Pharmacology
Anti-HTN ACEI / B-blockers / α-blockers
/ Ca-blockers / nitrates
/ other
Anti-arrhythmics Class I / Class II
/ Class III / Class IV / Others
Anti-coagulation ASA / Plavix / IIbIIIa
/ Heparin / Lovenox / Warfarin
Endocrine Diabetes, Hormone,
Thyroid
GI Antacid / Pro/Anti-Emetics
/ Prokinetic
Neuro Seizure / Parkinson’s / Psychopharmacology
/ Headaches
Chemotherapy Transplant Bone Urate
Narcotics / Anesthesia Poisoning / Environmental
/ Chelators
Pharmacokinetics Toxicity (teratogens) Homeopathic Vaccination
1 Tsp = 15 ml
1 oz = 30 ml
Positive Inotropes: Digoxin,
Milrinone
Pressors:
Dopamine
ACE inhibitors, B-blockers, alpha blockers, Ca channel blockers, nitrates
Anti-Arrhythmia (class I, II, III, IV)
Pressors [see
positive inotropes below]
|
|
Dose |
HR |
Contractility |
Vasoconstriction |
Vasodilation |
|
Dopamine |
1+ |
1+ |
0 |
1+ |
|
|
Dobutamine |
2.5-15 mcg/kg/min |
3-4+ |
0 |
2+ |
|
|
Norepinephrine |
2-20 mcg/min |
1+ |
2+ |
4+ |
0 |
|
Epinephrine |
1-20 mcg/min |
4+ |
4+ |
4+ |
3+ |
|
Phenylephrine
|
20-200 mcg/min |
0 |
0 |
3+ |
0 |
|
Milrinone |
37.5-75 mug/kg bolus; then 0.375-0.75 mug/kg/min |
1+ |
3+ |
0 |
2+ |
a1 G ® PLC ® IP3 ® Ca2+
a2 AC ® cAMP
a E > NE >> isoproterenol
b1 AC ® cAMP
b2 AC ® cAMP
b isoproterenol > E > NE
Catecholamines
·
increased potency, decreased T ½, decreased CNS effects
Epinephrine Low dose E b > a
High dose E a > b
Dobutamine a1b1b2
Dopamine D1 then b1 then a1 / IV only, rapid
inactivation by MAO
Norepinephrine (Levofed)
Isoproterenol b1, b2 agonist
Metaproterenol b2 > b1
Albuterol b2 > b1
Midodrine (Proamatine) used to
treat hypotension (e.g. patient’s with autonomic insufficiency) / Side effects:
paresthesias, pruritis
Non-catecholamines
·
increased T ½, increased CNS effects
Phenylephrine (neo-synephrine)
Ephedrine
Amphetamine
Indirect Action
·
increase NE release
Amphetamine
Tyramine
D1
> B1 > a1 / IV only, rapid inactivation by MAO
Dobutamine (Dobutrex)
a1b1b2 / positive inotrope /
increased contractility, HR / IV only / may cause arrhythmias (short refractory
period)
BPD (bis-phosphodiesterase) inhibitor / increases
cAMP, increases contractility and reduce afterload by vasodilation / IV only (short
term use only) [oral formulations
increase mortality?] / retain their full hemodynamic effects in the face of
beta blockade (action beyond beta-adrenergic receptor)
Amrinone
Mechanism: blocks Na/K tritransporter
1) myocytes, vagus more
excitable (causes arrhythmia, slower HR,
N&V, diarrhea)
2) prolonged refractory period
of AV node
3) increased contractility from calcium loading
4) sympathetics, vascular SMC
(causes arrhythmias, HT)
5) skeletal muscle
(hyperkalemia)
Drug
interactions:
·
quinidine, amiodarone, verapamil and propafenone decrease renal excretion and displace albumin binding
·
verapamil, propranolol worsen heart block
·
cholestyramine decreases GI absorption
·
Early: anorexia, nausea, vomiting
[direct stimulation of medulla]
·
Cardiac effects [EKG]: ↓SA node activity,
↓ refractory period, ↓ AV node, ↓ His, ↓ purkinje
o
arrhythmias: NPAT +/- AV block, PVC, bigemeny, VT, VF,
MAT,
and more
·
Chronic: weight loss, cachexia,
neuralgia, gynecomastia, yellow vision, delirium
·
Precipitating factors: hypokalemia from diuretics/aldosterone (most common), advanced age,
acute MI, hypoxemia, ischemia, hypomagnesemia, renal insufficiency, hypercalemia, electric cardioversion,
hypothyroidism
Treatment: atropine for bradycardia and heart block, lidocaine for tachyarrhythmias, also potassium (except with AV block and hyperkalemia) and phenytoin, can give mAb
FABs (Digibind) for severe toxicity
Dosing: high loading dose required
Digoxin
renal excretion, renal
disease increases half life
Dose:
0.035 mg/kg IV for premature infants
Digitalis
liver metabolism, has much
longer half-life
|
|
preload
reduction |
afterload reduction |
|
ACE inhibitors |
++ |
++ |
|
Calcium
Channel Blockers |
+ |
+++ |
|
B-blockers |
+ |
++ |
|
Hydralazine,
minoxidil, diazoxide |
+ |
+++ |
|
Nitroglycerine,
isosorbide dinitrate |
+++ |
+ |
|
Nitroprusside |
+++ |
+++ |
Actions:
·
Congestive Heart Failure / CAD
o
reduces afterload
and preload
o
protects against
myocardial remodeling (from CAD), have been shown to reduce mortality when
begun shortly after MI
Note:
some advocate combination of ACEI and ARB
renoprotective by at least 2
mechanisms
§
reduction of glomerular pressure (by relaxing efferent constriction)
§
blocking action and local formation of TGF-B1 (which causes
mesangial proliferation)
Other: ACE inhibitors are protective against FGS
(mechanism under investigation)
Note: studies on renal protection actually were done
using ARB’s, however, most people feel ACE provide same benefits / some say
using both ACEI and ARB together may provide further renal benefits (because
ACEI alone may not fully suppress AT-II effects and/or due to variation in
TGF-B1 activity)
ATII receptors
type 1 – vasoconstriction
(this is the one Losartan acts on)
type 2 – vasodilation + ?
type 3 - ?
may reduce TGF-B mediated
pulmonary fibrosis (various diseases)
·
More Actions:
many ACE inhibitors (except fosinopril) may increase
11-beta-HSD2 activity (this enzyme inactivates cortisol to cortisone
thereby protecting the non-selective mineralocorticoid receptor from cortisol)
Side effects:
·
ACE cough (5-15%) (PDP’s inactivate
bradykinin) / may occur anywhere from 3 weeks to one year after beginning medication; resolves
within weeks, recurs on rechallenge
·
Hyperkalemia (usually not a problem)
·
Acute renal failure (by decrease renal
perfusion, usually reversible)
·
Angioedema (1%) (life-threatening, do
not restart)
·
Other: increased renin,
proteinuria (esp. captopril), hypogustia, rash (sulfhydryl
group), neutropenia (rare),
hepatic failure (rare)
Contraindications:
·
Do NOT use ACE inhibitors with bilateral
renal artery stenosis!
·
Do NOT use in pregnancy (> 2nd trimester, causes fetal
renal damage)
·
may worsen cough in CF/asthma patients (via inadvertent PDP blockade)
·
synergizes with insulin to cause hypoglycemia
(insulin released by depolarization, hyperkalemia?)
Dosing: most (~70%) of afterload
reduction will be realized on low to medium doses / start at low dose and build
up / adjust dose for creatinine clearance / ?efficacy related to renin/AT II
levels so effects can be less predictable/titratable / only IV is enalaprit
Onset: minutes to maximum 2 hrs /
long term benefits for HTN may take 4-6 weeks to be fully realized
|
|
T ½ |
Onset |
Duration for BP |
Metabolism |
Dose |
|
|
Accupril |
|
|
|
|
|
|
|
Lisinopril (Lopril) |
|
Peak 7 hrs |
|
|
|
|
|
Fosinopril |
|
|
|
|
|
|
|
Quinapril |
|
|
|
|
|
|
|
Enalapril |
|
15 mins |
|
prodrug 12 to 24 h |
2.5 mg q 6 |
fewer side effects (carboxyl group rather than SH) |
|
Captopril |
|
|
|
|
30% protein bound short T ½ allows more rapid dose adjustment |
Angiotensin Receptor Blockers
Mechanism: direct inhibition of TGF-B / no cough
Side effects: dizziness, hyperkalemia,
uricosuria
AT 1 receptor antagonist / 2 hr onset / p450
metabolized (use valsartan with liver disease) /
Irbesartan
(Avapro)
Candasartan
(Atacand)
Valsartan
(Diovan)
Eprosartan (Teveten)
Mechanisms:
Have a variable effect on PR interval – in the
default state, they will have no change or shorten the PR interval in
association with decreased SA node firing rate, but in a high adrenergic state,
they tend to lengthen it
“use dependency” or “frequency dependency”
Note: some people think ISA
concept has little clinical relevance; also, some deny importance of b-blockade
masking adrenergic effect in DM patients
Note: some agents (atenolol,
nadolol, acebutolol, sotalol) require renal-dose adjustment
Uses:
Atrial fibrillation à1st line / b-blockers help reduce
relapse and when they
do relapse, the HR will be
lower Cardioprotection post-MI
CHF à b1 selective agents reduce
mortality
HTN à not first
line though unless compelling indication (e.g. CAD, MI)
Peri-operatively à although 7/06 AIM says only use with risk factors (high-risk surgery,
CAD, CHF, CVA, DM, Cr > 2.0)
Side effects (see labetalol for specific
unique side effects):
·
can increase TG, reduce HDL
·
depression
|
|
T ½ (in hrs) |
metabolism |
action |
Crosses
BBB |
Uses |
Dosage |
|
Atenolol |
6-9 |
Kidney |
b1 |
N |
HTN,
|
50-200 mg/d |
|
Metoprolol |
3-4 |
Liver |
b1 |
Y |
HTN,
|
50-200
mg |
|
Acebutolol |
3-4 |
Kidney |
b1 (ISA) |
|
|
|
|
Labetalol |
4-6 |
Liver |
a1, a2, b1, b2 |
|
HTN |
|
|
Carvedilol |
6-8 |
Feces |
b1 > b2 / a1? |
|
|
|
|
Propranolol |
4-6 (8-11) |
Liver |
b1, b2 |
Y |
HTN,
glaucoma, migraine, hyperthyroidism, angina, MI |
40-80 mg bid to qid 80-360 mg/d |
|
Pindolol |
12-24 |
|
b1, b2 (ISA) |
|
HTN,
tachy-brady |
|
|
Timolol |
4-6 |
|
b1, b2 |
|
Glaucoma,
HTN |
|
|
Esmolol |
10 mins |
|
b1, b2 |
|
HTN |
|
|
Nadolol |
20-40 |
Kidney |
|
N |
|
40-240 mg/d |
|
Sotalol |
7-18 |
Kidney |
|
|
|
40-160 mg bid |
Key: ISA = b1 agonist activity
Esmolol
Metabolized
by RBCs only / IV only
Carvedilol
(Coreg)
anti a1?, b1, b2/ lowers BP more than
metoprolol (has vasodilating effect not shared by pure beta antagonists) / has
been shown to reduce mortality in CAD, CHF / ?has antiproliferative and
antioxidant properties not shared by other B-blocking agents
has been shown to reduce mortality in CAD,
CHF
Toprol XL
Note: 50 mg Toprol XL qd = 25 mg metoprolol bid (same drug!) = 25 mg atenolol qd
Some
say action only ¾ day with q day dosing (duration only ~20 hrs)
Labetalol (Normodyne)
1:4 a:b (4x more b blockade) / IV or
Side effects: labetalol include
hepatocellular damage, postural hypotension, a positive antinuclear antibody
test (ANA), a lupus-like syndrome, tremors, and potential hypotension in the
setting of halothane anesthesia / reflex tachycardia may occur rarely because
of their initial vasodilatory effect.
Propranolol
(Inderal)
anti b1, b2 / used more for psychiatric
disorders (anxiety, etc)
contraindicated for CHF,
WPW, asthma, COPD
NOT for unstable angina
Nadolol
(Corgard)
Used
for esophageal varices to reduce portal pressure and risk of bleed
Timolol (Blocadren)
anti b1, b2 #1 glaucoma (decreases
aqueous humor secretion without affecting pupils,
accommodation) / Contraindications: NOT
for asthmatics
Forget
it
As different effects on different aspects of cardiac
conduction system / used by EP specialists in certain types of arrhythmias
(sometimes in sick sinus syndrome)
Alfuzosin (see other)
Tamsulosin (see other)
Terazosin (see other)
reduction in afterload
Uses: second line HTN med, used
for pheochromocytoma and pregnancy because of no side effects to fetus
multiple
daily dosing limits usefulness
Side effects: hemolytic anemia (10-20%
develop warm agglutinins; 1-5% develop serious hemolytic anemia; usu. responds
within weeks to months to steroids
Clonidine (Catapresan, Dixarit)
central acting a-2
agonist
Side effects: sedation, bradycardia, rebound HT (when stopped)
Note: can treat clonidine
withdrawal using fentolamine (Regitine), an a-agonist
Yohimbine
anti a-2
agent
cGMP / SMC relaxants / non-selective à reduce both afterload and preload
at lower doses (preload affect > afterload
effect)
Nitroglycerine
(NTG)
dilates veins > arteries
/ tolerance, vasospasm, HA, hypotension
high
doses ( > 1 ug/kg/ ) can get afterload reduction as well as preload
Note: tolerance to
nitroglycerin (but not nitroprusside) develops
Amyl nitrate
volatile liquid, inhaled, rapid action / used for CN
poisoning / Treat overdose with methylene blue?
Isosorbide
dinitrate (Isordil)
stable,
Isosorbide
mononitrate (Imdur)
Sodium nitroprusside (Nipride) [wiki]
IV
only, can use to titrate to exact BP (although in practice, can make BP drop
wildly; more likely to cause coronary (and pulmonary steal)
Side Effects:
·
thiocyanide CNS toxicity after 48-72 hrs (especially with renal
failure)
·
increased ICP (by relaxing cerebral vessels)
·
coronary steal à may divert bloodflow away
from heart / contraindicated for MI
·
lipid peroxidation (brain/liver)
·
ototoxicity – concentration and time dependent
Cyanide à thiocyanate (reaction in liver, excretion by kidneys, requires
thiosulfate)
RBC
cyanide
> 40 nmol/mL (metabolic changes), > 200 (severe symptoms), > 400
(lethal)
§
hydroxocobalamin (B12a) at 25 mg/h reduces toxicity (competes for rhodanase, the
converting enzyme)
§
consider thiosulfate
infusion at doses > 2 mug/kg/min
Complications: cardiac arrest, coma,
seizure, convulsions, focal neurologic abnormalities
Metabolism:
·
CYP3A4 metabolism (only
verapamil/diltiazem are important)
·
verapamil (only) also inhibits P-glycoprotein-mediated drug transport,
increasing
Mechanism:
vasodilation: dihydropyridines or DP’s > others (verapamil,
diltiazem)
verapamil and diltiazem for AF/SVT (slow AV conduction
and SA pacing; DP’s do not have this, which could be due to reflex sympathetic
discharge stimulated by vasodilation or different binding properties)
Uses:
·
Not as good as ACEI for patients with type 2 DM and HTN (they can make
proteinuria worse by increasing IGP)
·
Not
first-line (after B-blockers/ACEI) for post-MI control of HTN
·
Nimodipine for sub-arachnoid hemorrhage (NOT ischemic stroke)
Side effects: verapamil more likely to
cause constipation, lithium neurotoxicity / DPs more likely to
cause gingival hyperplasia / Torsades (up to 3-4% in susceptible patients)
|
|
Peak |
Half-life |
Contract-ility |
class |
AV node |
CO |
Vaso-dilation |
|
|
Amlodipine
(Norvasc) |
6-12 |
30-50 |
|
DP |
- |
|
++ |
|
|
Felodipine
(Plendil) |
2.5-5 |
11-16 |
|
DP |
- |
|
++ |
|
|
Nifedipine
(Procardia) |
0.5 6 |
2-5 |
¯ |
DP |
- |
|
++ |
|
|
Verapamil
(Calan) |
0.5-1 4-6 (AF/SVT) 5-15’ IV |
4-10 |
¯¯ |
DA |
¯¯ |
¯ |
+ |
IV |
|
Diltiazem
(Cardizem) |
0.5-1.5 6-11 (AF/SVT) 5-15’ IV |
3.5-7 |
¯ |
B |
¯ |
-/ |
+ |
IV |
|
Nicardipine |
0.5-2 ? 5-15’ IV |
8 |
|
|
|
|
|
IV |
|
Nisoldipine |
6-12 |
7-12 |
|
|
|
|
|
|
|
Nimodipine |
1 |
1-2 |
|
|
|
|
|
|
Central
cardiac > vasodilation / contraindicated: HF, SA
or AV disease, WPW, hypotension, edema
Metabolism: hepatic with 70% excreted in urine
Side effects: constipation (inhibit SMCs), HA, dizzy, may increase digoxin levels
increased
peripheral action - treats HT and angina / can dramatically increase
Peripheral (Dihydropyridines)
Metabolism: hepatic
Nifedipine (Procardia, Adalat)
peripheral > cardiac / this is the one most often
used for Raynaud’s (connective tissue diseases like CREST) / not used so much
for hypertension because of hypotensive effect (thought to increase risk of
CVA, MI)
(vasospasm) / GI, edema, HA,
pre-labor
Bepridil
Na and Ca blocker / angina
and arrhythmia / unpredictable effects
Vasodilators
Hydralazine (Apresoline) [wiki]
non-selective vasodilator (affects arteries and
veins) / use with nitrates as alternative to ACE for afterload reduction
Side effects: reflex tachycardia,
headache, flushing, SLE-like (25-30%,
somewhat dose-dependent in degree of severity)
Metabolism: individual variation in liver, kidney metabolism
Pharmacokinetics: IV form has initial latent
period of 5 to 15 mins then may have increasing effect up to 12 hrs
Minoxidil (Avacor, Rogaine) [wiki]
Side effects: hirsutism, fluid retention, peripheral edema, pericardial effusion
Sodium nitroprusside (Nipride) (see nitrates)
Diazoxide (Hyperstat, Proglycem) [wiki]
Mechanism: opens K channels (relaxes
arterial smooth muscles and interferes with K coupled insulin secretion)
Uses: given IV in HTN emergency,
given
Side effects: salt and water retention (can use ACE to counter), hyperglycemia (from blocking insulin
secretion, actually used to treat insulinoma),
hyperuricemia
Phentolamine [wiki]
Mechanism: selective DA1
receptor agonist (does not bind α or β receptors)
·
renal vasodilation (may reduce ARF in ICU setting)
·
inhibits Na reabsorption in proximal/distal à diuresis/natriuresis
Uses: only available IV / onset
< 5 mins / alternative to nitroprusside in HTN urgency/emergency / does not
cause rebound on stoppage
Metabolism: liver (not p450)
Drug interactions: Tylenol raises levels
Precautions: may raise intraocular pressure, hypokalemia (can ↓ 3.0 in <
6 hrs)
Not
used much anymore
nondepolarizing
ganglionic blocking on sympathetic/parasympathetics
Side effects: many including
tachyphylaxis within 2 days
Pinacil
requires fewer additional
drugs to counter sympathetic reflex
Mechanism: V2>>>V1 (SMC, CNS)
Used for diabetes insipidus, esophageal bleed, colonic diverticulum / not useful in nephrogenic DI
Pharmacokinetics: inhalant / 15 hr half-life
Drug
interactions:
clofibrate, chlorpropamide (increases ADH sensitivity)
Lysine vasopressin
IV or IN / short acting
Guanethidine
decreased NE, Epi release at
neuron
Side effects: orthostatic
hypotension
blocks NE storage in
vesicles?
Side effects: sedation, nasal congestion, diarrhea
Bosentan
(Tracleer) (see pulmonary)
Ketanserin
[wiki]
Serotonin receptor
antagonist
Class I Class II Class III Class IV Class V
|
|
|
T
½ |
|
|
|
Procainamide |
IA |
3-4,
6 |
prolonged
QRS, QT, (+/-) PR |
|
|
Quinidine
|
IA |
6-11 |
prolonged
QRS, QT, (+/-) PR |
|
|
Mexiletine
|
IB |
10-12 |
- |
|
|
Flecainide
|
IC |
12-26 |
prolonged
QRS, PR |
|
|
Encainide |
IC |
1-2 |
prolonged
QRS, PR |
|
|
Amiodarone |
III |
30-100
days |
prolonged
PR, QRS, QT; sinus bradycardia |
|
|
Sotalol
|
III |
12
hrs |
prolonged
PR, QT |
|
|
|
|
onset |
|
|
Lidocaine |
|
now |
|
|
Bretylium |
|
5
mins (for anti-fibrillation) and up to 2 hrs (ventricle) |
|
|
Procainamide
|
IA |
now |
|
|
Phenytoin |
- |
now |
For
digitalis toxicity |
Ia – Na channel blockers / inhibit rapid inward
current / prolong repolarization
Ib – Na channel blockers / inhibit rapid inward
current / accelerate repolarization
Ic – Na channel blockers / inhibit rapid inward
current / no effect on repolarization
II – B-blockers / accelerate repolarization / reduce
ischemia / reduce sympathetic arrhythmogenicity
III – potassium channel blockers / prolong action
potential duration
IV – calcium channel blockers / depress slow inward
current
Most require renal dose
adjustment
Quinidine (Ia) [wiki]
Mechanisms: binds inactive Na channels (slows
action potential) / state dependent decreased K channel function / actually
increases AV conduction increased
refractory period / directly slows SA, but vagolytic action compensates
(normal net rhythm)
Uses: ventricular or
super-ventricular arrhythmias (use with digitalis or B-blocker for rate
control)
Side effects: QT
prolongation, broad QRS, arrhythmia, diarrhea,
decreased contractility, type I reaction, cinchonism, pleural effusion, raises
digitalis level (displacement and decreased excretion inhibition of
P-glycoprotein-mediated excretion via renal, liver, GI)
Inhibits CYP 2D6 and CYP 3A4
Procainamide (Ia) [wiki]
not vagolytic (may suppress SA and AV node without
compensation) / fewer GI effects more negative inotropism (blocks ganglionic
activity)
Side effects: SLE-like
hypersensitivity (50-75% within a few months)
Disopyramide (Ia) [wiki]
parasympathetolytic (contraindicated in glaucoma) /
very negative inotrope (peripheral vasoconstriction, contraindicated in
CHF) / oral
IV only for ventricular
arrhythmias associated with MI / fast Na(I) binder (only shortens
refractory period by decreasing phase 0 depolarization, no K activity) / no vagal
effects / does not slow conduction as much (no effect on SA, AV rhythm) or
decrease ventricular function
Side effects
·
mental status changes (confusion,
lethargy, dysarthria, dysesthesia,
and coma)
· seizures (esp. older patients and rapid bolus)
·
decreased cardiac
function (also decreases clearance) / sinus node dysfunction
Tocainide (Ib)
long term ventricular arrhythmias /
Mexilitene – (Ib) [wiki]
neutropenia
Phenytoin
(Dilantin)
(Ib) (see psycdrug)
children with ventricular arrhythmias / teratogenic
Flecainide (Ic) Side effects: CHF
Encainide (Ic) Side effects: proarrhythmia
B-blockers (class II) (see other)
Propranolol, acebutolol /
prevent ventricular arrhythmias
associated with MI
Blocks IK and also has class II activity
(half maximal at 80 and maximal at 320 mg/day) / FDA approved for SVT (Afib,
AVNRT, AT) and VT, Vfib, Vflutter (more effective than lidocaine)
Mainly
renal excretion / Half-life 10-15 hrs
Side effects: new or worse VT in 4% (including dose-dependent torsades)
Mechanism: K channel blocker / prolongs phase 3
repolarization (plateau phase) thus prolonging refractory period of atria and
ventricles / (in theory, this may increase contractility)
When changes from one agent to another (e.g.
amiodarone to something else), try to give time to let first drug washout of
system before starting new one (this time will vary for different agents). Also
some agents require a certain number of days of telemetry when initiating.
Amiodarone (Cordarone) [wiki]
also has class I, II, IV activity / depresses
conduction at fast more than slow rates, reduces sinus/junctional rate and
prolongs AV conduction,
Note: long term anti-arrhythmic action depends on
buildup of metabolites (onset up to 6 wks) / 30 - 50 day half-life / only ½ will tolerate
IV: peripheral coronary
vasodilator - decreases HR, SVR,
PO: less effects on
ECG changes: prolongs QT (less than
others; common; usu. responds to dose-reduction), can cause U waves, prolongs
PR, widened QRS (more with IV)
Uses:
·
atrial fibrillation: chronic prevention
·
ventricular tachyarrhythmias: does not increase or
decrease mortality rates for symptomatic ventricular arrhythmias in patients
with depressed ventricular function (may, however, help prevent sudden death
from non-ischemia related ventricular tachycardias)
Side effects: some are dose-dependent,
less common < 200 mg/d, occur in 75% / necessitate stopping in 10-20% by first
year of use / pulmonary > GI
·
Cardiac: symptomatic bradycardia
(2%) (usu. dose-related)
·
Lungs: interstitial pneumonitis
leads to pulmonary fibrosis (5%, onset in 6 days – 60 months, usu.
> 1 month and (cumulative) dose dependent (> 400 mg) / lung changes
(start in upper, asymmetric, effusion uncommon, pleuritic pain in 10%, elevated
ESR, negative ANA), characteristic CT changes (can get dense lesions) [pic]
·
CNS (30%): ataxia, tremor,
peripheral neuropathy, insomnia, impaired memory
·
hyperthyroidism (1-2%)
·
hypothyroidism (5 to 20%)
·
hepatic toxicity (nonalcoholic steatohepatitis)
·
photosensitivity and skin discoloration (cumulative
dose)
·
optic neuritis (rare), alopecia (rare)
Contraindications: liver disease, pregnancy,
lung disease, severe sinus-node dysfunction
Clinical: before starting check LFT,
thyroid (and q 6 months), PFT, CXR (then annually), EKG (then get regular EKGs
for a while) / also decrease warfarin dose by 25% when loading and gradually
increase as needed
Bretylium [wiki]
IV only for ventricular fibrillation
/ increases catecholamines (used for hypotension)
Side effects: initial hypertension but
later causes severe orthostatic
hypotension (persists for days after drug stopped)
Requires renal dose-adjustment
blocks IK and also slow INA
(lowers sinus rate)
30% to 45% success converting atrial fibrillation, 100% if used with DC conversion / can be used with EF 25-30%
Side effects: danger of torsades de
pointes (4-8%) only mainly just during first 8 hrs (increased risk for female,
long QT, hypokalemia, hypomagnesemia)
given IV / mostly renal clearance
blocks only rapid IK / approved for chemical conversion of Afib
and chronic suppression of Afib
Side effects: prolonged QT (torsades in 2-4%) / monitor for 2 days in
hospital for initiation
Half-life 7-13 hrs / urinary
excretion 60%, hepatic 40% / available as
pending
approval /
blocks rapid and slow IK IV or
Ca blockers (class IV)
better for atrial rather than ventricular / gCa
dependent: slows nodal conduction (phase 4,2) more than myocardial (phase 0) /
negative inotrope
Side effects: gives many patients a
variable degree of edema which resolves
with renal compensation
P1 receptors in AV node / negative Ca inotrope /
used to either break or briefly slow down and help identify certain SVTs (PAT,
AVNRT), not supposed to break Afib/flutter
Dosing: given as IV bolus of 6 mg
and if needed, 12 mg / duration 15-30 second (although metabolism inhibited by dipyramidole)
Side effects: brief asystole [very
frightening to patient], flushing, chest pain
Treatment of Specific
Cardiovascular Conditions
HTN crisis (see other)
Labetalol (for added a blockade)
Nitroprusside
Procardia (most potent)
Nitroglycerin reduces preload more than afterload and should be used with caution or avoided in patients who have inferior MI with right ventricular infarction and are dependent on preload to maintain cardiac output
Vasodilators for CHF à lower LVEDP may increase subendocardial
perfusion (more for systolic heart failure)
Ca channel blockers are more for diastolic heart
failure
vasodilators do not help with pure diastolic heart
failure
Sit up, dangle legs
Morphine – decreases anxiety, reduces PCWP
Furosemide – diuresis, IV also provides immediate
venodilation
IV nitro – afterload reduction
Inotropic support for systolic failure
Albuterol/atrovent nebs for cardiac wheeze
Acute Coronary
Occlusion
(see other)
Peripheral
Vascular Disease (PVD)
Cilostazol
PDE inhibitor with
vasodilatory and antiplatelet properties
1st
line (ahead of Trental) for PVD
Side
effects: headache, diarrhea, palpitations, dizziness / contraindicated with
heart failure
ASA / Plavix / Anti-2B3A / Hirudin
/ Heparin
/ Lovenox
/ Warfarin
/ AA
Platelet Aggregation
vWF + platelet glycoprotein
1B à release of thromboxane A2 and ADP
glycoprotein
IIB/IIIa receptors recognize fibrinogen
Mechanism: irreversibly inhibits
COX-1,2 (TXA2) / inhibits platelet and WBC interactions
Onset/Duration: peak effect by 1 hour / duration 1-2 weeks (life of platelet)
Side effects: GI ulcers, systemic
bleeding / rare: Reye’s syndrome / overdose: severe mixed triple acid base (1o
metabolic acidosis and respiratory alkalosis; can be very severe in infants)
Dosing: increased benefit of 325 mg
for prevention of MI may be outweighed by increased risk of GI bleed; general
rule is 81 mg for prevention, 325 mg w/ known CAD
Note: aspirin resistance occurs
in 20% of people; Plavix may be especially useful in these patients
Uses: MI prevention, CVA
prevention, AFIB in patients < 65 yrs with no structural heart abnormalities
or other risk factors (which would require coumadin)
Trends:
6/06 low-dose ASA for healthy women 50-65 shown
little CAD benefit, mild stroke prevention, but cancelled out by increase GI
bleed // so recommendation is maybe don’t give to this population
6/06 debate on usefulness in decreasing colon CA
risk (not shown at normal cardiac doses, however)
Clopidrogel
bisulfate (Plavix)
inhibits
ADP-induced platelet aggregation
Uses:
·
post-stenting to prevent in-stent restenosis [these guidelines are
constantly shifting] [annals]
·
primary or secondary stroke prevention (CAPRIE à ARR from 8% to 7% versus
ASA)
Side effects: increased bleeding risk, can cause TTP (very rare)
Trends: AIM 7/07 suggest ASA + PPI
safer than plavix for pts with NSAID ulcers (only if need for plavix is
relative) // plavix may impair healing of ulcers by suppressing release of
PDGF’s
Mechanism: increases cAMP 1) impairs platelet aggregation 2) causes
arteriolar vasodilation
Aggrenox =
ASA + dipyramidole
used
in secondary stroke prevention (ESPRIT trial), also used in chemical stress
tests (in conjunction with thallium or sestamibi)
Uses: acute coronary syndrome to
reduce risk of infarction and during/after PTCA w/ stenting
Note: especially beneficial for
acute coronary syndrome in diabetic patients (26% reduction in 30-day mortality
rate)
monoclonal
antibody
Eptifibatide (Integrelin) [wiki]
can
cause thrombocytopenia (sometimes acute because for naturally occurring
antibodies to IIbIIIa and formation of neoepitopes)
Agrestat (LMW)
Anti-IIa and/or Xa Agents
Mechanism: binds alpha-2-antithrombin
(Antithrombin III), which then inactivates IIa and Xa
Labs: increases aPTT (intrinsic) >> PT
Metabolism: 1-5 hr half-life /
increased activity with renal, liver disease / does not cross placenta
Side effects: early/paradoxical
thrombosis (abrupt discontinuation makes it worse)
Other side
effects:
HIT syndrome (see other), ?hyperkalemia (via decreased aldosterone action), skin necrosis, osteoporosis (6 months onset,
osteoclast activation, occurs in 2%, give Ca supplements)
Overdose: use protamine to bind heparin (do diabetics have more adverse reactions
with protamine?)
Studies have proven efficacy for DVT (some say not formally proven for PE,
but many people use anyway)
Mechanism: inhibits Xa more than IIa
LMW heparin - 30 or 60 mg
given SC/IV (not IM) / peak 3-5 hrs / half-life 4-5 hrs
(12 hrs duration) / reduce dose for renal impairment
(people tend to avoid using with creatinine > 2.0)
APPT and PT are not altered / less platelet
inhibition (less microvascular bleeding), and thrombocytopenia (from HIT) is
less frequent and severe (less platelet factor 4 interaction)
Dose: can measure target plasma
heparin level (0.3 to 0.7 U/ml) at 4-6 hrs post-dose
Overdose: does protamine help? / give amount equal to dose of Lovenox injected
once
daily anti-Xa (like Lovenox) / same uses / studies ongoing
Dalteparin
(Fragmin) [wiki]
Fondaparinux (Arixtra) [wiki]
anti-factor Xa / approved for prevention of DVTs
Danaproid
(Orgaran)
LMWH heparin /anti-Xa / supposedly less cross-reactive to heparin /
not marketed in US?
Dermatan sulfate (heparinoid with anti-Xa activity)
Others: Dabigatran, Defibrotide,
Rivaroxaban
Direct
thrombin inhibitors
direct thrombin inhibitor / useful for patients with
HIT antibodies / different method of monitoring activity than with heparin
Lepirudin (recombinant Hirudin) [wiki]
IV or SC / short half-life / contraindicated in
renal failure (GFR < 60) / no effective antidote / 40% develop antibodies
against it (decreases renal clearance)
Dabigatran (Rendix) [wiki]
can
be taken orally / may some day replace warfarin in some clinical situations
Argatroban [wiki]
hepatically
cleared / safe for renal disease
Ximelagatran à same
idea / failed due to too much liver toxicity
Others: Bivalirudin, Desirudin, Melagatran
competitive inhibitor of vitamin K reductase
/ prevents y-carboxylation of II, VII,
IX, X
PT (extrinsic) >> PTT [diagram of clotting cascade]
Side effects: may unmask underlying
protein C/S deficiency, coumadin skin necrosis /
teratogenic
Metabolism: onset may takes several
days (~3) / long-term agent / activity depends on vitamin K level (green vegetables
increase, antibiotics decrease), liver enzymes, plasma protein displacement (e.g.
NSAIDs) / be careful starting elderly patients (perhaps 7.5 or 5 then 2.5
rather than 10 then 5)
Therapeutic
aim (INR):
atrial fibrillation, severe
CHF, DVT/PE à 2 to 3
SLE/APA syndrome à 3 to 3.5
prosthetic valve à 2.5 to 3.5
Drug interactions: CYP2C9 and CYP1A2
Increase
effects:
some antibiotics (ciprofloxacin;
high), NSAIDs (mild) cimetidine, omeprazole,
a-methyldopa, quinidine, anabolic steroids, phenylbutazone, thyroxine,
sulfinpyrazone, clofibrate, ?gingko biloba
Decrease effects: vitamin K, antihistamines, certain antacids, rifampin,
cholestyramine,
barbiturates, griseofulvin
Note: NSAIDs, history of CVA,
older age and INR > 4.0 increases
risk of bleeding complications / INR > 8, 10% will have serious bleeds
Reversal:
hemorrhagic strokes evolve during 24 hrs in 50% on
warfarin and 10% controls / so start giving FFP and vitamin K and call heme/onc
immediately with life-threatening hemorrhage
·
FFP
8-15 ml/kg / does not always
correct INR < 1.3
·
Prothrombin (II, IX, X)
works faster (?6 to 14 hrs), brings down INR more
completely, and might have a lower complication rate for immediate reversal /
25-50 units/kg based on factor IX content
(use fixed dose since INR is insensitive to factor IX level)
·
vitamin K1 (phytomenadione)
given 5 to 20 mg IM/PO (not IV) / onset of action 4
to 6 hrs (may take longer) / (vitamin K1, given in small doses to step-down
anticoagulation) / Note: avoid IV vitamin K if possible, as it tends to cause
more allergic reaction (from added preservative)
prevents plasminogen from
binding to fibrin / used for DIC
Lyses clots but also activates platelets (give with
antithrombin and aspirin)
Risk of bleed (main concern is ICH): ~2%
Contraindications to thrombolytic therapy
Absolute
hypertension ( > 180/110, 14x risk of CNS bleed)
/ ?200/120
active bleeding, defective hemostasis (bleeding
disorder)
recent major trauma (less than 2-4 weeks), extensive
CPR
surgical procedure (less than 10 days ago)
invasive procedure (less than 10 days ago) (e.g.
hepatic/renal biopsy)
neurosurgical procedure (less than 2 months)
GI/GU bleed (less than 6 months)
hemorrhagic stroke or TIA (less than 12 months)
history of CNS tumor/aneurysm/AVM
acute pericarditis
aortic dissection (or suspected)
active PUD/IBD/cavitary lung disease
pregnancy
prolonged CPR
allergy to agent/prior reaction
Relative
recent SBP > 180, diastolic > 110 (>2
readings)
bacterial endocarditis
diabetic retinopathy (hemorrhagic)
history of intraocular bleed
stroke or TIA over 12 months ago
Tissue
Plasminogen Activator or tPA
binds fibrin, activates fibrin-bound plasminogen to
plasmin / onset 45 mins / debate ongoing as to which patients should go to
angioplasty versus thrombolysis [NEJM] / not antigenic; can be
given multiple times
Alteplase [wiki]
approved for use in massive PE; given
along w/ heparin / risk of ICH about 3%
acts more quickly (25-30
mins) / longer half-life than alteplase (13-16 mins)
Streptokinase – no longer manufactured
B-hemolytic Strep protein / loading dose
to overcome IgG / anti-streplase is combination of streptokinase and
plasminogen (targets to clot) / should not be given a second time within a year
(?Ab production?)
Less successful as clot ages – 1st hr – 60-75% success – 5
hrs – less than 1/3 success
Trends: no longer recommended for treatment of complicated pneumonia
(pleural infection/loculation/decortication) 9/06 AIM
Urokinase
expensive and non-selective / bah-humbug
Criteria (for use in sepsis): symptoms
< 24 hrs duration, patient expected to survive, infection being treated, at
least 3 of 4 SIRS criteria met (T > 38, HR > 90, RR > 20, WBC >
12), one or more of following end-organ dysfunction present (CV, pulmonary,
renal, < 80 platelets, pH < 7.30)
Contraindications: active internal bleeding,
recent hemorrhagic or ischemic CVA, trauma with increased bleed risk, < 12
hrs post-general or spinal anesthesia, + epidural catheter, CNS (mass
lesion/tumor/aneurysm/AVM), platelets < 30, INR > 3.0, < 6 mo GI bleed,
< 3 d. thrombolysis, recent coumadin or IIb/IIIa inhibitors or ASA, known
bleeding diathesis
Not studied (in PROWESS trial): stem
cell and solid organ transplants, CD4 < 50, pregnancy, ESRD, liver failure,
protein C/S/ATIII deficiency
HMGCoA reductase inhibitors (Statins)
Lipid effect: ↓ LDL, ↑ HDL,
↓TG [all to varying degrees]
Other CAD effects
·
Acute: may
improve vasodilatory tone via NO pathways
·
Plaque
stabilization (not regression)
Side effects: < 1% risk of myopathy
(can look like PM), lovastatin may be worse, can also get rhabdomyolysis, liver toxicity
(1-2%), ?cataracts
Pharmacokinetics: levels increased by diltiazem
Dose effects: some say doubling dose can
decrease LDL by additional 6%
Trends: 6/06 toward maximizing
dose of statins for known CAD
Lovastatin
Supposed
to be more myopathy
Simvastatin
Pravastatin
(Pravachol)
Some
say pravachol may be less liver toxic
Atorvastatin
(Lipitor)
50% risk reduction for MI
has been proven
Probucol
anti-oxidant, prevents foam
cells, decrease ↓ LDL /
decrease ↓ HDL, diarrhea
Fibrates
Gemfibrozil
increased LPL production,
increase ↑ HDL, decrease ↓ TG, LDL
Side effects: GI upset, rash, high mortality / Fenofibrate (new drug)
Drug interactions: can cause ?proximal muscle weakness when used with
HMGCoA reductase inhibitors / some say it is not
unsafe to combine statins w/ fibrates
Clofibrate
3rd line / increased LPL
activity, decreased LDL, TG / Drug interactions: displaces
warfarin, inhibits platelet
aggregation, increases sensitivity to ADH, higher risk of
myopathy / high mortality
Other
For increasing HDL: niacin >
fibrates > statins
increases ↑ HDL (10-30%), decreases ↓ LDL
Mechanism: blocks adipocyte lipolysis, blocks liver synthesis of TG
Side effects: flushing (supposedly can be reduced by taking ASA just prior),
pruritis, GI ulcer, jaundice, glucose intolerance, uricemia
newer generation of cholestyramine / not absorbed so
no direct side effects / benefit may be additive with statins
Cholestyramine
Drug interactions: digitalis, tetracycline, hydrocortisone,
warfarin, thiazides, iron,
phenobarbital, thyroxine /
decreases LDL
Neomycin
2nd
line bile-acid sequestrant / nausea, diarrhea, nephrotoxic, ototoxic
decreased TG (inhibits synthesis), anti-platelet
aggregation, anti-inflammatory (N-3 FA competes with N-6 FA for cox, lox),
hypotensive
Vitamin E
anti-oxidant
/ 800 IU/day // 6/06 AIM says no benefit (high doses even shown to
increase all-cause mortality)
·
can worsen hyperglycemia (in diabetes)
·
can worsen hyperuricemia
site 1 diuretic / blocks carbonic anhydrate / used
for epilepsy, acute mountain sickness, to alkalinize
urine, glaucoma (2nd
line)
Side effects: acidosis, neuropathy, NH3
toxicity, sulfa allergies
Mechanism: site 2 (tri-transporter of
TAL) / acts on tubule side
Pharm: 50 hr half-life, 6 hours
duration of action
Uses: edema, hypercalcemia
(temporary treatment), hypertension (w/ decreased RBF) / has immediate vasodilatory action (when given IV
acute heart failure)
Side effects: weakness, nausea,
dizziness
hypokalemia from K diuresis (use w/ K sparing agent)
metabolic
alkalosis (excretion of Cl, H, K), circulatory collapse, hyperglycemia and
hyperuricemia, renal stones from
hypercalciuria
Drug
interactions:
ototoxic drugs (AGs) or aspirin (inhibits vasodilatory effect)
/ may cause interstitial nephritis, sulfa group allergic reaction causes
highly albumin
bound
(displaces propranolol)
contraindications: DM (increases TG and hyperglycemia) / increases excretion: Na, K,
H, Ca, Cl, Mg / decreases excretion:
urate, Li
use if allergic to
furosemide / less hyperglycemia (better for diabetics)
Ethacrynic
acid
NO sulfonamide group (less allergies) / more GI
upset, less hyperglycemia steeper dose-response curve / hyperuricemia,
ototoxicity (irreversible), skin rash, granulocytopenia
2x bioavailability of
furosemide / increased half-life allows QD dosing
Hydrochlorothiazide
(HCTZ) [wiki]
Mechanism: block Na/Cl co-transporter
in distal collecting duct/ requires GFR above 30
Effects:
·
can cause hypokalemia (via diuresis)
·
increased Ca retention (increases sensitivity to
PTH)
·
increased urate, Li retention (more than site 2 drugs)
·
increased glucose, cholesterol, TG
·
lowers BP by mechanism apart from diuretic effect
Uses: HTN (often given as 1st line in uncomplicated HTN but
this seems to always be debated; depends on patient), cardiovascular,
hypocalcemia, hypercalciuria, diabetes insipidus
(believed to limit kidney’s ability to dilute the urine)
Side Effects: ↓K, ↑Ca as per
its mechanism of action, also has sulfa component (triggers sulfa allergy in
some patients)
Note: shown to be protective
against hip fracture due to hypercalemia (while taking + 4 months)
Metolazone
(Zaroxylin) [wiki]
similar to thiazide diuretics, often used in
combination with loop when patient is refractory (“Lasix with a metolazone
chaser”) / may be better for renal insufficiency?
Side effects
(rare): aplastic
anemia, pancreatitis, agranulocytosis, and angioedema
Benzthiazide [wiki]
Indapamide [wiki]
Spironolactone (Aldactone) [wiki]
competitive inhibitor of aldosterone (use for Conn’s
syndrome, PCOS)
Side effects: acidosis, hyperkalemia,
gynecomastia (metabolite competes for androgen binding site), impotence (in
males)
Contraindications: diabetes mellitus, renal disease,
potential teratogen
Eplerenone
(Inspra) [wiki]
similar
to spironolactone
Amiloride [wiki]
blocks tubular Na channel / resulting hyperkalemia
cannot be countered with endogenous aldosterone / excreted unchanged by kidney
/ increased serum Li and urate / may also decrease Mg2+ wasting from
cisplatin
toxicity
Triamterene [wiki]
only
oral / shorter half-life / rare nephrotoxicity with indomethacin
filtered but not reabsorbed / countercurrent
washout, prevent mannitol (IV) tubular reabsorption / used to decrease ICP,
IOP, prevent acute glycerol (IV/PO) renal failure (may get CNS edema as a
sequelae of partial diffusion isosorbide (IV/PO) across BBB
Contraindications: anuria, peripheral edema,
heart failure, dehydration / isosorbide may be better for IOP reduction
Newer
line phosphate binders
SODIUM
BALANCE
tetracycline derivative /
blocks ADH function in tubule (mechanism unresolved)
Uses: SIADH
Side effects: azotemia, hypersensitivity to sun, decreased GI absorption of
antacids, milk, Vitamins
Dose:
600 mg (divided doses bid/tid) / renal dosing
Lithium (see other)
blocks
aquaporin induction by antagonizing cAMP / SIADH
AT II
IP3/DAG / vasoconstriction,
aldosterone production, increased thirst
ANP
cGMP / vasodilation,
decreased aldosterone, increased GFR
Fludrocortisone (Florinef) [wiki]
Synthetic mineralocorticoid
Uses:
replacement / use in combination with glucocorticoid for broad adrenal
insufficiency (as with hydrocortisone, must increase
dose with intercurrent illness/stress)
Note: escape phenomenon prevents
sodium retention beyond 15 days, but K excretion continues / aldosterone also
promotes H ion excretion
Sodium Bicarbonate
Use in code
setting:
generally thought not to be so useful, however, definitely still first line for
TCA overdose
NSAIDs okay
for pain relief unless PUD or renal disease
ASA bad
/ blocks tubular secretion of urate
competes for urate transporters / low dose causes
retention, high dose causes excretion
acts on filtrate side of tubule to block
reabsorption
Uses: mild gout (usu. only with
young patients)decrease clearance of penicillin
in GC
Contraindications: active renal stones
Drug
interactions:
ASA blocks urate secretion (ruins efficacy of probenecid) / uricosuric effect
is additive with sylfinpyrazone
Sulfinpyrazone
much higher GI side effects / less hypersensitivity
/ 2nd line / some anti-thrombotic properties (unknown mechanism)
Do not give during acute gout attack (any acute
change in uric acid level is bad)
Mechanism: metabolized by xanthine
oxidase (XO) to alloxanthine à inhibits XO
Uses: gout patients with
renal stones or renal disease, prevention of tumor lysis syndrome
Side effects (5%): fever, leukocytosis,
GI, liver, renal dysfunction, pruritic skin rash
Uses: prevents attacks of gout / can be
given safely during acute attack
Mechanism: impairs chemotaxis and phagocytosis by binding tubulin
Side effects: hard to take at high
doses, diarrhea and abdominal pain, many other adverse effects / can cause
myopathy (proximal muscle weakness, elevated CK, vacuolar myopathy)
Drug
interactions:
careful with NSAIDS, cyclosporine etc.
Uricase
metabolizes uric acid (like birds) into allantoins
(harmless?)
used for tumor lysis syndrome
? gout
muscarinic cholinergic antagonist (M1, M2, M3) /
applied locally to reduce secretions / inhaled for asthma / additive with B2
agonists
comes off M2 receptor more rapidly
(same on M1, M3); somehow this is better
Epinephrine
topical / may cause rebound congestion, rhinitis
medicamentosa / oxymetazoline / oral
(phenylpropanolamine, pseudoephedrine) / be careful
with hypertension, phenylephrine
hyperthyroid, diabetes mellitus
Uses: specific uses listed
separately
Mechanism: [diagram]
·
inhibit PLA2 and blocks formation of arachidonic acid (leukotrienes and
PG/PC)
·
causes metabolic alkalosis
·
depress immune response
·
suppresses hypothalamic-pituitary axis
·
decreases mucous production
Side effects:
muscle wasting
thin skin, bruisability, ulcers
Cushingoid (central obesity, moon face, acne,
hirsutism)
Bone
osteoporosis (get BMD via DEXA scans /
Ca, vitamin D, Evista, bisphosphonates
AVN
(hip, knee)
Eyes: cataracts, glaucoma
Neuro: depression, psychosis
(uncommon)
Infection 2x risk usually at >
10mg/d (esp. PCP)
Hyperglycemia 4x
risk of diabetes in long term
Hypertension
Growth retardation
myopathy normal
EMG
pseudotumor cerebri fluid
shifts
Withdrawal
syndrome:
depression, weight loss, nausea, HA, malaise, desquamation, fever, arthralgia,
myalgia (proximal, lasts 3-5 days)
·
Adrenal suppression usually does not occur with
< 7 days (regardless of dose), but with longer term therapy (>2 weeks),
complete HPA recovery may take up to several weeks
Lab tests:
·
urinary free cortisol
gives rough idea but cannot use cortisol levels to
assess HPA axis / ½ of patients with impaired HPA axis may still have normal
free cortisol level / must have random level > 20 mg/dl / ACTH test (check
baseline cortisol then 30 and 60 mins after injection of cosyntropin),
hypoglycemia, metyrapone (11-hydroxylase inhibitor)
·
ACTH stim test
check baseline cortisol then 30 and 60 mins after
injection of cosyntropin; a rise > 20 rules out adrenal insufficiency / must
not be off steroids for test (except dexamethasone)
Potency: hydrocortisone <<
prednisone < solumedrol <<< dexamethasone (1 : 4 : 5 : 30)
Hydrocortisone (Solucortef)
best choice for stress dose
steroids (given SC BID)
does not need to be de-methylated by liver /
best choice for liver disease
Dexamethasone
used to decrease CNS inflammation (various
indications), does not cross-react with free-cortisol test (can still do
ACTH stim test while on dexamethasone)
Inhaled
Steroids
For persistent asthma (of any severity) / given bid
Mechanism: increase B2 number and
sensitivity
Metabolism: 1-2 wk onset / rapidly metabolized / use
a spacer to try to avoid recurrent oral Candida infections
Side effects: low-doses do not have systemic effects
/ higher doses shown to increase open-angle glaucoma / effects on
osteoporosis being studied / low-doses safe for pregnancy
Beclomethasone
Triamcinolone
acetate
Only
inhaled steroid proven effective with once-daily dosing
inhaled, eye, nose drops / 1-2 wk onset / prevents
histamine release (blocks IgE action
on mast cell?) / block the early and late responses to allergens
/ used for maintenance therapy (but some say can help in exercise-induced
asthma if used immediately before) / safest of all antiasthmatic drugs
Nedocromil
inhibits resident cells / inhibits WBC chemotaxis /
3-4 day onset / unpleasant taste
epinephrine alpha,
Beta agonist / short acting, inhaled or SC
isoproterenol B1,
B2 / short acting, inhaled
metaproterenol B2
> B1 / long acting, inhaled or
terbutaline B2
> B1 / long acting, inhaled, SC,
salmeterol B2
> B1 / very slow onset, longer acting, inhaled
formoterol same
(newer)
Side effects: vasoconstriction, cardiac
stimulation, skeletal muscle tremor, refractoriness (must switch agents), masks disease progression
Trends: long-acting B2 agonists have come under scrutiny 7/06 for possibly increasing
mortality (in black asthmatics) / LABA – may actually
be harmful for subgroup with specific genotype (mostly in black population;
reasons for this are somewhat unclear) / many still advocate combination
low-dose inhaled steroids + long-acting B-agonist as effective therapy 10/06
Theophylline, aminophylline
(methylxanthines)
block adenosine receptors (PDE inhibitor), relax airway SMC, increase
clearance, stimulate medullary respiratory center, strengthen diaphragm and
more / acute asthma if B2 fails, maintain pt with chronic asthma, recurrent apnea of prematurity
Side effects: HA, anxiety, insomnia,
tremor, convulsions, cardiac arrhythmia (MAT) / very narrow TI (must titrate dose over
weeks) / metabolized by liver, renal excretion (depends on disease, drugs,
diet)
Pirfenidone
Anti-inflammatory,
anti-oxidant, anti-fibrotic effects / may be showing some promise in reducing
progression of IPF
Morphine
Analgesic effects: Mu (CNS analgesia,
respiratory depression, euphoria, constipation) / delta (spinal analgesia) decrease cAMP via G-proteins /
pre-synaptic (decrease Ca channel fxn) / post-synaptic (opens K channel)
·
cellular
tolerance to analgesia, respiratory depression, euphoria, NOT constipation
Other effects
·
respiratory depression: direct inhibition / decrease CO2 sensitivity
·
Hypotension
o
decreased vasomotor function and histamine release (used
in acute CHF)
o
pools blood in splanchnic circulation (out of lungs)
o
reduces sympathetic tachypnea reflex (reducing the work of breathing)
·
miosis: stimulates Edinger-Wesphal nucleus
Contraindications: head trauma (increased CO2
causes vasodilation, hemorrhage), pregnancy (prolonged labor)
nausea
and vomiting: initial stimulation of CTZ, later inhibition
