Pharm 2.1 Flashcards
1
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A
2
Q
Where do CA inhibitors have action? How do they work?
A
Work in proximal tubules of kidney as diuretics. Also in eye and brain (glaucoma and cerebral edema)Inhibition of CA in kidney -> diuresis by increasing passage of H2CO3 in urine (no water is freed in CA rxn). Also, reduced bicarb resorption -> metabolic acidosis.(review CA function)
3
Q
Dorzolamide
A
CA inhibitor used in treatment of glaucoma. Topical ap to eye.
4
Q
Why must mannitol be administered IV?
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It does not permeate the luminal membrane (no reabsorption)If given orally -> osmotic diarrheaIV produces profound diuresis (osmotic diuresis)
5
Q
Describe the action of furosemide
A
Loop diuretic. It directly inhibits NKCC2 symporter in the thick ascending limb of the Loop of Henley.Results in decreased reabsorption of Na (higher luminal [Na]) and increased water loss.**Increased Na+ delivery to the collecting tubule -> increased K+ loss and can lead to hypokalemia
6
Q
Where are juxtaglomerular cells located and what do they do?
A
In afferent arteriole to glomerulus.Secrete renin in response to:-Decreased renal perfusion pressure-B1 adrenergic stimulation-Decreased Na+ load in distal tubule
7
Q
Why are loop diuretics often administered with an ACE inhibitor?
A
Macula densa cells are sensitve to intracellular [Na] and use the furosemide sensitive NKCC2 symporter.Loop diuretic -> lowered intracellular [Na] -> increased renin secretion via juxtaglomerular cells.ACE inhibitor counteracts this effect by preventing formation of Angiotensin-II
8
Q
What are examples of thiazide diuretics, how and where do they work?
A
Hydrochlorothiazide and ChlorthalidoneInhibit the Na/Cl symporter (NCC) in the distal convoluted tubule. **Increased Na+ load in collecting duct -> Increased K+ loss
9
Q
Where does PTH have action and what is its effect?
A
Works in the distal convoluted tubule to increase Ca++ reabsorption. Increases activity of the Na+/Ca++ transporter
10
Q
What are examples of potassium sparing diuretics and what are their mechanisms of action?
A
Amiloride: Inhibits ENaC (Na+ channel of collecting duct)Spironolactone: Competitive antagonist of aldosterone (prevent up-regulation of Na/K ATPase in distal tubule and collecting duct.Both reduce loss of K+ while increasing loss of Na+ and H2OMild diuresis. May be used to blunt K+ diminishing effects of loop and thiazided diuretics.
11
Q
What effect does Lithium have on the kidney?
A
Decreases expression of Aquaporin 2 in response to ADH -> Nephrogenic Diabetes Insipidus
12
Q
Bumetanide, Ethacrynic acid, Torsemide
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Loop diuretics
13
Q
What is furosemides half-life and how is it eliminated?
A
t1/2 = ~1.5 hrRenal elimination- tubular secretion and filtration
14
Q
How is furosemide useful in treatment of CHF?
A
Reduction of preload (decrease fluid volume)Direct effect on reducing pulmonary congestionIncrease renal blood flow** reduces LV pressure and pulmonary congestion before diuretic action**
15
Q
What are loop diuretic side effects?
A
Hypokalemia and alkalosisHypomagnesemiaHyperuricemia (hypovolemia induced reabsorption of urea in prox tubule) and gouty attacksDose-related hearing loss, allergic reactions
16
Q
What is the effect of NSAID use on loop diuretic effectiveness?
A
Decreases effectiveness of loop diureticsInhibition of COX1 / COX2 -> decreased PGE expression in kidney where there are many dependent mechanismsNSAIDs can -> kidney failure, esp. in elderly population
17
Q
What are the short / long term effects of thiazide diuretic use?
A
Initially: ECV decrease, decrease in COLong term: reduction in peripheral resistance - decrease in intracellular Na -> decreased in intracellular Ca++ (transport by Na/Ca exchanger) -> smooth muscle more refractory to contractile stimuli
18
Q
How does chlorthalidone differ from hydrochlorothiazide?
A
It is more potent and has a longer half-life (40 hr. vs. 15hr.)
19
Q
What conditions other than hypertension are thiazide diuretics helpful in treating?
A
Idiopathic hypercalciuria with kidney stones - thiazides -> reduced intracellular Na+ in distal convoluted tubule cells. Na/Ca exchanger then pumps Na into cell and Ca out - driving Ca reabsorption from lumenNephrogenic Diabetes insipidus (including that caused by Li)- unknown mechanism
20
Q
What are potential side effects of thiazide diuretics?
A
hypokalemic metabolic alkalosishyperuricemiahyperglycemiahypercholesterolemiahyponatremia - potentially fatal in predisposed individuals
21
Q
What is spironolactone and what is it used for?
A
Competitive antagonist of aldosterone.Helpful in severe CHF - reduced morbidity and mortality when used with ACE inhibitor- antagonizes aldosterone’s pro-fibrosis effect on heartPotassium conservation when used in concert with loop and thiazide diuretics
22
Q
What are the side effects of spironolactone?
A
HyperkalemiaEndocrine like effects: gynecomastia, impotence, peptic ulcersIncreased risk of breast cancer
23
Q
What are the uses of Amiloride?
A
Limit diuretic induced hypokalemic alkalosisUsed in Li induced diabetes insipidus - limits Li’s ability to interfere w/ aquaporin 2 expression
24
Q
What are the effects of Angiotensin II?
A
-increased arterial pressure-increased SS tone (via direct action on CNS - area posterna)-Na and fluid retention-Aldosterone release-Vascular and Cardiac remodeling-all via AT-1 receptor
25
Enalapril and Lisinopril are what class drugs?
ACE inhibitor-pril
26
What are the primary desirable effects of ACE inhibitors?
decrease peripheral resistance without increasing HRreduction of cardiac and vascular remodelingnatriuresisIn CHF patients - reduce preload and afterload -\> increased CO and SV
27
How is use of an ACE inhibitor useful in chronic renal disease?
Decreases resistance in efferent glomerular arteriole -\> decreased glomerular pressure (decrease GFR) and improves renal BFReduces proteinuria and improves renal function (natriuresis)
28
ACE inhibitor pharmacokinetics
taken as prodrug - metabolized to active state in the liver (ester bond cleavage)subject to first pass metabolismEnalapril and lisinopril - t1/2 = 12 hrs.
29
What are the side effects of ACE inhibitors?
Initial severe hypotension in patients w/ high renin activityPersistent dry cough (increased bradykinin and lung PGE)hyperkalemia (w/ NSAIDs, K-sparing diuretics, B-blockers)acute renal failure in pts w/ bilateral renal artery stenosisteratogenic
30
What is aliskiren? Uses and side effects?
Renin inhibitor - reduces angiotensin II syntheffective antihypertensive ( as good as thiazide + Ca channel blocker combo)Cough and GI disturbancesTeratogenicDecreases serum conc. of furosemideCyclosporin increases blood concentration of aliskiren
31
Losartan and Valsartan - what kind of drugs?
ARB- AT-1 receptor blockersSimilar properties to ACE inhibitorsDo not produce ACE inhibitor cough - may be used as a replacement optionshould not be used during pregnancy
32
What are 4 important effects of Beta Blockers?
1. decreased cardiac excitability2. antihypertensive (reduced TPR by decreased renin release)3. reduced cardiac inotropy (force of contraction)4. reduced cardiac remodeling
33
Propanolol
Non-specific Beta 1 and 2 blockerUndergoes 1st pass metabolismnegative effects on serum lipid profiles
34
Metoprolol
Selective beta blockerLow dose: preferentially blocks B1CHF: increases longevity and decreases hospital admission timeContraindicated in COPD / asthma as it has some effect on B2 - risk of bronchospasm
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Bisprolol
B1 selective blocker
36
Carvedilol
non-selective Beta and alpha-1 blockerblocks B1, B2 and a1
37
Atenolol
B1 selective antagonistDoes not undergo first pass metabolismNot for use in asthmatic patients
38
Pindolol
Non-selective Beta blockerB1 partial agonist - stimulation before blockade-less cardiodepression and less effect on serum lipidsNot for use in MI patients
39
Labetolol
Non-selective Beta antagonist, and alpha-1 antagonistHas beta sympathomimetic activityReduces TPR with less effect on HR and CO. Does not effect serum lipidsOnly B-blocker used in mgt. of simple HTN.Preferred drug for HTN in pregnant women.
40
Carvedilol
Non-selective B-antagonist and a-1 antagonist (B-activity more prominent)Inhibits Oxygen radical mediated lipid peroxidation and reduces vascular smooth muscle mitogenesis - relevant to use in CHFQuinidine (anti-arrhythmic) and fluoxetine (Prozac) compete for metabolism by CYP2D6
41
Esmolol
Ultra short acting selective Beta-1 blocker (t1/2 = ~10min)IV admin for supraventricular arrhythmia, acute hypertension, and myocardial ischemia in acutely ill patients
42
Sotalol
non-selective Beta blockerK+ channel blockerUsed as anti-arrhythmic
43
Nebivolol
Selective B-1 antagonistMetabolized to B-2 AGONISTB2 activity: NO production, lower TPR3rd gen Beta blocker w/ secondary anti-hypertensive effects
44
Beta blocker untoward effects
Hypotension, bradycardia, heart failureB2 blockade - bronchospasm (esp. in asthmatics)CNS: depression, fatigue, insomnia, hallucinations, impotenceHypoglycemia (B2 blockade) - may mask symptoms (hunger, tremor, but not sweating)Lipids: elevate triglycerides, lower HDL, decrease HDL/LDLWithdrawal - remove slowly (upreg of receptors) - may precipitate hypertensive emergencyNSAIDs reduce anti-hypertensive effectsBBs may be less effective in African-Americans
45
Methyldopa
Selective alpha-2 agonistactive transport into brain, metabolism to methyl norepinepherineMost importantly active at NTS in medulla -\> decreased sympathetic outflow, reduction of vasomotor toneEffect: reduction of peripheral resistance w/o effect on HR, CO, RBF, renin, or plasma volumeSide effects: hemolytic anemia (20% develop positive Coomb's test, ~5% actual hemolytic anemia), sedation, drymouth, reduced libido, parkinsonian signsEffective anti-hypertensive, esp. when coupled w/ diuretic. May be used during pregnancy.
46
Clonidine
Selective A2 agonistInhibits central release of NE, reduction in SS outflow from NTS.Also activates imidazoline receptors in rostral ventrolateral medulla -\> lowered BPNo effect on HR, CO, RBF, renin, or plasma volumeUsed transdermally to blunt SS activity caused by some vasodilatorsAnti-hypertensive activity potentiated w/ diuretic useDo not give to depressed patients, withdraw if depression occursSide effects: sedation, dry mouth, postural hypotension, impotence, bradycardia, sinus arrest in pts. w/ defect of SA node, AV block in pts. w/ AV node defect.Discontinue use slowly.
47
Phentolamine and Phenoxybenzamine
Non-selective Alpha blockersUsed to treat pheochromocytoma and impotence
48
Reserpine
Blocks vesicular storage of NE in nerve terminalsReduces peripheral resistance and COat high doses: depletion of central amine stores -\> parkinson's symptoms, depression, sedationInfrequently used. If used, often low dose coupled w/ diuretic for HTN.
49
Guanethidine
No central action (does not cross BBB). Peripherally: replaces NE in synaptic vessicles. Stabilizes membrane (anesthetic-like quality), impairing release of NE.Reduces peripheral resistance. Side effects: postural hypotension, bradycardia, depressed CO, diarrhea, impaired ejaculation.rarely used
50
Guanabenz and guanfacine
Similar to clonidineRarely used.
51
Prazosin
Selective alpha-1 antagonist (-osin drugs)Lowers BP by decreased arteriolar resistance, increased venous capacitanceInitial drop in TPR, increase in HR, CO and renin - this effect subsides in timeAlso used for prostatic urinary symptoms (esp. tamsulosin) - inhibit prostatic contraction. Side effects: orthostatic hypotension, doxazosin linked to HFNot recommended as monotherapy for HTN. Often given w/ diuretic or Beta blocker
52
What are the two main categories of Ca++ channel blockers and how do they differ?
Dihydropyridine (nifedipine and amlodipine)and Non-dihydropyridine (diltiazem, verapamil)Dihydropyridine: bind channel in open state - slow Ca++ entry, do not affect rate of recovery - preferential binding in arterial smooth muscle.Non-dihyrdopyridine: decrease both Ca++ entry and rate of recovery. Cardioselective - decrease inotropism and CW. Treatment of angina.
53
Do Ca++ channel blockers affect preload or afterload more prominently?
Afterload. No effect on venous bed, so no effect on preload.
54
What class of calcium channel blocker is used in the treatment of hypertension?
Dihydropyridines - prominent reduction in smooth muscle tone -\> decrease in TPR
55
What class of Ca++ channel blocker is more useful in treatment of SVT and why?
Supraventricular tachycardia: Non-dihydropyridines (verapamil and diltiazam) - affect both Ca++ flow and rate of recovery - strong impact on AV node conduction\*\* because of decrease in contractility and AV conduction, do not pair non-dihydropyridines with Beta blockers. Can -\> bradycardia, heart block, death
56
Nimodipine and application
Dihydropyridine - affects cerebral vessels more than other DHPs - decreases morbidity in subarachnoid hemorrhage patients.
57
What DHP drugs are best suited to treatment of emergency HTN?
Nicardipine and ClevidipineClevidipine has shorter half-life
58
What DHP is favored for use in a HF setting? Why?
Amlodipine - long acting, slow onset. 40 hr. half-life (vs. fast-action of nifedipine, 3 hr. half-life)reduces morbidity in patients w/ LV dysfunction
59
Calcium channel blocker metabolism and side effects
Metabolized in liver (P450) Rifampin (antibiotic) and phenytoin (anti-seizure) increase rate of metabolism, Azole antifungals decrease it.Side effects: flushing, peripheral edema, dizziness,
60
Nondihydropyridine specific side-effects
Heart failure, bradycardia, cardiac block, hypotensionVerapamil has a1 blocking property. If paired w/ other a1 blocker (quinidine) -\> severe hypotension\*\*\*Verapamil - decreases renal clearance of digoxin\*\*\*
61
Describe the action of NO
NO activates guanylyl cyclase -\> increased cGMP -\> dephosphorylation of myosin light chains and smooth muscle relaxationVeins most sensitive, then arteries, arterioles, pre-capillary sphinctersEnd result is decreased filling pressure, decreased TPR, reduced afterload, improved cardiac perfusion, improved CO and decreased pulmonary congestion
62
Describe 3 types of angina
Classic - due to atheromatous obstruction of coronary vesselsVariant - due to coronary vasospasmUnstable - increased coronary artery tone or non-occlusive platelet clots near atherosclerotic plaques
63
What is the benefit of nitrate treatment in various types of angina?
Classic: reduction of myocardial O2 consumption: reduced filling pressure and ventricular radius; reduction in IVP, end diastolic VP -\> increased perfusion; decreased afterloadVariant: dilation of epidural arteries, redistribution of coronary blood flow to endocardium, prevention of arterial spasmUnstable: decrease in platelet aggregation. Also, reduced myocardial O2 demand and coronary artery dilation
64
What are side-effects of nitrates?
Throbbing headache (meningeal artery pulsation), hypotension and reflex tachycardia\*\* action is potentiated w/ PDE-5 inhibitors (viagra) -\> profound hypotension, MI\*\*\*
65
What is a PDE-5 inhibitor?
Seldenafil (viagra)inhibits degradation of cGMP by PDE-5 -\> sustained action of NO, sustained smooth muscle relaxation
66
Explain the concept of "coronary steal"
Coronary arterioles downstream from atherosclerotic plaques area maximally dilated to maximize perfusionAdministration of an arterial dilator has no effect on these, but dilates other, healthy coronary arterioles redirecting blood flow to those areas. This can induce anginal attacks or MI
67
What is hydralazine, what is it used for?
Hydralazine relaxes arterial smooth muscle by unknown mechanism.Usually administered w/ a beta blocker and diuretic to treat complex hypertensionUseful in HF that is not responsive to standard treatment (ACE inhibitor, loop diuretic, beta blocker). Used in combo w/ nitrate (isosorbide dinitrate - reduce preload) in this setting to reduce afterload
68
Hydralazine side effects
20% of patients develop lupus-like symptoms after ~6mosbecause of this, use is rare.
69
Minoxidil
Activates ATP-modulated K+ channel in sm. muscle -\> K+ efflux, hyperpolarization and sm. muscle relaxationAlways used w/ beta blocker and diureticRare use for complex HTN that is unresponsive to other therapyMay produce hypertrichosis - use in male pattern baldness
70
Sodium nitroprusside
DOC for emergency HTN - arterial vasodilatorreduces preload and afterloadalso used in aortic dissection caseshigh dosing can lead to cyanide / thiocyanate poisoning
71
What is the basic MOA of a local anisthetic?
Uncharged (deprotonated) particle must cross the Neuron's plasma membrane, be protonated, then bind the open Na+ channel.Once bound the drug stabilizes the closed conformation of the channel - prevents AP.
72
What is the basic structure of local anesthetics?
Aromatic ring connected by an ester or amide bond to an ionizable group, commonly a tertiary amine.
73
Describe the MOA of local anesthetics
Diffuse through membrane in non-protonated state, protonated inside cell, block voltage gated ion channel.Only able to bind when the channel is in OPEN state.Stabilizes the INACTIVE state - no Na+ influx - blocks AP propogation
74
Are local anesthetics weak acids or bases? pKa range? What does a drug's pKa say about its activity?
Weak basespKa 8-9Lower pKa -\> faster acting
75
What determines a local anesthetic's length of action?
Affinity for Na+ channel binding site.
76
Why is epinepherine often administered with LA for a nerve block?
VasoconstrictionElevation of LA concentration around nerve, decrease amount released in systemic circulation
77
Are ester or amide LA drugs longer lasting? why?
Amide Metabolism by hepatic P450 vs. Ester metabolism by plasma pseudocholinesterase. Ester short duration of action.
78
What are side effects of local anesthetics?
1. CNS stim: depression of cortical inhibition pathways -\> activity of excitatory pathways. Unbalanced excitation, then depression, restlessness, dizzy, tremors, confusion, resp. depression. Benzodiazepine prophylaxis2. Myocardial depression: same Na+ channel blocked -\> decreased conduction velocity, contraction, CO. Also vasodilation (sm. muscle relaxation by all except cocaine)3. Hypersensitivity mostly esters (PABA derivatives)
79
Cocaine
Local anesthetic - ester linkage-vasoconstrictor -medium duration of action-high toxicity (reduce catecholamine uptake in CNS and PNS)-addictive (mesolimbic pathway)Topical use only (oral, laryngeal, nasal) - vasoconstrictive action decreases operative bleeding.
80
Procaine (Novocaine)
Ester linked LApKa = 8.9 - slow onset (2-5 minutes)Short half-life (20 sec.), no toxicityPoor protein binding, low hydrophobicity - rapid dissociation\*\*reduces effectiveness of sulfonamides - hydrolyzed to PABA\*\*Infiltration and dental procedures
81
Benzocaine (Americaine)
Ester LA - small - fits in pore in CLOSED state, stabilizes CLOSED statelacks tertiary amineshort acting (15-20 min), low potency, rapid onset (1min)Cream, aerosol, ointment - TOPICAL onlyIncreased risk of methemoglobinemia, esp. aerosol and smokers
82
Tetracaine
Ester LAHigh potency, long durationButyl group -\> highly hydrophobicPossibly increased systemic toxicity (slow release from tissue -\> blood, slow metab)Spinal and topical anesthesia
83
What is Minimum Alveolar Anesthetic Concentration?
Concentration (% alveolar gas mixture - partial pressue) resulting in immobility in 50% of patients when exposed to noxious stimulusAnalgesia ~0.3MACAmnesia ~0.5MACSurgical anesthesia \>1MAC
84
What is the oil:gas partition coefficient?
Lipid solubility. Equal to potency of an anesthetic.Potency =1/MACPotency of inhaled anesthetic = quantity required to produce desired effectPotency of IV anesthetic = free plasma conc. required for lack of response to pain stimulus in 50% of people
85
What are the primary targets and general effect of general anesthetics?
Target: Ligand gated ion channelsEffect: potentiation of inhibitory NTs or inhibition of excitatory NTs
86
What are the two modes of administration of General Anesthetics and what groups of drugs fall under each?
Inhaled GAs: Gasses and volatile liquidsIntravenous GAs: Barbituates, Benzodiazepines, Misc. (propofol), Dissociatives
87
What is the general structure of IV general anesthetics?
Small, hydrophobic, substituted aromatic or heterocyclic compounds
88
3 barbituates, mode of administration, and general characteristics
Sodium Thiopental, Thiamylal, MethohexitalGiven IVHighly lipid soluble, ultra-short acting (2-5 minutes)\*\*Induction of surgical anesthesia w/in seconds\*\*
89
How are barbiturates metabolized and distributed in the body?
Metabolized in plasma and liverDistributed from blood -\> heart, brain, highly vascular tissues, lean tissue before fat.Drug may deposit in fat and produce "hangover" effect in patients w/ high % body fat.
90
3 benzodiazepines, general characteristics and use
Diazepam, Lorazepam, MidazolamUsed for anxiolytic and anterograde amnesic propertiesAdmin 15-60 min before induction of GA, may be used as intraoperative sedatives
91
How long does a single IV bolus of opioid analgesic typically last?
~30-60 minutes
92
What are opioids used for in General Anesthesia and what are examples?
Analgesics. No amnesic effect. May be used in certain high-risk cases where a patient is not likely to survive full anesthesia.MorphineFentanyl
93
Propofol
Most popular IV anesthetic - not analgesic.Used for induction and, with continuous infusion, maintenance.rapid recoverygood for outpatient surgeriesProlonged anesthesia in critical care settingsAntiemeticliver metabolism
94
Etomidate
Used for general anesthesia - Not analgesicDoes not cause significant cardiovascular or respiratory depression - used where risk for hypotension or impaired ventricular functionHigh incidence of post-op N/VPain w/ injection - co-administer LidocaineLiver metabolism
95
Ketamine
PCP analog - NMDA receptorDissociative agent, produces profound analgesia\*\*\*Only IV anesthetic that produces dose-related cardiovascular stimulationLiver metabolism
96
What inhalation anesthetic agents are used for induction of children?
Sevoflurane - expensive. sweet smell.Halothane - non-pungent
97
What is the most widely used inhalation anesthetic agent?
Isoflurane - has pungent smell
98
Nitrous Oxide
Inhalation anesthetic agent.Not used alone outside of dental proceduresAnalgesic - low potency
99
Desflurane
Inhalation anesthetic - widely used in outpatient setting
100
System effects of inhaled anestheticsCV, respiratory, brain, kidney, liver
CV: Decrease systemic BPResp: Reduce /eliminate respiratory drive (except NO)Brain: Increase cerebral blood flow, volume and ICPKidney: Conc. dependent - decrease GFR and RBF, increase filtration fractionLiver: Conc. dependent reduction in hepatic BF (15-45%)
101
Compare effects of Ketamine, Etomidate, and Propofol on CV, Resp and Cerebral activity
CV Resp. Cereb. HR MAP Vent B.dill CBF CMO2 ICPKetamine ++ ++ - +++ +++ + +++Etomidate 0 - - 0 --- --- ---Propofol 0 --- --- 0 --- --- ---
102
Describe Malignant Hyperthermia
Rare autosomal dominant disorderOccurs in susceptible individuals undergoing general anesthesia with volatile agents and muscle relaxants (succinylcholine)Increase in free Ca++ in skeletal muscle -\> rapid and severe HTN, tachycardia, muscle rigidity, hyperthermia, hyperkalemia, acid/base imbalance w/ acidosis
103
What does the blood:gas partition coefficient say about a drug's ability to induce anesthesia?
Low coefficient = more rapid effectLow solubility -\> lower coefficient. Lower solubility means faster equilibration and less drug has to be delivered for maximum effect.
104
Does high pulmonary blood flow speed or slow equilibration of anesthesia (inhaled agent)?
High pulmonary blood flow (increased CO) slows equilibration. Larger volume of blood exposed to same conc. of agent per time unit, so slower equilibration
105
What is the process of anesthetic emergence? What determines rate?
Anesthetic redistributes from brain -\> blood and is eliminated through lungs or metabolism / excretionLow blood:gas partition coefficient -\> faster emergenceRate is proportional to duration of anesthesia (muscle/ fat conc increases with time)Rate of respiration - higher rate -\> faster emergence
106
3 opioid receptors and associated activities
Mu: Primary site of action of opium and other drugs. (endogenous proteins less active here)Delta: Less potent, but can mediate analgesia. Enkephalin activatedKappa: Can mediate analgesia, but psychotomimetic effect.
107
What is the molecular effect of opiate receptor activation? How does heterodimerization play a role?
Result is a decrease in nerve transmission. Closure of VGCC on presynaptic terminal and opening of K+ channel on postsynaptic.
108
What is naltrexone?
Added to SR morphine capsules in embedded capsule (Embeda) - opioid antagonistIntended to discourage abuse
109
What are morphine's major metabolites? How are they eliminated?
Morphine-6-glucuronide: active analgesic effect, esp. w/ chronic useMorphine-3-glucuronide: neuroexcitatory effect - proconvulsantMetabolites renally excreted. Renal insufficiency - adverse effects from agitation - respiratory depression
110
In what brain centers is morphine thought to exert effect on mood and cognition? What are the effects?
Locus coeruleus, mesolimbic DA, nucleus acumbens (pleasure ctr)Produces feelings of euphoria, tranquilityConfusion and sedation are common - esp. in elderly
111
What is the important role of prompt morphine administration in combat wounded patients?
Reduction in PTSD incidence
112
What is morphine's effect on the eyes?
Miosis (pinpoint pupils)PS activation (atropine sensitive) - sign of abuse / toxicity
113
What is morphine's effect on respiration / cough reflex?
Respiration: Dose-related depression via brainstem ctrsdecreased response to CO2 (important in COPD setting and in combo w/ other CNS depressants)Cough: suppression via medullary ctr (easily dissociated from respiratory effect)
114
What effect does morphine have on ICP and why?
Due to increased pCO2 -\> cerebrovascular dilation -\> increased ICP\*\*head trauma\*\*
115
What effect does morphine have on the CV system?
Minimal CV depressionperipheral vasodilation, reduced resistance, inhibition of baroreceptor response\*\*orthostatic hypotension\*\*
116
How is morphine used in the setting of CHF?
Direct relief of dyspnea associated with LV failureDecrease anxiety, venous tone, TPR
117
What effect does morphine have on the GI system?
decrease in propulsionincreased water absorption-\> constipation - QOL issue, esp w/ chronic use
118
Oxycodone
Painkiller w/ morphing backboneMore orally active than morphine. Potent w/ same efficacyPopular drug of abuseCurrent formulations including additives -\> upleasant effects if crushed or turns to gel - unusable
119
Fentanyl
80-100x more potent than morphineShort duration of action, no active metabolitesSurgical anesthetic (often w/ droperidol)Trans-dermal patch for acute post-op pain\*\*\*CYP3A4 metabolism\*\*\*
120
Meperidine
DemerolOpioid Painkiller of rapid onset and short durationIrritating to tissue if admin IMUnique toxicity: delerium, seizures, twitches, due to long-lived metabolite accumulationUse limited to moderate-severe pain, short duration (1-2 day post-surgical)NO OUTPATIENT USE
121
Methadone
Opioid: Full Mu agonist w/ very long half-life (up to 5 days)High fat solubilityHepatic metabolism - no active metabolitesUsed for chronic pain and addiction management.Inovolved in 30-40% of opioid deaths
122
Codeine
Prodrug - metabolized to morphine (CYP2D6 demethylation)High oral/parenteral potency ratio - largely avoids first pass metabolismWeak agonist - moderate analgesic activityUsually used in combo formulationNot for peds in minor procedures
123
How is codeine metabolized and what variants exist in population?
Demethylated by CYP2D6 to morphine10% of pop lack CYP2D6 - poor responders1-7% of pop are ultra-rapid metabolizers, poss of OD
124
Buprenorphine
OpiatePartial agonist at mu receptor - slow dissociation -\> long activityModerate-severe pain and addiction managementIV, patch, sublingual (also w/ naloxone available)
125
Tramadol
Ultram - synthetic codeine derivativeProdrug - O-desmethylated product is activeweak mu agonist and 5-HT / NE reuptake inhibitorpossible GABA mechanismNeeds slow titration - use for chronic painInhibition of CYP2D6 and 3A4 -\> toxicity, decreased efficacySeizures reported, but unknown mechanism
126
Tapentadol
Similar to TramadolWeak mu agonist and NE uptake inhibitor (not 5-HT)ER availableRisk of abuseShivering, diaphoresis, muscle pain
127
Naloxone / Naltrexone
Naloxone = NarcanOpioid receptor antagonists (mu \> kappa, delta)Naloxone: used in ED for opiate OD - also blocks antidiarrheal and antitussive effectsNaltrexone: Used to prevent relapse to heavy drinking in alcoholism -\> hepatic damage at 3-4x normal dose
128
Methylnaltrexone
Opiate receptor antagonist - does not cross BBBUsed to relieve opiate constipation - action in gut
129
Diphenoxylate
Opiate - poor absorption from gutUsed for diarrhea
130
Dextromethorphan
D-isomer of methylated levorphanol - no typical opioid effectUsed for antitussive effect in lower airway diseaseContraindicated in childrenCombo admin is discouragedNMDA receptor antagonist, sigma receptor agonistpotential for abuse
131
Nalfurafine
Kappa receptor agonistreduces substance P-induced scratching in animalsapproved in Japan for uremic itching (dialysis related)
132
How much acetaminophen may be included in an opiate combination drug?
325 mgFDA imposed max
133
What are some non-prescription hypnotics?
diphenhydramine, doxylamine, L-tryptophan (serotonin precursor), and melatonin
134
What are the two major classes of sedative-hypnotic drugs?
Benzodiazepines and barbiturates
135
Describe benzodiazepine receptor function
Part of GABA-a receptor Cl- channelresults in increased frequency of opening in response to GABA, increased GABA potency and membrane hyperpolarization
136
Flumazenil
BZ receptor antagonist - reversal of CNS effects of Benzos
137
Describe the Barbiturate receptor
Barbiturates bind to a site on the GABA-a receptor (separate from BZ) -\> prolongation of duration of opening and increased GABA efficacy
138
What drugs are preferred for treatment of anxiety?
those w/ longer duration of actionEx. Diazepam
139
What drugs are preferred for treatment of panic and phobic disorders?
Alprazolam and Clonazepam have higher efficacy than other drugs
140
What drug is preferred for treatment of general anxiety in a patient with a hx of substance abuse?
Buspirone - does not have a sedative / cognitive impairment effect-may take a week or more for effects to develop
141
What is standard treatment for status epilepticus?
IV diazepam or lorazepam, followed by IV fosphenytoin or phenobarbital-Watch for CNS depression
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What did the RAMPART study demonstrate?
Use of midazolam (EMS admin) better than IV lorazepam in treatment of status epilepticus
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What is a Ketogenic Diet and what is its use?
Non-pharmacological treatment of chronic seizures / epilepsyMimics fasting: High fat, low carb diet : 4gm fat / gm protein or carbCreates ketosis - brain uses ketones (acetone, acetoacetate, beta-hydroxybutyrate) for fuelRequires strict adherence and initial hospitalization
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What are the roles of monamine NTs in the brain?
NE and serotonin:Modulate behavioral stateRegulate how neurons function rather than produce rapid excitatory / inhibitory signals as in the periphery
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qualities of a migraine headache
pulsatileunilateralassoc. with N/VIntense enough to interrupt daily activities4-72 hrs if left untreated.
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What is thought to be the underlying cause of migraine headaches?
Neurogenic inflammationTrigeminal afferents to the brain release pro-inflammatory peptides -\> vasodilation and inflammation
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What are 3 non-amphetimine treatments for ADHD?
Atomoxetine - NE reuptake inhibitorGuanfacine - Extended release a2 agonistClonidine - a2 agonist\*none are first line drugs
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2 non-amphetamine drugs that can be used to treat daytime sleepiness (narcolepsy)
Modafinil - DA uptake inhibitor (Provigil)Sodium Oxybate - GHB - narcolepsy - condenses sleep so occurs in one stretch rather than multiple short periods through the day.
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How are migraines treated?
Mild, w/o vomiting: NSAID, acetaminophenSevere: Triptans - 5-HT agonists: block inflammatory peptide release. Best w/ NSAID Dihydroergotamine - old. can -\> serotonin syndrome\*\*\*Early treatment mandatory! As soon as prodrome is recognized
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What drugs can be used for migraine prophylaxis?
Beta blockerAntiepileptic (Valproic Acid, Topiramate)TCA (Amitriptiline) - SSRI/SNRI evidence lackingBehavioral therapy
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What is a CGRP antagonist?
future treatment of migraineblocks peptide believed to be responsible for neuro-vascular inflammationCurrent investigation: anti-CGRP Ab
