autonomic and cardiovascular drugs
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- botulinum toxin mechanism
- blocks ACh release
- choline acetyltransferase action
- synthesizes ACh
- acetylcholinesterase
- breaksdown ACh
- rate-limiting step in NE synthesis
- Tyrosine hydroxylase (tyrosine to dopa)
- metyrosine action
- inhibits tyrosine hydroxylase
- uptake I
- norepinephrine transporter into neuron
- uptake II
- uptake by extraneuronal tissue
- Monoamine oxidase action
- makes catecholamine aldehydes
- Catechol-o-methyltransferase (COMT) action
- makes (nor)metanephrine
- physostigmine action
- inhibits cholinesterase
- carbidopa action
- dopa decarboxylase inhibition
- receptor type which stimulates adenylyl cyclase
- Beta 1,2
- Gi receptor types
- a2, M2
- receptor types stimulating PKC
- a1
- phenylephrine mechanism
- a1 agonist
- methoxamine mechanism
- a1 agonist
- mydriasis
- dilated pupil
- Phentolamine mechanism
-
competitive a1 antagonist
**short half life - phentolamine uses
- dx pheochromocytoma
- pphenoxybenzamine mechanism
-
noncompetitive a1 antagonist
*long acting - phenoxybenzamine use
- treat pheochromocytoma
- prazosin mechanism
- alpha1 antagonist
- prazosin use
- tx of hypertension and CHF
- prazosin risks
-
syncope after first oral dose
reduced efficacy with chronic use - clonidine mechanism
- a2 agonist--> reduced symp outflow
- clonidine use
- tx of hypertension
- methyldopa mechanism
- metabolite a-methyl*norepinephrine* is a2 agonist
- methyldopa use
- tx of hypertension
- yohimbe mechanism
- alpha 2 antagonist
- Isoproterenol mechanism
- stimulates b1 and b2
- dobutamine mechanism
- b1 agonist
- uses of dobutamine
- tx of pulmonary edema, coronary bypass post op
- Propranolol mechanism
- competitive inhibitor of b1 and b2
- uses of propranolol
-
tx of angina
ventricular arrhythmia
htn *dec renin*
post myocardial infarction - propranolol side efx
-
worse heart failure
reduced AV conduction
nightmares
fatigue
cold extremities - Metoprolol mechanism
- b1 blocker
- atenolol mechanism
- b1 selective blocker
- atenolol uses
-
htn (one a day)
glaucoma - bromocriptine mechanism
- dopanergic agonist
- tyramine mechanism
- displaces NE into synaptic cleft
- population vulnerable to tyramine related hypertension
- pts on monoamine oxidase inhibitors
- Phenylpropanolamine mechanism
- indirect sympathetic stim
- methacholine mechanism
- cholinergic
- bethanachol mechanism
- muscarinic agonist
- pilocarpine mechanism
- muscarinic agonist
- bethanachol uses
-
improved gastric emptying
tx of urinary retension (if no physical obstruction) - pilocarpine uses
-
induce salivation
open angle glaucoma--constricts iris sphincter (miosis) - methacholine use
-
provoke bronchoconstriction for dx testing
(methacholine challenge) - atropine mechanism
- muscarinic antagonist
- atropine use
-
raising heart rate when vagal activity is pronounced **vasovagal syncope
decreased respiratory secretions for intubation - Bezold-Jarisch reflex
- bradyardia, hypotension, nausea from high nicotine dose
- ganglionic blocking agents mechanism
- block Nn receptors
- insectiside mechanism
- anticholinesterase
- physostigmine mechansim
-
"reversible" short acting cholinesterase inhibitor
enters CNS - neostigmine mechanism
-
"reversible" short acting cholinesterase inhibitor
does not enter CNS - physostigmine side effects
-
enters cns, restlessness, apprehension, hypertension
typical muscarinic/nicotinic efx - why neostigmine no enter cns?
- quaternary amine (charged)
- uses of neostigmine
-
myasthenia gravis
glaucoma - propranolol "traditional" frequency of dosing
- 4 times a day
- metroprolol mechanism
- b1 blocker
- metabolism of propranolol
-
heavily liver metabolized
protein bound
interindividual variability - atenolol metabilism
- reduced hepatic metabolization (vis a vis propranolol)
- metroprolol metabolism
- less hepaticlly metabolized (vis a vis propranolol)
- esmolol clinical use
- b blocker for critical care
- esmolol metabolism
- short half life, IV use only
- labetolol mechanism
- b blocker with a1 effect
- carvedilol clinical use
- CHF
- carvedilol mechanism
- beta blocker with a1 blocking
- type of b blocker for treatment of portal hypertensive bleeding
- non selective (propranolol in US)
- betablocker type for essential tremor
- non selective
- vascular headache prophylaxis betablocker type
- propranolol (non selective and more lipophilic)
- methyldopa side effects
- sedation, depression, dry mouth
- special situations in which methyldopa is particularly safe
-
for htn in pts with ischemic heart disease (no efx on CO)
does not block baroreceper rflx
--safe for anti-htn in elective surgery - dosing of methyldopa
-
delayed onset of effect (needs to be metabolized to methyel-NE)
twice a day for maintanence - drug of choice for hypertensive pregnant pts
- methyldopa
- why clonidine is poor choice in pts with *severe* HTN?
- clonidine rebound. withdrawal syndrome w/ massive symp discharge
- pharmacokinetics of prazosin
- hepatic metabolism
- pharmacokinetics of terazosin and doxazosin
- longer lasting than prazosin
- labetolol R R stereoisomer mechanism
- b1 antagonist and partial b2 agonist
- labetalol SR stereoisomer mechanism
- a1 antagonist
- S isomer of Carvedilol
- b blocker (both isomers a1 blockers)
- The critical factor affecting the therapeutic utility of nitrates
- tolerance
- what is given along with nitroprusside?
-
Na2S2O3 (Na thiosulfate)
the antidote to CN - pharmacokinetics of nitroprusside
-
infusion only--dissolved immediately prior to use in glucose/water
rapid/potent/fast half life - nitroprusside clinical use
- acute hypertensive crisis
- mechanism of hydralazine
- who the fuck knows
- clinical utility of hydralazine
-
hypertension--use with beta blocker and diuretic
heart failure - metabolism of hydralazine
- acetylated (pt variability)
- hydralazine side effects
- Na retention, coronary steal
- minoxidil mechanism
-
sulfate metabolite opens atp sensitive k channel
--hyperpolarizes cell
--arterial vasodilation - chemical class: nifedipine
- 1,4 dihydropyridines
- chemical class: verapamil
- phenylalkamines
- chemical class: diltiazem
- benzothiazepines
- verapamil mechanism
-
L type calcium channel blocker
cardiac selective - diltiazem mechanism
-
L type calcium channel blocker
intermediate cardiac/vascular selective - nifedipine mechanism
-
L type calcium channel blocker
vascular selective - diltiazem and verapamil tx for what arrythmia
- supraventricular tachycardia
- CCB metabolism
-
protein bound and big first pass effect
low bioavailability - CCBs inhibit what entity important for drug interactinos
- CYP 3A4
- interaction of CCBs and beta blockers
-
profound conduction and contractile depression
decreased liver flow (betas) less clearance of CCBs - chemistry of captopril
-
contains a sulfhydryl group at zinc ligand site.
--other ACE inhibs do not - hyperkalemia in ace inhibitors???
-
decrease in aldosterone
**beware in pts with bad kidneys - he "diluting segment" of the nephron.
- thick ascending limb
- mannitol site of action
- proximal tubule
- mannitol characteristics of diuresis
- loss of H2O in excess of Na and Cl
- Acetazolamide site of action
- proximal tubule, inhibits carbonic anhydrase
- acetazolamide characteristics of diuresis
- loss of Na, HCO3, Cl, and K
- Furosemide site of action
- thck ascending loop of henle
- furosemide characteristics of diuresis
-
loss of Na, Cl, K
Lose Mg and Ca
potentially loss of 50% filtered Na - Thiazide like diuretics site of action
- distal tubule +/- proximal tubule inner medullary collecting tubule
- thiazide like diuretics characteristics of diuresis
-
loss of Na, Cl and K
increase blood Ca and uric acid
**prevent kidney stones
**inhibit osteoporosis - chemistry of carbonic anhydrase inhibitors
-
contain sulfamyl moiety
i.e. are sulfonamides - acetazolamide mechanism
- noncompetitive carbonic anhydrase inhibitor
- pharmacokinetics of acetazolamide
-
absorbed from GI
eliminated by kidney
actively secreted by organic acid transport system - clinical uses of carbonic anhydrase inhibitors
- glaucoma
- toxicity of carbonic anhydrase inhibitors
-
metabolic acidosis
renal stone formation (renal stones from alkaline pH)
K+ wasting
decreased NH3 secretion - furosemide mechanism
- Na-K-Cl2 symport inhibitor
- ethacrynic acid mechanism
- Na-K-Cl2 symport inhibitor
- ethacrynic acid chemistry
- not a sulfonamide
- furosamide chemistry
- contains sulfamyl moiety
- loop diuretics and mg++, ca++
-
substantial urinary loss of these divalent cations
**abolishes lumen positive potential - pharmacokinetics of loop diuretics
-
absorved in GI
secretion via organic acid secretion
threshold effect--once at effective dosage, more wont help
**can increase frequency for more urination - toxicity of furosemide
-
K+ loss
ototoxicity
H loss with metabolic alkalosis - hydrochlorothiazide chemistry
- sulonamide (sulfamyl moiety)
- hydrochlorothiazide mechanism
- inhibit Na trnasport in distal convoluted tubule
- pharmacokinetics of hydrochlorothiazide
-
rapidly absorbed from GI
filterd and secreted in proximal tubule
binds to plasma proteins - thiazide diuretics and calcium
- increase Ca++ reabsorption
- triamterene chemistry
- organic base, not sulfonamide
- amiloride chemistry
- organic base, not sulfonamide
- triamterene mechanism
-
inhibition of Na+ channel in collecting tubule
k sparing - amiloride mechanism
-
inhibition of Na+ channel in collecting tubule
k sparing - amiloride pharmacokinetics
-
partially absorbed from GI
completely eliminated in kidney - triamterene pharmacokinetics
-
well absorbed from GI
elimenated by renal excretiona and metabolism - toxicity of amiloride and triamterene
-
do not combine with spironolactone
caution with ace inhibitors
do not combine with K+ supplements - spironolactone mechanism
- competitive aldosterone inhibitor
- Na+ channel blocking drugs terminate and prevent arrhythmias by
-
· slowing conduction to interrupt a reentrant circuit
· increasing refractoriness to terminate functional reentry and so that there is "less room" for premature beats (which cause slowed conduction Þ reentry to occur) - Tx of atrial flutter/fibrillation to slow ventricular response
-
AV nodal blockers:
verapamil/diltiazem
beta blockers
digitalis - tx of atrial flutter/fibrillation to maintain normal rythm
-
(increase refractoriness in fast respone tissue)
class Ia
Class Ic
Class III -
tx of supraventricular reentrant tachycardias: Acute (IV)
***(Almost always, the reentrant loop involves the AV node) -
adenosine (drug of choice)
verapamil or beta blocker
digitalis
maneuvers to increase vagal tone: vasalva, carotid massage - txt of svt reentrant (assuming AV node) tachycardia: oral (chronic)
-
verapamil or diltiazem
beta blocker
digitalis
class Ic -
tx of svt using a bypass tract
(fast response tissue) -
Class Ia
Class Ic
Class III
**avoid empiric tx with AV node blockers -
tx of ventricular arrhythmias: acute (IV)
**(slow condux, increase refractoriness in fast response tissue->ventricles) -
lidocaine--Ib
procainamide--Ia
amiodarone--III - tx of ventricular arrhythmia: chronic
-
class Ia
Class Ib
Class Ic
class III - tx of undiagnosed wide complex tachycardia
-
could be PSVT or VT. "all bets are off"
**avoid verapamil - tx for narrow complex tachycardia
-
usually slow response=av node
adenosine
verapamil
esmolol - tx of unstable rhythm causing hemodynamic compromise
- shock the muthafucka
- QUINIDINE class and mechanism
-
Ia
blocks Na+ and multiple K+ currents
a-receptor block and vagal inhibition - Quinidine antiarrhythmic use
- chronic therapy of atrial fib/flutter (and VT)
- Quinidine problems
-
diarrhea
more death in pts with a-fib?
torsade de pointes 2-5% - procainamide class and mechanism
-
Ia
blocks Na and K+
metabolite N-acetylprocainamide blocks K+ channels - procainamide use
- IV for SVT adn ventricular arrhythmia
- procainamide things to look out for
-
dose adjustment in renal disease
lupus syndrome w/ chronic therapy - LIDOCAINE class and use
-
Ib
decrease incidence of V fib
**mortality increase - lidocaine dosage issues
-
rapid distribution half life
slow elimination half life
clearance reduced in CHF and liver disease - Flecainide Class Ic use
-
effective at surpressing isolated PVC and reentrant SVT
*BUT INCREASED mortality in patients following myocaridal infarction. wtf - esmolol class and usage
-
Class II, beta blocker
short half life=9 min
useful for reckless beta blockade - why does bretylium (class III) suck?
- due to hypotensive effect, bretylium can cause hemodynamic collapse during previously well-tolerated VT (therefore use lidocaine, procainamide first)
-
amiodarone useage, but sucks b/c?
class? -
Class I + II + III + IV action
· very effective for most arrhythmias, but NOT first-line oral therapy because . .
· multiple toxicities: eye, *lungs*, liver, skin, thyroid during chronic treatment - verapamil: NEVER USE WHEN
-
undiagnosed, wide complex tachycardia (Ë hemodynamic collapse)
· "preexcited" atrial fibrillation over an accessory pathway in the Wolff-Parkinson-White syndrome (may cause È heart rate, VF)
· heart failure
· sinus node dysfunction, AV block (*caution: Class I + IV*) - DILTIAZEM usefulness
- · intravenous form: useful AV nodal blocker usually without hypotension (especially for rate control of atrial fibrillation)
- ADENOSINE good for?
-
Acute therapy of choice for: supraventricular tachycardias, undiagnosed wide-complex tachycardia
**short acting--seconds -
Quinidine, Verapamil, Amiodarone, (? Flecainide)
interactinos with
Digitalis - inc digitalis concentration and toxicity
-
amiodarone interactions with
warfarin, digoxin, procainamide, quinidine -
decreased drug metabolism and excretion
increased drug effects -
renal disease interaction wtih
procainamide (Ia) and dofetilide (III) - decreased clearance
- liver disease interaction with lidocaine
- decreased clearance
- heart failure interaction with lidocaine
-
decreased clearance
decreased central volume (lidocaine) whatever the fuck that means -
disopyramide, flecainide, beta blockers, verapamil interaction with
heart failure - worsen heart failure
- dofetilide interaction with cimetidine and ketoconazole
- increased dofetilide concentrations
- plasmin, enzyme type
- serum protease
- enzyme that dissolves clots
- plasmin
- what do kringle domains on plasminogen activators bind
- fibrin
- Streptokinase mechanism
- indirect activator of plasminogen...helps one plasminogen activate another
- streptokinase problems
-
allergic rx's
bleeding, hypotension - urokinase mechanism
- direct activator of plasminogen
- urokinase metabolism
- liver, short half life 15 min
- urokinase inactivation
- inactivated by PAI-1
- second generation thrombolytic with long half life
- APSAC....60 mins. given by bolus
- APSAC, what is it?
- complex of streptokinase and plasminogen
- t-PA mechanism
- binds to fibrin and activates plasmin **clot specific**
- pharmacokinetics of t-PA
-
PAI-1 irreversibly inhibits
cleared in liver
short half life, 6 mins - Reteplase, what is it?
-
genetically engineered derivative of t-PA
just the kringle and protease, not glycosylated - TNK-t-PA (tenecteplase), wtf is it?
- t-PA with no glycosylation site
- the two antifibrinolytics?
- Amicar (e-aminocaproic acid) or tranexamic acid
- digoxin effects at AV node
-
increased ERP, and decreased conduction
slower ventricular rate during atrial flutter/fib - Digoxin effects at His-Purkinje fibers
-
increased automaticity
premature ectopic beats - digitalis effect on PR interval
- increased
- digitalis effect on ST segment
- depressed
- digitalis effect on amplituted of T waves
-
decreased
may invert - digitalis effect on QT interval
- decreased
- aspirin mechanism
- blocks cyclooxegenase--> no thromboxane A2
- Dipyridamole action
-
Inhibits cyclic nucleotide phosphodiesterase to increase intraplatelet accumulation of cAMP
¨ Blocks the uptake of adenosine - Ticlopidine and Clopidogrel mechanism
-
Metabolites Inhibit platelet activity via effects on
· Inhibition of ADP induced platelet activation (primary)
· Glycoprotein IIb/IIIa receptor
· von Willebrand factor - pharmacokinetics of ticlodipine and Clopidogrel
-
delay in onset
effects persist several days - ticlodipine and Clopidogrel interactions
-
activated by CYP3A4
inhibitors of CYP3A4 may reduce activation - Adverse effects of Ticlodipine and Clopidogrel
- neutropenia in 3% of pts. ticlodipine problem
- (Abciximab mechanism
- antibody to the IIb/IIIa receptor,
- factors inactivated by heparin
-
thrombin (II)
activated IX, X, XI, and XII
**inactivates free thrombin, thus best for preventing clots - administration of heparin
- IV, not absorbed thru GI
- never ever administer heparin this way
- intra muscular
- Two forms of heparin-induced thrombocytopenia (HIT)
-
1 heparin induced platelet aggregation leading to decreased platelets
2 Rarer. b/t 7 and 11 days. immune response with thrombotic complications - what to do if in case of severe bleeding from heparin overdose
-
discontinue infusion
protamine administration - protamine mechanism
-
binds to and inactivates heparin
**possible allergic toxicity - mechanism of low molecular weight heparin
- bind antithrombin/factor Xa
- LMWH and PTT
-
b/c very little binds to AT-III/thrombin, little effect on PTT
NOT USED FOR MONITORING - advantages of LMWH over regular heparin
-
less frequent administration
sub-q administration
more predictable response to dose - Direct Thrombin Inhibitors?
- lepirudin, agatroban
- lepirudin, agatroban mechanism
- directly inhibit binding of thrombin to fibrinogen
-
warfarin action
which factors affected? -
antagonist of vitamin K
affects synthesis of II, VII, IX, X, protein C, and protein S - adverse effects of warfarin
-
bleeding, yo
paradoxical thrombis
--pretein C and S fucked up first - beta blockers and hepatic metabolism
- atenolol only beta blocker not metabolized in liver