protein binding >90% V and N; half-life 3-5 hours -urine: N & V, feces: D |
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adverse effects of Calcium Entry Blockers
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1. cardiac depression (V,D) - bradycardia, A-V block, CHF
2.excessive hypotension (N) 3. flushing, edema, dizziness, nausea |
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β-adrenergic antagonists
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↓ severity/freq of attacks in typical, not useful in variant and may worsen (↑ coronary resistance); ex. propanolol
-negative ino and chronotrope |
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ivabradin
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new antianginal; blocks pacemaker current in SA node (If channels) = ↓HR w/o iono change
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ranolazine
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inhibits fatty acid oxidation (req. more O2 to generate ATP than glucose) = ↑ gluc utiliz. for ATP prod = ↓ O2 consumption
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chemistry of digitalis
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-cardiac glycoside; unsaturated lactone ring is essential, angle of C and D ring is unique, pham act. resides in aglycone, sugars determine water and lipid sol
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sources of digitalis
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plants: foxglove (D. purpurea) = digitoxin, D. lananta = digitoxin, digoxin, deslanoside;
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congestive heart failure: common causes and result
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cx: coronary artery disease, myocardial infarction, hypertension
= ↓contractility = ↓CO below phys requirements |
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intrinsic compensatory mechanisms of congestive heart failure
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*pressure-volume relationship: ↓ ejection fraction = ↑ventricular V & P = ↑fibre stretch = ↑contractility
(frank-starling) |
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extrinsic compensatory mechanisms of congestive heart failure
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*↑sympathetic activity
CV: ↑HR & contractility renal: ↑renin/angiontensin/aldost ↑NaCl/H2O retention, BV |
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therapeutic modalities for congestive heart failure
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*salt restriction
*diuretics *vasodilators *positive inotropic agents (digitalis) |
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effects of digitalis on congestive heart failure
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↑CO = ↓compensatory mechanisms
= ↓ heart size, symp act, HR, vasoconstrict, edema, renal perfusion, venous congestion |
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Mechanism of Action of digitalis
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binds and inhibits Na/K ATPase in cardiac tissue leading to an increase in [Ca2+]
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pharmacological actions of digitalis
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mechanical: ↑contractility
electrical direct and indirect effects |
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direct electrical pharmacological effects of digitalis
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↓RMP = ↓phase 0 slope & cond velocity
↓duration phase 2 = ↓APD & ERP ↑slope phase 4 = ↑ automaticity |
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indirect electrical pharmacological effects of digitalis
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*↑ vagal act in CNS
*↑ baroreceptor sensitivity *↓ response to NE at SA and AV nodes =↓conduction vel &↑ERP |
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adverse effects of digitalis
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*GI: anorexia, nausea, vom, dia
*neuro: headeach, fatigue *vision: clurred, dist colour *CV: (elec. eff) sinus brad, A-V block, ventric. dysrhythmia |
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treatment of adverse effects of digitalis
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*GI/visual: withhold dose
*occ extra beat/bigeminy = oral K+ and drug withdrawal; more serious = IV K+ & antdysrhyth *OD: digitalis antibodies |
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drug interactions with digitalis
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*K+ competes for Na/K binding
*quinidine: displaces from tissues, double levels, ↓ clear *antibiotics: inhib gut flora from inact dig = ↑ blood levels |
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pharmacokinetics of digoxin
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absorption: 40-70%
PPB: 25% Peak Time: 3-6 hrs Half-life: 1.6 days therap []: 0.5-2 ng/mL |
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methods of digitalization
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*rapid: loading + maintenance dose
*just maintenance dose: dep on renal fxn (1.6 days, 35%/day or 4.4 days, 14%/day) |
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RMP
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resting membrane potential
~= E(K+) |
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Nernst equation
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EK+ = -61*log[Ki]/[Ko]
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pacemaker rate
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depends on
1. maximum diastolic voltage 2. slope of phase 4 3. threshold voltage |
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ERP
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effective refractory period
many antidysrhythmics lengthen it |
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responsiveness
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maximum rate of depolarization in phase 0 (Vmax)
-depends on RMP at moment of depolarization, reflects recovery of Na channels |
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conduction velocity
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depends on:
1. action potential amplitude 2. slope of phase 0 |
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causes of dysrhymthias
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ischemia, altered electrolytes, ↑ catecholamines, drugs (digitalis), diseased/scarred tissue = disturbed impulse generation or conduction
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automaticity
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disturbed impulse generation
*altered normal automat = ectopic focus, changes in P4 *abnormal automat: delayed after depolarizations |
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ectopic focus
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SA node slows down or latent pacemakers speed up
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disturbed conductance
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re-entrant dysrythmias
-need: obstacle to cond, unidirectional block, conduction time through damaged area > in other areas |
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mechanisms of antidysrhythmic drugs
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*reduce pacemaker activity by ↓ P4 slope
*modify impaired conudction (Na or Ca channel block, β block, ↑ ERP) |
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Class I Na-Channel blockers (incl mechanism and examples)
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↑affinity for A/I state, ↓ R
ex. quinidine, lidocaine *use-dependent blockade *↓# avail channels, ↑ R recovery time |
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Quinidine (class, etiology)
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Class IA
1.uni → bidirectional block: A state(↓cond v), I state(↑ ERP), K+block(↑APD) 2.↓ automaticity |
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uses of quinidine
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-wide spectrum
-ventricular and supraventricular tachydysrhythmias |
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toxicities of quinidine
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SA, AV block
GI upset Cinchonism (tinnitus, blurred vision, headache) |
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Lidocaine (cardiac)
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Class IB;short half-life (15 min) = IV; greater effect in ventric and Purkinje cells;
1.↓automaticity 2. ↓ cond v in depolarized tissue only (I>A) |
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uses of lidocaine (cardiac)
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-ventricular dysrhythmias
-myocardial infarct -open heart surgery -digitalis toxicity |
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Class II Antidysrhythmics
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β-blockers; ex. propanolol
-opp symp act, esp in AV node =↑ REP, control ventric rate -used for supraventricular dys |
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Class III
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Amiodarone (lots o toxicities)
-blocks Na & K channels; I state block ↑ ERP, K block ↑ APD -long half-life 13-100 days -prophyl control of vent tachy |
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Class IV
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Ca-Entry blockers; Verapamil, Diltiazem
= ↓A-V conduction -used for supraventricular dys |
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Class V (Other)
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Adenosine
↑K conduct = hyperpol membrane = slowing AV conduction -very short 1/2life (secs) -use: paroxysmal surpavent tachy |
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primary/essential hypertension
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systolic: > 140 (majority, rel to age)
diastolic: > 90 -majority don't have both -no known cause |
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secondary hypertension
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known cause
ex. renal artery stenosis ex. adrenal tumours (medulla = pheochromocytoma, cortex = hyperaldosteronism) |
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factors controlling blood pressure
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*cardiac output
*vasocontrictor tone (PVR) *blood volume (kidney) *vascular structure (contractility) |
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regulatory mechanism for cardiac output
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baroreceptor reflex: ↓stretch = ↓BP = ↑symp outflow = ↑HR and contractility = CO (also vasoconstrict = ↑PVR)
*to maintain steady state |
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regulatory mechanisms for vasoconstrictor tone
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local: EDRF = NO, EDCF, kinins, ET-1;
neural: sympathetic nervous system humoral (NF, EPI, Ang II, etc) |
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regulatory mechanisms for blood volume
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↓renal perfusion or ↑symp act
= ↑renin, Ang II, aldosterone = ↑H2O and [salt] *kidney established set-point for long-term arterial P level |
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regulatory mechanisms for vascular structure
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*structurally-based ↑ in vasc resistance by:
↑wall thickness |
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therapeutic targets for vasocontrictor tone
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*sympathetic nervous system inhibitors
*vasodilators *??renin-angiotensin system blockers |
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sympatholytics
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inhib SNS: centrally acting (chlonidine), ganglionic blocking, α/β/mixed-receptor antagonists
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vasodilation of constricted blood vessel as rx for hypertension
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*vasodilators: hydralazine, minoxidil; *Ca channel clockers: verapamil, amlodipine; *K channel activators
-wide var of adverse effects |
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therapeutically targetting blood volum as rx for hypertension
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1. diuretics
2. act on RAS system |
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targetting RAS system for tx of hypertension
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*angiotensin convertin enzyme (ACE) inhibitors: ramipril etc
*angiotensin II receptor blockers (ARBs): losartan etc -block AT1's; = fewer adv effect |
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disorders that need diuretics
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-hyptertension
-heart failure -edema -acute altitude sickness |
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natriuretics
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increase in urine sodium, are also diuretics because water follows sodium (most important diuretics)
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average extracellular fluid
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12.5 L
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average GFR
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glomerular filtration rate
125 ml/min |
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average urine production
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1 ml/min
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glomerular filtration (and drugs that target)
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affected by BP and flow
rx: inotropes (tx congestive heart failure), vascular agents |
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osmotic diuretics (prototype, mechanism, requirements)
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*mannitol
mech: maintains osmotic strength in forming urine req: freely filtered, not reabsorbed, pharm inert |
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osmotic diuretics (adverse effects)
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-high osmotic load may shift too much fluid into intracellular space = pulm congestion, congestive heart failur
-dose used; 50-200g/day, 25% |
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osmotic diuretics (pharmcokinetics, uses)
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p: not absorbed from GIT, excreted unchagned in urine
u: prevent renal failure, diuretic, ↓CSF and intraocular pressure |
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thiazides (prototype, mechanism)
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*hydrochlorothiazide
m: ↓NaCl reabsorp at luminal surface = ↑ water excretion |
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thiazides (pharmakokinetics)
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-absorbed orally
-actively transported into lumen, proximal convoluted tubule -uric acid retention |
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thiazides (adverse effects)
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*hypokalemia
-↓carbohydrate tolerance -hyponatremia -↑lipids, LDL |
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loop/high ceiling diuretics (prototype, action)
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*furosemide
-acts on ascending limb -↓ Na/K/Cl transport -potency weak at low doses, but higher limit |
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loop diuretics (adverse effects)
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-mainly hyopkalemia
-uric acid retention -excessive fluid and electrolyte loss |
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carbonic anhydrase inhibitor (prototype, mechanism)
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*acetazolamide
-blocks bicarbonate conversion = retention in urine -must have 90% of CA inhibited to produce effect |
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diuretic combinations
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furosemide + HCT: may be supra-additive
HCT+amiloride: for hypokalemia, safest treatment is K+ supplementation |
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potassium sparing diuretics
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*spironolactone and amiloride
-both may induce hypokalemia |
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amiloride
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inhibits K+ excretion
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spironolactone
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competitive aldosterone antagonist
-slow action, most useful in aldosterone excess conditions |
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acetazolamide action and adverse effects
|
-metabolic acidosis (tx alkalosis); effect wanes
-tx for acute altitud sickness (die of pulmonary and cerebral edema); AE: paresthesia, drows |
