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Pharmacology

 

Cardiovascular

     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

Lipid          

Diuretics

Pulmonary                Renal                            

Rheum                     

Endocrine                 Diabetes, Hormone, Thyroid

GI                               Antacid / Pro/Anti-Emetics / Prokinetic

Urology

Neuro                        Seizure / Parkinson’s / Psychopharmacology / Headaches

Ophthalmology

Chemotherapy                   Transplant           Bone           Urate         

Antibiotics                

     anti-fungal

     anti-viral              [HIV meds]

     anti-parasite

 

Narcotics / Anesthesia       Poisoning / Environmental / Chelators

 

Pharmacokinetics    Toxicity (teratogens)       Homeopathic         Vaccination

 

1 Tsp = 15 ml

1 oz = 30 ml

 

 

Cardiac drugs

 

Positive Inotropes: Digoxin, Milrinone

Pressors: Dopamine

 

Anti-HTN

ACE inhibitors, B-blockers, alpha blockers, Ca channel blockers, nitrates          

 

Anti-Arrhythmia (class I, II, III, IV)

 

CHF           

Hypertensive crisis

Pulmonary edema

 

 

Pressors [see positive inotropes below]

 

 

 

Dose

HR

Contractility

Vasoconstriction

Vasodilation

Dopamine

1-20 mcg/kg/min

1+

1+

0

1+

Dobutamine

2.5-15 mcg/kg/min

1-2+

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

 

Positive Inotropes

 

Dopamine

            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)

 

Milrinone

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

 

 

Cardiac glycosides

 

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

            Side effects/Toxicity

·        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

 

Anti-Hypertensive Agents

 

 

                     

preload reduction

afterload

reduction

ACE inhibitors 

++

++

Calcium Channel Blockers

+

+++

B-blockers

+

++

Hydralazine, minoxidil, diazoxide

+

+++

Nitroglycerine, isosorbide dinitrate

+++

+

Nitroprusside

+++

+++

 

ACE inhibitors

 

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

·        Renal / DM / HTN / (and probably any form of) proteinuria

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 - ?

·        Lungs

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

2 hrs

 

 

 

 

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

 

Losartan (Cozaar)

AT 1 receptor antagonist / 2 hr onset / p450 metabolized (use valsartan with liver disease) /

 

Irbesartan (Avapro)

 

Candasartan (Atacand)

 

Valsartan (Diovan)

 

Eprosartan (Teveten)

 

B-blockers

 

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, CHF, MI AF

50-200 mg/d

Metoprolol

3-4

Liver

b1

Y

HTN, CHF, MI AF

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

 

Metoprolol (Lopressor)

has been shown to reduce mortality in CAD, CHF

 

Toprol XL

Long acting metoprolol

Note: 50 mg Toprol XL qd = 25 mg metoprolol bid (same drug!) = 25 mg atenolol qd

 

Atenolol (Tenormin)

            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 PO

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

 

Bucindolol

            Forget it

 

Pindolol (Visken)

As different effects on different aspects of cardiac conduction system / used by EP specialists in certain types of arrhythmias (sometimes in sick sinus syndrome)

 

Alpha blockers

 

a-1 blockers (see BPH)

 

Alfuzosin (see other)

Tamsulosin (see other)

Terazosin (see other)

 

Prazosin (Minipress) [wiki]

reduction in afterload

 

Doxazosin (Cardura) [wiki]

 

Methyldopa (Aldomet) [wiki]

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

 

 

a-2 blockers (see BPH)

 

Clonidine (Catapresan, Dixarit)

central acting a-2 agonist

Onset: 30 mins to 2 hrs / duration: 6 to 8 hrs

Side effects: sedation, bradycardia, rebound HT (when stopped)

Note: can treat clonidine withdrawal using fentolamine (Regitine), an a-agonist

 

Yohimbine                  

anti a-2 agent

 

Nitrates

 

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, PO, used during nitrate “holiday”

 

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

 

Ca channel blockers

 

Metabolism:

·        CYP3A4 metabolism (only verapamil/diltiazem are important)

·        verapamil (only) also inhibits P-glycoprotein-mediated drug transport, increasing PO absorption of cyclosporine and elevating digitalis levels (itra/ketoconazole does this too)

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

 

Verapamil (Calan) [wiki]

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

 

Diltiazem (Cardizem) [wiki]

increased peripheral action - treats HT and angina / can dramatically increase

 

Peripheral (Dihydropyridines)

 

Amlodipine (Norvasc) [wiki]

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)

 

Felodipine (Plendil)

(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 PO for HTN

Side effects: salt and water retention (can use ACE to counter), hyperglycemia (from blocking insulin secretion, actually used to treat insulinoma), hyperuricemia

 

Phentolamine [wiki]   

 

           

Other Antihypertensives

 

Fenoldopam (Corlopam)

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)

 

Trimethaphan [wiki]  

                        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

 

Desmopressin (DDAVP) [wiki]        

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

 

Reserpine [wiki]                    

blocks NE storage in vesicles?

Side effects: sedation, nasal congestion, diarrhea

 

            Bosentan (Tracleer) (see pulmonary)

 

            Ketanserin [wiki]       

                        Serotonin receptor antagonist

 

 

Anti-Arrhythmia Agents

 

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

 

Class I agents

 

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

 

Lidocaine (Ib) [wiki]  

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

Drug interactions: propranolol increases levels / cimetidine decreases liver metabolism

 

Tocainide (Ib)

long term ventricular arrhythmias / PO / CNS (sedation, tremor, seizures), GI upset, pulmonary fibrosis

 

Mexilitene – (Ib) [wiki]         

neutropenia

 

Phenytoin (Dilantin) (Ib) (see psycdrug)

children with ventricular arrhythmias / teratogenic

 

Flecainide (Ic) Side effects: CHF

Encainide (Ic) Side effects: proarrhythmia

 

Class II agents

 

B-blockers (class II) (see other)

Propranolol, acebutolol / prevent ventricular arrhythmias associated with MI

 

Sotalol (Betapace) [wiki]

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)

 

 

Class III agents

 

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, LV contractility

PO: less effects on LV contractility

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]

        • Findings: dyspnea, non-productive cough, fever, rales, hypoxia, decreased DLCO, decreased TLC
        • Diagnosis: some say Ga67 distinguishes from CHF, would really need lung biopsy (foamy macrophages occur with exposure, do not rule in amiodarone pneumonitis)
        • Treatment: steroids for 6 months after stopping drug generally thought to benefit, may be able to follow ESR

·        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

 

Ibutilide [wiki]

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

 

Dofetilide [wiki]

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 PO

 

Azimilide [wiki]

pending approval / blocks rapid and slow IK IV or PO/ mostly renal clearance, some hepatic metabolism / prolonged QT (torsades in 1%)

 

Class IV agents

 

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

 

Class V agents

 

Adenosine  [wiki]

 

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

 

CHF

 

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

 

Pulmonary Edema

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

 

 

Anticoagulation [contraindications] [diagram of clotting cascade]

 

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

 

Aspirin (ASA)

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

 

Dipyramidole (Persantine) [wiki]

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)

 

IIb/IIIa (2B3a) Antagonists

 

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)

 

Abciximab (Reapro) [wiki]

            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

 

Heparin

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?)

 

Enoxaparin (Lovenox) [wiki]

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

 

Reviparin

            once daily anti-Xa (like Lovenox) / same uses / studies ongoing

 

Dalteparin (Fragmin) [wiki]

shown to be effective alternative to warfarin for long term treatment of DVT/PE in cancer patients [NEJM]

 

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

 

Hirudin [wiki]

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

 

 

Warfarin (Coumadin)

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)

 

Aminocaproic acid     

prevents plasminogen from binding to fibrin / used for DIC

 

Thrombolysis

 

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

brief CPR (less than 10 minutes)

chronic warfarin therapy

severe renal/liver disease

severe menstrual bleeding

 

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%

 

Reteplase or rPA [wiki]

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

 

Activated Protein C

 

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

 

Lipid metabolism

 

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

 

Niacin                        

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

 

Zetia

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

 

Marine Oils

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)

 

Diuretics

 

 

Loop                              Lasix, Bumex, Demadex

Thiazide diuretics         HCTZ

K-sparing                       spironolactone

Osmotic diuretics

 

ACE inhibitors

 

·        can worsen hyperglycemia (in diabetes)

·        can worsen hyperuricemia

 

Loop Diuretics

 

Acetazolamide (Diamox)

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

 

Furosemide (Lasix)

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

 

Bumetanide (Bumex)

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

 

Torsemide (Demadex)

2x bioavailability of furosemide / increased half-life allows QD dosing

 

Thiazide diuretics

 

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]

 

K-Sparing Diuretics

 

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

 

Osmotic diuretics

 

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

 

 

Renal Pharmacology

 

 

Renagel

            Newer line phosphate binders

 

Nephrocaps

 

 

SODIUM BALANCE

 

Demeclocycline [wiki]           

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

 

Acid/Base

 

Sodium Bicarbonate

Use in code setting: generally thought not to be so useful, however, definitely still first line for TCA overdose 

 

 

Urate pharmacology

 

NSAIDs           okay for pain relief unless PUD or renal disease

ASA                bad / blocks tubular secretion of urate

 

Probenecid     

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)

 

Allopurinol

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

 

Colchicine      

            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

 

Airway pharmacology

 

Ipratropium (Atrovent)

muscarinic cholinergic antagonist (M1, M2, M3) / applied locally to reduce secretions / inhaled for asthma / additive with B2 agonists

 

Tiotropium (Spiriva) [wiki]

            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

 

Corticosteroids     

 

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)

 

Prednisone

 

Hydrocortisone (Solucortef)

best choice for stress dose steroids (given SC BID)

 

Solumedrol

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

 

Flunisolide

 

Triamcinolone acetate

 

Budesonide

            Only inhaled steroid proven effective with once-daily dosing

 

 

Cromolyn       

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

 

B2 agonists

 

epinephrine                   alpha, Beta agonist / short acting, inhaled or SC

isoproterenol                B1, B2 / short acting, inhaled

metaproterenol B2 > B1 / long acting, inhaled or PO

terbutaline                     B2 > B1 / long acting, inhaled, SC, PO

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

 

 

Narcotics

 

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

            pain: biliary, urinary spasm / urine retention

 

MS Contin (long acting)

 

Hydromorphone (Dilaudid)

            better for renal / comes IV or PO

 

Meperidine (Demerol)

short acting (high peak/trough, high addiction potential) / overdose causes CNS excitation and seizures (a metabolite which is renally excreted and accumulates in ESRD patients) / weak anticholinergic

Side effects: less N&V, constipation / SZ in renal patients

 

Fentanyl (patch)

shorter acting / pre/post-op anesthesia / severe rigidity if given too fast / no histamine release problem (less hypotension)

 

Methadone    

oral / long-acting / opioid withdrawal therapy

 

Codeine         

increased oral bioavailability / used for combination pain management

 

Oxycodone / long acting: oxycontin

 

Hydrocodone (Vicoden/Lortab)

 

Propoxyphene           

very mild pain / chronic use may cause dependence

 

Diphenoxylate           

poor CNS absorption / used for diarrhea

 

Loperamide

 

Pentazocine               

kappa agonist, ? partial agonist, Mu antagonist / less dependence buprenorphine resistant to naloxone reversal

Contraindications: pentazocine increases preload (contraindicated for MI pt)

 

Naloxone (Narcan) (see reversal agents)

 

Non-Narcotic Analgesics

 

Acetaminophen (Tylenol)

analgesic, anti-pyretic (not anti-inflammatory) / renal toxicity with chronic

use, liver toxicity (depletes GSH) with overdose (Uses: N-acetylcysteine)

Side effects: blood dyscrasias, peptic ulcers

 

Ultram

 

 

Cough Suppressants or Antitussives

 

Central Acting

 

Codeine                      opioid analgesic and anti-tussive action

Dextromethorphan     stereoisomer / not analgesic, not addictive (OTC), less constipation

Diphenhydramine       decreases CNS cough centers / sedation

Guaifenesin                expectorant / triggers vagal reflex

 

Peripheral Anesthetics

 

Benonatate (Tessalon pearls)           most effective / 100 mg tid prn

Phenol/menthol          

 

 

Cholinergic pathway

 

Succinyl choline         

depolarizing muscle relaxant, used for surgery / can produce too prolonged apnea in patients with congenital pseudocholinesterase deficiency (human pseudocholinesterase is available for use)

 

 

 

Sleeping Medications

 

For patient’s with liver disease, use in this order: Ambien, Ativan, benadryl, chloral hydrate

 

Seizure Pharmacology

 

febrile               phenobarbital (safer than VPA)

absence            ethosuximide, clonazepam, VPA

myoclonic         clonazepam, VPA

partial               phenytoin, phenobarbital, carbamazepine, VPA

tonic-clonic       phenytoin, phenobarbital, carbamazepine, VPA

epilepsy            phenytoin, phenobarbital / plus diazepam/lorazepam for status epilepticus

 

Note:

·        VPA is the most broad-spectrum

·        2nd line for broad-spectrum is lamotrigine and topiramate

 

Phenytoin (Dilantin) [wiki]

            partial or generalized seizures (grand mal, epilepsy) / blocks Na channel in fosphenytoin active state / induces microsomal enzymes (decreases anticoagulant, OC, quinidine levels) / not for antibiotic-induced SZ (i.e. GABA effect)

Side Effects: rash (10%), gingival hyperplasia, hirsutism, nausea/vomiting, drug-induced lupus, nystagmus, diplopia, ataxia, anemia, leukopenia, polyneuropathy, fetal malformations (mental retardation, cardiac, growth retardation, hand and face malformations)

 

Ethosuximide (Zarontin)

Absence (not for grand mal) / reduces T-type Ca current of thalamic pacemaker

Side effects: rash, anorexia, leukopenia, aplastic anemia, N/V, fatigue, HA, dizziness, anxiety

 

Barbiturates

Mechanism: low dose (potentiate GABA) / high dose (GABA mimetic)

oral absorption, hepatic metabolism, strong CYP3A4 inducers

Clinical: recommended use for less than 3-4 wks, continued use is associated with tolerance, dependence, withdrawal

Note: tolerance does not develop to LD50 (death can occur with doses that are barely sedating)

Common Side Effects: dizziness, sedation, motor and cognitive impairment

Drug interactions: other CNS sedatives, many CYP3A4 drugs including an unpredictable effect on phenytoin levels / Valproate (Depakote) inhibits barbiturate metabolism (HPD ’99 – did they mean carbamazepine?)

Contraindications: hepatic dysfunction, porphyria (barbiturates increase porphyrins)

Pt Ed: common side effects, dependence and tolerance, pregnancy category D (infants may have respiratory depression or undergo withdrawal)

 

thiopental (short), pentobarbital (medium), phenobarbital (long)

 

Phenobarbital (Luminal)

preferred in newborns, young infants (over phenytoin)

febrile SZ, tonic-clonic, partial, epilepsy / increases GABA action, reduces Glu excitation of AMPA receptors / microsomal inducer / can be used to increase bilirubin conjugation in Gilbert’s/Crigler-Najjar’s

Side effects: rash (10%), paradoxical hyperactivity in children/elderly, sedation, nystagmus, ataxia, withdrawal SZ / decreased excretion by alkalinization of urine

 

Amobarbital (Amytal)

Y uses:  “Amytal Interview” (do not allow patient to fall asleep)

Half life is 8-42 hrs

Available as: caps, tabs, IV/IM

Sedation: 50-100 mg PO or IM

Hypnosis: 50-200 mg IV (max 400 mg/day)

Clinical: lorazepam has replaced Amytal for psychotic agitation

 

Pentobarbital (Nembutal)

Y uses: Pentobarbital Challenge can help quantify sedative usage.

Half life is 15-48 hrs

Available as: caps

Clinical:  200 mg PO, assess at one hour, and give 100 mg more, each hour (max 600 mg/day), observing for signs of intoxication (nystagmus is the most sensitive sign, sleep is the most obvious) / substitute with long half-life drug in divided doses and taper 10%/day

 

primidone        similar to babiturates / se: N&V, sedation, dizzy

 

Clonazepam (Klonopin) (see above)

 

Valproic acid (Depakote) (see above)

 

Carbamazepine (Tegretol) (see above)

 

Others

 

Lamotrigine (Lamictal) [wiki]

 

Topiramate (Topamax) [wiki]

 

Carbamates

 

Emylcamate, Felbamate, Meprobamate

 

Pyrrolidines

 

Brivaracetam, Nefiracetam, Seletracetam

 

Levetiracetam (Keppra) [wiki]

Uses: seizures, neuropathic pain

Side effects: ataxia, hair loss, pins and needles sensation in the extremities; psychiatric symptoms

·        B6 (pyridoxine) may alleviate some psychiatric effects

                        Dosing: levels not monitored

 

Parkinson’s Disease

 

L-Dopa

            Uses: Parkinson’s, NPH (2nd line after shunting)

Pharmacokinetics: must give with carbidopa (L-amino acid decarboxylase inhibitor) / useful 2-5 yrs

Side effects: tardive dyskinesia, on-off akinesia, psychoses 15%, N&V 80% (CTZ), postural hypotension, abrupt withdrawal can cause NMS

Contraindications: psychoses, glaucoma, ulcer

Drug interactions: antipsychotics inhibit, aromatic amino acids compete for BBB transport, competes for MAOs may cause HT, B6 (pyridoxine) increases peripheral dopa decarboxylase

 

Synemet (L-Dopa/Carbi-Dopa) [wiki]

            Side effects: nausea (usu. improves within a few weeks)

 

Bromocriptine (Parlodel) [wiki]

            D2 agonist

Uses: pituitary tumors, PD

 

Pergolide (Permax)

D2 agonist / give test dose to check CV response

Side effects: prolactinemia, cumulative dose dependent valvular heart disease (regurgitation) (suggest follow up echocardiograms) [NEJM]

 

Carbergoline [wiki]

D2 agonist

            Uses: mono or combination therapy for PD

Side effects: cumulative dose dependent valvular heart disease (regurgitation) (suggest follow up echocardiograms) [NEJM]

 

Ropinirole (Requip) [wiki]

            D3 receptor agonist

            Uses: PD, restless leg syndrome

 

Pramipexole (Mirapex) [wiki]

            D3 receptor agonist

            Uses: PD, restless leg syndrome

 

Amantadine   

Anti-influenza agent that happens to increase dopamine release

Side effects: HA, confusion, edema

long term: skin discoloration (?livedo reticularis) / monitor toxicity, renal function

 

Selegiline

MAO-B inhibitor / blocks DA metabolism

 

Benztropine (Cogentin), Trihexyphenidyl (Artane)

anticholinergic / used for tremor / only helps 25% of pts (pt may also become refractory)

Side effects: confusion, hallucinations

Contraindicated: glaucoma, prostatic hypertrophy, paralytic ileus

 

Multiple Sclerosis

 

Interferon-beta-1b (Betaseron)

Prevents relapses early in course of MS / given SC qod / can cause increased spasticity in many pts / use limited to young, ambulatory pts with relapsing-remitting disease / may worsen depression (rare)

 

Avonex (IFN-B)

Works quickly / shots q wk

 

Glatiramer acetate (Copaxone)

Polypeptide mixture that resembles a component of myelin / reduces frequency of relapses ~30% / does not slow progression of disease / usu. takes 4-8 wks for maximum benefit

Side effects: not well-studied

 

Headaches

 

Migraine headaches (abortive agents)

 

Ergotamine, Dihydroergotamine

Used with caffeine or triptans to abort migraines (60-70% effective) / nausea (50%) / given PO, PR, SL / metoclopramide can be given 20 mins before vasoconstrictive agents and NSAIDS to control nausea

 

Contraindications: hypertension, peripheral vascular disease, coronary artery disease

 

Triptans

Used with ergotamine to abort migraines (60-70% effective) / unaffected by gender, age and the presence of aura or the relationship to menses.

 

Sumatriptan – better tolerated than other triptans

naratriptan, rizatriptan, zolmitriptan (newer)

 

SC injection, suppository, nasal spray for faster onset

Oral tablets:  associated GI stasis or nausea/vomiting may prevent timely oral absorption

Contraindications: hypertension, peripheral vascular disease, coronary artery disease

Side effects: chest pain from esophageal smooth muscle interactions

 

Butalbital

Refractory migraines / given with ASA or Tylenol / may cause rebound headache / often overused

 

 

Other Neurological Agents

 

Riluzole [wiki]

Uses: slows progression of ALS (20%) by decreasing glutamate toxicity

Side effects: nausea, weight loss, increased LFTs

 

Provigil (like a stimulant, but mechanism ?unclear)

 

Baclofen

Muscle relaxant used for spasticity of central origin / used for spasticity in MS

 

Cyclobenzaprine (Flexeril)

Used for muscle spasm of local origin / not useful with central origin (although action is at level of brainstem)

Contraindications: hyperthyroidism, recent MAO use, CHF

Side effects: sedation (40%), dry mouth (30%), dizziness (10%)

 

 

 

Psychopharmacology

 

·        Anti-Depressants (MAO, TCA, SSRI, Atypical)

·        Anti-Psychotics (Typical, Atypical, Grouped by Potency)

·        Anxiolytics (benzodiazepine, non-benzodiazepines)

·        Sedative/Hypnotics

·        Mood Stabilizers (Lithium, Tegretol, VPA, Neurontin)

·        Seizure Pharmacology

·        Stimulants

·        Substance Dependence

·        Anti-Parkinson’s

·        ECT Therapy

 

[Quick Reference Tables]

 

 

ANTI-DEPRESSANTS

 

 

MAOI’s

 

Phenilzine (Nardil)                 30-90 mg

Isocarboxazide                       25-50 mg

Tranylcypromine (Parnate)   10-40 mg

 

Y uses: atypical depression (approved) (70% vs. 50% efficacy for TCAs), panic attacks, anxiety disorder, social phobia, OCD

Onset: 4-5 wks / can take 6-8 weeks

Side effects:  orthostatic hypotension (common), hypertensive rxn (rare), weight gain, sedation

Other side effects: liver toxicity, agitation, dry mouth, constipation, seizures, sexual dysfunction, insomnia, edema, pyridoxine deficiency

Drug interactions: 

tyramine-containing food (MAO’s active in GI cause increased absorption of tyramine, which can act as NE agonist to increase blood pressure) (aged cheeses, beer, wine, liver, dry sausage, fava beans, yogurt)

opioids such as meperidine (ANS instability, delirium, death)

sympathomimetics such as cocaine, amphetamines, epinephrine, dopamine, b-blockers

anti-hypertensives can potentiate hypotension

Oral hypoglycemics can be potentiated by MAO

2 wks off-time MAOI to TCA, SSRI, atypical AD (must replenish enzyme)

5 wks from SSRI to MAO or TCA to avoid severe hypertension and/or serotonin syndrome

no drug holiday required from TCA to MAOI (mechanism not clear)

Contraindications: poor compliance, asthmatics, surgery

Pt Ed: discuss many diet restrictions, avoid pregnancy

Overdose: can be fatal, acidification of urine may help

 

Phenilzine (Nardil)    

Dosing:  15 mg BID, increase 15 mg/day for each weeks / 30-60 mg/day / TR 15-90 mg/day

elderly start with 7.5 mg/day, max 50 mg/day

Side effects:  more weight gain, sedation, dry mouth, sexual dysfunction than Parnate

 

Tranylcypromine (Parnate)

Dosing:  10 mg BID, increase 10 mg/day for each weeks / 20-40 mg/day / TR 10-60 mg

elderly start with 7.5 mg/day, max 50 mg/day

Side effects: more insomnia than Nardil

 

Tricyclic Antidepressants (TCA)

 

Mechanism:    inhibit re-uptake of NE and 5HT, also blocks ACh, His, a1,2

 

Main Y Uses: major depression (acute or prevention of relapse), dysthymia, depressed phase of bipolar, secondary depression, anxiety, OCD, post-traumatic stress disorder, pseudodementia in elderly, bulimia, chronic pain

enuresis (NE decreases NREM sleep) and ADHD (imipramine)

 

Proposed:        peripheral diabetic neuropathy, narcolepsy (clomipramine), migraine, sleep apnea (protriptyline), phobia/separation anxiety in children, peptic ulcers, behavioral disorder in MR, anorexia nervosa/bulimia, cocaine abuse, antiarrhythmia, dysmorphophobia

 

Contraindications:

recovery from myocardial infarction, do not follow MAO immediately, not recommended for pregnancy or lactation, hyperthyroidism, narrow angle glaucoma, prostatic hypertrophy

be careful with psychosis, bipolar, children, elderly

pregnancy category D (use only if necessary)

 

Major concern: sudden death from overdose / treat (carefully) w/ 1-2 mg physostigmine IV, to reduce cardiac toxicity/arrhythmia: NaHCO3 (to alkalinize blood and urine), avoid certain anti-arrhythmics (can use phenytoin for membrane stability, can use b-blockers)

 

Biochemical Effects

 

·        Acute (hours): 

block amine uptake, temporarily reduce NE and 5HT firing and turnover rates, side effects

 

·        Later (weeks):

Most have 7-21 day onset of efficacy / block amine uptake, decreased receptor sensitivity, increased NE release, decreased B1 sensitivity (5HT permissive?), increase in number/affinity/sensitivity of a1 receptors , probably increased sensitivity of 5HT receptors, probably decreased sensitivity of DA autoreceptors,

variable increase in muscarinic ACh receptors

 

Clinical Effects

 

Blockade of NE reuptake at nerve endings

Efficacy, tremors, tachycardia, erectile/ejaculatory dysfunction, counters guanethidine (hypertensive)

 

Blockade of 5HT reuptake at nerve endings

Efficacy, GI problems, anxiety

 

Blockade of H1 receptors (more than H2)

Potentiation of CNS depressants, sedation, weight gain, hypotension?

 

Blockade of muscarinic receptors

Common:  blurred vision (use pilocarpine 2-4%), dry nose/mouth (pilocarpine tablets Q6h), constipation (use diet, avoid laxatives), urinary retention

Serious:  sinus tachycardia, (bethanechol 10-20 mg BID or TID), memory dysfunction, induction of glaucoma

 

Blockade of a1-adrenergic receptors (more than a2)

postural hypotension (tolerance), reflex tachycardia (tolerance), dizziness

potentiates antihypertensive action of prazosin

quinidine-like Ia effects (EKG changes), ?angina

 

Blockade of a2-adrenergic receptors

Blocks antihypertensive effect of clonidine, guanabenz, aMethyldopa / causes priapism

 

Blockade of D2 receptors

            EPS, increased prolactin

 

Blockade of 5HT2 receptors

            Ejaculatory dysfunction, hypotension, alleviation of migraines

 

Major side effects by organ system:

                        Cardiac: tachycardia, prolonged QT

Dermatological effects: urticaria, photosensitivity, cutaneous vasculitis

Sexual dysfunction: erectile disorder, retrograde ejaculation, anorgasmia

Weight gain

Hepatic/renal: jaundice, hepatitis, hepatic necrosis, increased LFT’s

Neuro: fine action tremor (10%), agitation, insomnia, EEG changes, EPS, contraindicated in seizure disorder

Psychiatric: may worsen manias and ?psychoses

 

tertiary (5HT>NE)                                                        secondary (NE>5HT)  

 

Imipramine (Tofranil) 75 –300 mg/day             Desipramine (Norpramin) 75–300 mg/day

Amitriptyline (Elavil) 75 –300 mg/day             Nortriptyline (Pamelor) 75–300 mg/day

Trimipramine (Surmontil) 75 –300 mg/day      Nordoxepin

Clomipramine (Anafranil) 75 –300 mg/day      Protriptyline (Vivactil)            25-75 mg/day

Doxepin (Sinequan) 75 –300 mg/day  

 

Note:

 

·        Secondary TCA’s (Nortriptyline) have less blockade of ACh, His1/2 and adrenergic receptors (Safer in overdose)

 

·        Nortriptyline has a TI of 50-150 whereas other TCA’s are dose dependent

 

·        Doxepin (Sinequan) (H1-sedation), Trimipramine (Surmontil), and Amitriptyline (Elavil) (H2-gastric) / these are high H1,H2 blockers that are used for pruritis, gastric ulcers, neurologically related pain

 

Clinical:

 

·        tertiary TCA’s metabolized to respective secondary compounds / lipophilic distribution, dealkylated and oxidized by liver microsomal enzymes and conjugated with glucuronic acid (different individuals have different metabolic rates)

 

·        Only Amitriptyline (Elavil), Imipramine (Tofranil) and Clomipramine (Anafranil) are available for injection

use divided doses until tolerance is developed, reduce dose in children and elderly

 

·        Resistant depression may be treated with TCA plus [stimulants, estrogens/testosterone, lithium, anticonvulsants, amantidine/bromocryptine/pergolide, tryptophan, tyrosine, SSRI, SARI, bupropion, T3/T4 (good for females)] [Pinell 7/99]

 

 

Sumatriptan

5HT action – used to treat migraine headaches

 

Tetracyclics

 

Amoxapine (Asendin) (rarely used)

Analog of loxapine (may cause EPS)

1/100 anti-psychotic activity of haldol, can treat depression + psychosis similar to

Side effects: hyperprolactinemia, gynecomastia, galactorrhea, amenorrhea, increased risk of seizures

Similar? to desipramine, maprotiline (NE selective)

25-50 mg qhs, 150-250 mg/day, half-life 8 hrs

 

Maprotiline (Ludiomil) (rarely used)

most NE selective / less anti-ACh, sedation / increased SZ risk (Na channel effect), watch with EtOH or benzodiazepine discontinuation

225 mg/day (upper threshold), half-life 43 hrs

75 mg qhs for 2 weeks, increase in 25 mg ever few days to 100-150 mg/day (less in elderly)

 

Nefazodone (Serzone)

Pulled off market 2004 due to small risk of liver failure

 

SSRI’s

 

Mechanism: selective serotonin reuptake inhibitor

Y uses: major depression, dysthymia, OCD, panic disorder (lower dose), bulimia nervosa, bipolar disorder, premenstrual dysphoric disorder, social phobias, PTSD, certain chronic pain syndromes, affective instability of borderline PD

Common: headaches, GI (nausea, heartburn, diarrhea) [usually transient], sleep loss, (excitation, anxiety), weight loss, sexual dysfunction (decreased libido, delayed ejaculation, anorgasmia)

Less common: (rare) serotonin syndrome / SIADH

Drug interactions:  inhibits liver microsomal enzymes / fluoxetine and paroxetine strongly inhibit CYP2D6, while fluvoxamine strongly inhibits CYP1A2

all SSRI’s moderately inhibit CYP2C9 (phenytoin) and CYP2C19 (b-blockers)

Pt Ed: irritability, upset GI (take with food), decreased libido etc. (try cyproheptadine 4-8 mg  pre-sex, low dose bupropion or change SSRI), can produce manic “switch”, class C teratogen, avoid breast feeding

 

Serotonin syndrome

nausea, confusion, ANS instability, tremor, hyperthermia, rigidity, seizures, CV collapse, coma, death

 

Clinical:

·        2-3 weeks onset, 6-8 weeks for full-effect

·        dose titration required for OCD, eating disorder (20 mg toward max dose)

·        taper up with panic disorder to prevent side effects from causing anxiety

·        lack of response or side effect problems with one SSRI does not contraindicate trying another SSRI [HPD]

·        may precipitate manic episode or “switch” in undiagnosed bipolar disorder

·        SSRI’s can destabilize bipolar patients, increasing depressive or manic symptoms and therefore, should not be given chronically to bipolar patients.  Use antidepressants to treat acute depressive episodes, and aim to taper off after 6 weeks.  Chronic antidepressant use can lead to rapid cycling or mixed bipolar, which is more resistant to monotherapy (must use lithium + anticonvulsant)

·        abrupt discontinuation may precipitate withdrawal symptoms

·        allow 2 wks before or after MAOI to avoid serotonin syndrome

·        give one dose qAM (to avoid insomnia) / divide high doses to bid

·        current trend is toward lower doses for the same efficacy

 

Fluoxetine (Prozac) [wiki]

Y uses: approved for depression, OCD, bulimia, social phobias (9/99)

Long half-life (1 month to reach steady state, norfluoxetine)

5 wks before MAOI no withdrawal problem

Side effects:  causes more insomnia (use trazadone 50-100 mg qhs), akathisia-like syndrome (rare)

Inhibits CYP2D6 (severe) and CYP3A4 (mild)

available as oral solution

20-80 mg/day / increase dose by 20 mg after one month if necessary

 

Paroxetine (Paxil)     

Y uses: approved for depression, OCD, bulimia

most potent (short half-life), less selective / 1st in sedation (some say 2nd)

must taper down to avoid withdrawal (cholinergic rebound)

strongest inhibition of CYP2D6 (TCA, antiarrhythmics)

20-50 mg/day

 

Sertraline (Zoloft)     

Y uses: approved for depression, OCD, bulimia

less inhibitory of CYP2D6, causing fewer co-drug plasma level increase (cimetidine, haldol, phenytoin, propranolol)

metabolite is desmethylsertraline (2-4 day half-life)

50-200 mg/day

 

Fluvoxamine (Luvox)

Y uses: Only approved for OCD (used least often due to P450 interactions)

80% PPB, less risk of co-drug displacement / 2nd in sedation (some say 1st)

Drug interactions:

·        strong inhibition of CYP1A2 (theophylline, clozapine), CYP3A4

·        (moderate) (Ca channel blockers, alprazolam, triazolam, terfenadine, astemizole, carbamazepine)

·        least inhibition of CYP2D6

·        can increase methadone levels

Other: ? ventricular tachycardia

Start 50mg/day, then 100-300mg/day (150mg max individual dose)

 

Citalopram (Celexa) [wiki]

supposed to have fewer side effects

 

Escitalopram (Lexapro) [wiki]

 

 

Alaproclate, Etoperidone, Zimelidine

 

 

Atypical Antidepressants

 

Phenylpiperazines (5-HT2 antagonists, reuptake blockers)

 

Trazodone (Desyrel) 

Mechanism:  5HT reuptake blocker and 5HT2a antagonist (or agonist, HPD?)

Y uses: depressive disorders / anxiety, agitation, aggression for organic mental disorder (often used in elderly), used as hypnotic agent for pts who should not take benzodiazepines (chronic pain), often combined with other antidepressants for insomnia

Common side effects: sedation, dry mouth, gastric irritation, hypotension / little anticholinergic action, 6% dizziness when taken on empty stomach

Other side effects: priapism (1 in 800, 1 in 6000 HPD, a-2 blockade),

Drug interaction:  short half-life, sedatives, Prozac (low dose trazadone is okay), may elevate digoxin, phenytoin, avoid MAOs (serotonin syndrome)

Contraindications: (mildly arrhythmogenic) PVC, VT, VC (avoid w/ recent MI), possible teratogen, avoid breast feeding, do not take with other depressants (can be fatal), not recommended with ECT

200-600 mg/day, 50-500 mg/day elderly, 25-150 mg/day insomnia

 

NE Reuptake Inhibitors

 

Atomoxetine, Reboxetine, Viloxazine, Maprotiline (also a tetracyclic)

 

 

NE and 5HT Reuptake Inhibitors

 

Venlafaxine (Effexor) [wiki]

Y uses: depression, dysthymia, ADHD, chronic pain

Mechanism: NE and 5HT reuptake blocker

Side effects: almost no effect on muscarinic cholinergic, histaminergic, adrenergic or dopaminergic receptors.

Most common: insomnia, nervousness (especially with abrupt discontinuation)

Common: nausea (tolerance), sedation, fatigue, sweating, dizziness, headache, loss of appetite, constipation, dry mouth [there is evidence that higher initial starting dosages may expedite tolerance to the common side effects as with Remeron, HPD]

Serious:  hypertension (3-7% at 100-300mg, 13% above 300 mg for immediate release formulation, measure BP when starting therapy), sexual dysfunction (ejaculatory dysfunction, anorgasmia in 10%), seizures (0.3%)

Contraindications:  avoid in pregnancy, breast feeding, do not combine with MAO (serotonin syndrome)

Metabolism: dosage should be decreased 50% with renal/hepatic disease, 5 hrs and 10 hrs half-life of metabolite

Immediate release:  40-75 mg/day (BID) / ↑ every few days to 75-225 mg/day

Extended release:  38-75 mg qd w/ food / increase up to 225 mg/day as needed

Dosage range: 75-375 mg/day, same in elderly / discontinuation should be tapered over several weeks if possible / Venlafaxine is thought to be more effective than SSRI’s at higher doses?

 

Duloxetine (Cymbalta) [wiki]

 

Milnacipran [wiki]

 

Noradrenergic and SS Reuptake antidepressant (NaSSA)

 

Mirtazapine (Remeron) (SARI-like)

Selective a-2 adrenergic antagonist that enhances NE and 5HT

5HT2 antagonism reduces sexual side effects (DA release not decreased by negative feedback mechanism)

5HT3 antagonism may help in patients with stomach upset

Common: weight gain, strong sedation (usually reduces by week 2), reduced nausea, few sexual side effects, increased appetite (2 kg/6wks with paradoxical decrease at high doses)

Serious:  leukopenia (<1%)

Pt Ed:  dry mouth, constipation, fatigue, dizziness, orthostatic hypotension

15 mg qhs, up to max 45 mg qhs (30 mg in elderly), half-life 20-40 hrs

 

NE and DA Reuptake Inhibitors

 

Bupropion (Wellbutrin) [wiki]

Y uses: depression, dysthymia, bipolar, ADHD, sexual dysfunction 2o to SSRI’s

Mechanism:  pure NE reuptake inhibitor (some DA effects also)

(Zyban) used for smoking cessation, anorexia nervosa

Note:  minimal cardiac effects, less orthostatic hypotension, less sedation, less weight gain, less anti-ACh, less sexual dysfunction

Common: insomnia, increased agitation, anxiety (usually goes away, 98%), headache, constipation, dry mouth, tremor

Contraindicated: seizure disorder or bulemia (underlying electrolyte imbalance) [increased risk to 0.4% SZ rate at 450 mg], avoid in pregnancy, breast feeding

Drug interactions: CYP3A4 (liver/renal disease may increase levels to toxicity), avoid with MAO, DA agonists à may lead to confusion or dyskinesias

Dosage: 200 mg/day up to 300-450mg/day after 3 wks / do not give single dose over 150mg / increased risk over 450mg/day / sustained release available

 

DA Reuptake Inhibitors

 

Amineptine, Phenmetrazine, Vanoxerine

 

 

Mood Stabilizers & Anticonvulsants

 

·        Carbamazepine (Tegretol)

·        Valproic Acid (Depakote)

·        Gabapentin (Neurontin)

·        Lamotrigine (Lamictal)

·        Tiagabine

 

·        Mania with psychosis can be treated with both a mood stabilizer and an antipsychotic (taper off the antipsychotic or use a depot formulation).

 

 

Lithium [wiki]

Y uses: normalizes mood by 2-3 wks in 70% of bipolar depressive pts

refractory depression (augmentor) / schizoaffective (augment anti-psychotics)

borderline personality disorder, impulse control disorders, behavioral disorders in developmentally disabled

treats chronic aggression (bipolar or not) [serotonin theory]

Most common:  GI irritation (N&V), sedation, tremor, headache

Less common: weight gain (long term problem), edema, polyuria (collecting duct unresponsive to ADH), polydipsia, acne, psoriasis

Most serious: SZ, renal impairment with long term use, hypothyroidism with goiter from thyroid inhibition (female > 8x male), arrhythmia (may block IP3/DAG producing EKG changes), 1st trimester teratogen (Ebstein's anomaly), hypercalcemia (raises threshold of calcium allowed by PTH)

Drug interactions: toxicity potentiated by diuretics, NSAIDS, carbamazepine, Ca blockers, ACE inhibitors, metronidazole, neuroleptics

Pt Ed: GI irritation, sedation, mild tremor, thirst, increased WBC [expect], moderate tremor, slurred speech, muscle twitching, change in fluid balance, memory impairment, rash, edema [report], lab rationale, weight control, sodium intake, teratogenicity

Overdose: measure level (mild, saline), (severe, hemodialysis and anticonvulsants)

Non-compliance:  long term weight gain, acne

Contraindications:  renal problems, acute MI, myasthenia gravis, pregnancy

Renal: watch Cr/BUN / dietary Na competes for reabsorption, Cl decreased by vomiting, diarrhea

Dosing: 300 mg BID, then titrate up to 1200 mg (or level needed to control symptoms)

Decrease dose in elderly due to low GFR and sensitivity to effects

Low therapeutic index (TI) / check levels as needed / TR is 0.6 - 1.2 mEq per L

 

Anticonvulsants are indicated with:

1) failure on lithium or anti-psychotics

2) manic symptoms

3) rapid cycling

4) EEG abnormalities

5) head trauma

 

 Carbamazepine (Tegretol)

Medical uses: partial SZ, tonic-clonic SZ / paroxysmal pain (TN and phantom limb)

Y uses:  acute mania, depression, psychosis? 2o  seizures, augments anti-psychotics for acute schizophrenia, schizoaffective, episodic dyscontrol symptoms, chronic aggressive behavior

Mechanism: (under investigation)  involving GABA, 5HT

Common: N&V (temporary), rash (10%), diplopia, sedation, dizziness, ataxia (gait), cognitive impairment, elevated LFT, GI (nausea, anorexia, pain)

Less common:  hepatitis, aplastic anemia, skin (rash, erythema, toxic epidermal necrolysis, SJS)

Serious: leukopenia (10%) (agranulocytosis, thrombocytopenia)

Other:  crosses placenta (possible teratogen), may worsen pre-existing cardiac conduction disorder, stimulates ADH receptor function (causes SIADH), suppresses T3 levels, SLE, alopecia

Drug interactions: lithium and carbamazepine (neurotoxicity)

Metabolized by liver p450 (90%) / CYP3A4 inducer

Levels decreased by: phenytoin, phenobarbital, theophylline

Levels increased by: erythromycin, lithium, verapamil, isoniazid, diltiazem, propoxyphene, cimetidine, digitalis, H2 blockers, clomipramine

Decreases: clonazepam, haldol, TCA, tetracycline, valproic acid, warfarin, ethosuximide, oral contraceptives, T3

Pt Ed: sedation, GI symptoms, lightheadedness [transient], rash, jaundice, incoordination, irregular heartbeat, edema [report], weight control, many drug interactions, teratogenicity, vitamins

Dosing: 200mg BID, increase 200mg every few days / TL 6-12 ug/ml

 

Trileptal (oxcarbazepine)

Basically like a safer version of Tegretol (way fewer side effects)

Y uses:  now 2nd after lithium for manic depression

More common: sedation (pt may get used to it), hyponatremia

Less common: skin rash, lymphadenopathy, liver toxicity

 

Valproic Acid (Depakote)

Mechanism: GABAergic? among other things (not clear).

Uses: myoclonic, tonic-clonic, absence seizures à works within days

Y uses:  bipolar and schizoaffective disorder

Common: nausea & vomiting (5%), sedation (5%), hand tremor, dizziness, abdominal pain, headache, transient dose-dependent LFT increase

Less common: hair loss (comes back green), weight gain (usually less than Tegretol), ataxia, teratogenicity

Serious: rare fatal hepatitis (higher risk? in MR or seizure disorder), decrease or dysfunction in platelets (thrombocytopenia) with increased coagulation time, anemia?, leukopenia?, pancreatitis

Drug interaction: clonazepam (rare absence seizures), lamotrigine (SJS)

Pt Ed: sedation, tremor, GI [transient] / bruising, swelling, rash, jaundice [report] / weight control, drug interactions, teratogenicity (neural tube defects), use of vitamins

Crosses placenta / 90% plasma protein bound / inhibits own metabolism and metabolism of other drugs (aspirin, anticoagulants, fatty acids)

Available as: generic VPA or Dapakene (di-VPA) which has less GI irritation

Dosing: 250 mg TID, ↑ 2-3 days (gradual) / TR 750 - 3,800 mg / TL 40-150 ug/ml

 

Gabapentin (Neurontin)

Contraindications:  liver/renal impairment

Common: dizziness, sedation, unsteady gait, incoordination, cognitive impairment, blurred vision, diplopia / elevated LFTs / GI (nausea, anorexia, pain)

Pt Ed: sedation, GI, lightheadedness [expect], rash, jaundice, incoordination, irregular heartbeat, edema (facial) [report], weight control program, drug interactions, teratogenicity, use of vitamins

Dosing: 300-600 mg qd 1 wk, then increase 300-600 mg/wk to 900-3600 mg (also see rapid titration plan)

 

Lamotrigine (Lamictal)

psychiatric uses: acute and prophylaxis of mood episodes (bipolar) / works within ?weeks for grand mal seizures

Contraindications:  liver/renal impairment

Common: rash (20%), sedation, dizziness, nausea & vomiting, ataxia, increase anxiety

Less common: hair loss, weight gain, ataxia

Serious: Stevens-Johnson rash [some say this is a reason to titrate up for 2 wks], DIC, blurred vision, diplopia, esophagitis, teratogen C

Drug interactions: may induce hepatic metabolism / levels increased by valproic acid (higher risk of severe skin reaction), decreased by carbamazepine, phenytoin / folate inhibitors

Pt Ed: sedation, insomnia, nausea, dizziness [transient], bruising, swelling, rash, jaundice, edema (facial) [report], drug interactions, teratogenicity, use of vitamins

Dosing: 50 mg qd for 2 weeks, then BID, then increase 100 mg/week to 300-500 mg

 

Tiagabine

MOA: specific inhibitor of GABA

contraindications:  liver/renal impairment

common: dizziness, sedation, asthenia, tremor, ataxia, nausea, nervousness

more serious: abdominal pain, confusion, esophagitis, headache, anxiety

drug interactions: levels increased by valproic acid, levels decreased by carbamazepine, phenytoin

Pt Ed: sedation, nausea, dizziness, tremor [transient], bruisability, rash, jaundice, confusion, [report], drug interactions, teratogenicity, use of vitamins?

Dosing: 4-8 mg/day, increase 4-8 mg/wk / 32-56 mg/day with food

 

[missing drug name]

contraindications:  liver/renal impairment

common: dizziness, anxiety, sedation, tremor, psychomotor slowing, confusion, cognitive impairment, GI (weight loss, anorexia)

more serious: renal stones, depression, teratogen class C

drug interactions: levels decreased by carbamazepine, phenytoin, valproic acid?, OBC, digoxin / acetazolamide, dichlorophenamide

Pt Ed: sedation, GI Sx, lightheadedness [expect], weight loss (>5%), confusion, incoordination, edema (facial) [report], drug interactions, teratogenicity

Dosing: 50 mg qd/wk, increase 50 mg/wk / 200-600 mg/day

 

Topiramate (Topamax)

New broad-spectrum anti-epileptic drug / also used for refractory migraines / once it works, it usually keeps working
Side effects: actually decreases appetite, memory disturbances, sedation (drowsiness)

Y uses (not approved): performance anxiety (peripheral acting), lithium-induced tremor, neuroleptic-induced akathisia, ethanol withdrawal, anxiety and panic disorder, has even been used to slow down very psychotic patients

Mechanism: b1,2,3 blockers also have some agonist activity / decreases renin release  decrease heart contractions, decrease NE release (pre-synaptic b-receptors were increasing NE release)

more lipid soluble ones act in CNS (esp. locus ceruleus)

Common: hypotension, bradycardia, dizziness, depression, fatigue, nausea, diarrhea

Contraindications:  conduction block (cardiac collapse), bronchial asthma, insulin dependent diabetes (hypoglycemia), ?

 

Zonegran (zonisamide)

More common: 1% renal stones, somnolence, wt loss, nausea

Less common: skin rash, blood dyscrasias, hepatotoxicity

 

Clonidine

Mechanism: a-2 agonist

Medical use: antihypertensive (see other)

Y uses (not FDA approved): opioid withdrawal:  treats ANS Sx

liver (50%), kidneys (50%) / acts in CNS and peripherally

Common: dry mouth, sedation, dizziness, nausea, impotence, fluid retention, additive with alcohol, vivid dreams and nightmares, insomnia, restlessness, depression , anxiety

Drug interactions: decreased anti-hypertensive effect with TCAs (why? because  receptors have increased?)

Methadone withdrawal:  0.1 mg 2-3x/day, taper on completion

Tourette’s: may take 2-3 months for response / start at 0.5 mg/day

Mania: 0.2-0.4 mg bid

Anxiety disorder (?)

Neuroleptic-induced akathisia: 0.2 - 0.8 mg/day

Clinical: taper to prevent rebound hypertension

 

Anxiolytics

 

Benzodiazepines  [see non-benzodiazepine anxiolytics] [see sedative/hypnotics]

 

Mechanism: binds g-subunit of GABA (potentiates GABA binding)

Y Uses:  anxiety, insomnia, seizures, pre/post-anesthetic, muscle relaxant, withdrawal from CNS depressants, acute aggression for psychosis or mania

absorbed quickly from GI tract (except Librium)

Common: sedation, rebound anxiety, respiratory depression, anterograde amnesia, withdrawal is abrupt, worse with short acting BZ

Less common:  GI, skin

Serious:  memory problems, CNS problems, paradoxical reaction (rare)

Drug interactions:  use cimetidine to increase half-life / reduce dose for liver disease and elderly patients

tolerance develops to the sedating activity, but not the anti-anxiety activity Contraindications:  glaucoma (must be careful), myasthenia gravis, history of substance abuse, porphyria?, pregnancy (1st trimester), compromised pulmonary function (be careful)

Clinical: treat overdose with flumazenil

 

Short 5h                      Triazolam (Halcion), Midazolam (Versed) (sustain sleep)

 

Medium 8-10h            Alprazolam (Xanax), Lorazepam (Ativan), Oxazepam (Serax)

 

Long 24-72h               Chlordiazepoxide (Librium), Diazepam (Valium)

Flurazepam (Dalmane), (Doral)

           

High Potency

·        A short half-life (more lipophilic?) is more likely to produce dangerous BZ withdrawal

·        BZ that are absorbed more quickly from GI tract more likely to produce dependency

 

Triazolam (Halcion)

0.25-0.5 mg PRN for agitation (not to exceed 10 mg/day)

FDA approved for insomnia (0.125-0.25 mg)

CYP3A4 / half-life 2-3 hrs (great for initiating sleep)

 

Lorazepam (Ativan)

approved for insomnia / used for panic attacks, sedative withdrawal

0.25-0.5 mg PRN for agitation (not to exceed 10 mg/day)

non-hepatic inactivation and renal excretion (impaired renal function is not a problem) can be given IM/IV safely

 

Alprazolam (Xanax)

panic attacks, social phobia, generalized anxiety disorder, adjustment disorder with anxious mood used in pre-menstrual dysphoric disorder [only BZ in US with well-proven antidepressant activity, also SSRI or Buspar

Clinical: Despite ~10 hr half-life, clinical effect is short-lived and qid dosing may be required with high risk of interdosing anxiety (no longer a 1st line drug for general anxiety disorder)

0.5-5 mg/day up to 10 mg, elderly may respond to lower doses

 

Oxazepam (Serax)           high potency?  Can be given PO for withdrawal

 

Clonazepam (Klonopin)

rapid onset, but not too much euphoria [HPD]

Medical uses: absence SZ, myoclonic SZ, akinetic SZ, infantile spasms

Y uses (not approved): acute mania, panic attacks, generalized anxiety disorder, sedative withdrawal, Tourette’s, antidepressant~? [currently under investigation for maintenance treatment of bipolar disorder]

Mechanism: enhances 5HT synthesis, potentiates GABA, mimics glycine

Contraindications: narrow angle glaucoma, dyscontrol syndrome, sedative abuse

Common: sedation, ataxia, memory loss

Serious: withdrawal, glaucoma, irritability, excitement, rage, sexual dysfunction (rare)

Drug interactions: H2 blockers, disulfiram, estrogen, isoniazid, valproate, digoxin

Pt Ed: sedation, psychomotor, danger of alcohol [expect], eye pain, memory impairment, paradoxical behavioral effects [report], withdrawal, addiction, teratogenicity [discuss]

12-16 h half-life / HPD says 25-50 hrs

Anxiety: 0.25-6 mg / start 0.25 mg bid or 0.5-2 mg qhs / increase every 3 days / max 3-6 mg/day

Mania: 0.25-10 mg/day / Elderly: 0.25-1.5 mg/day

 

Chlordiazepoxide (Librium)

Absorbed less rapidly from GI tract, so it produces less dependence

Drug of choice for status epilepticus (Ativan also)

Use Lorazepam (Ativan) if patient’s liver is not working or if you need IM/IV (avoid giving IM Librium due to its unpredictable absorption pattern)

Anxiety: 5-25 mg PO bid/tid

Alcohol Withdrawal: 25-50 mg bid/tid/qid / 25-50 mg q 4h PRN (max 400 mg/day)

Half-life > 100 hrs

Note: elderly or medically incapacitated may become suddenly obtunded

 

Clorazepate (Tranxene)

 

Diazepam (Valium) (see above)

given IV for status epilepticus / can also be used for dizziness secondary to anxiety

tolerance with long term use, paradoxical hyperactivity

 

Flumazenil (see reversal agents)

 

Disulfiram (Antabuse) (see reversal agents)

 

Halazepam (Paxapam)

Prazepam (Centrax)

 

Benzodiazepines

 

Sedative/Hypnotics

 

·        Temazepam (Restoril)

7.5-30 mg / half-life 10-12 hrs, decrease dose in elderly (Safe with luvox, effexor, serzone)

 

·        Triazolam (Halcion)

0.25-0.5 mg PRN for agitation (not to exceed 10 mg/day) / approved for insomnia (mostly sleep initiation) / CYP3A4 (certain AD (-), carbamazepine)

 

Estazolam (ProSom)

More potent / 1-2 mg qhs, 0.5-1 mg in elderly / half-life 17 hrs (not often used) / CYP3A4

 

Flurazepam (Dalmane)

15-30 mg qhs, decrease dose in elderly / half-life 100 hrs (not often used) / CYP3A4

 

Quazepam (Doral)

7.5-30 mg / half-life 100 hrs (not often used) / CYP3A4

 

Non Benzodiazepine Sedative/Hypnotics

 

[Also See Seizure Pharmacology/Barbiturates]

 

 

  • Zolpidem (Ambien) [wiki]

Non Benzodiazepine, but binds to the GABA receptor

Y uses: insomnia / great for initiating sleep (good for maintaining also)

Half-life 2-3 hrs

Common: dizziness, GI, nausea and vomiting, anterograde amnesia can occur

Hepatic (not renal) impairment will increase levels

To date, there is no clear evidence of withdrawal or dependency

Pregnancy category B

 

  • Eszopiclone (Lunesta) [wiki]

 

  • Ramelteon (Rozerem) [wiki]

 

 

Diphenhydramine (Benadryl) (see other)

 

Chloral Hydrate (Noctec)

Mechanism unknown

Contraindications: GI inflammation or ulcers

Drug interactions: addition of IV furosemide may cause unpleasant reaction

Causes tolerance and dependence / lethal in overdose (hepatic/renal toxicity)

Used in research for short term sedation because it has no known CNS neurotransmitter activity

Half-life 8 hrs

Nausea, vomiting diarrhea, sedation, decreased coordination

Available as: tablets, PO, PR

Insomnia: 500-1000 mg qhs (short term therapy only)

 

Barbiturates

 

 

Non-Benzodiazepine Anxiolytics

 

Buspirone (Buspar)

5HTA1 partial agonist

Y uses: FDA approved for generalized anxiety disorder (not panic attacks)

used to augment treatment of major depressive disorder and OCD

used to treat disruptive behavior in the elderly and developmentally disabled

1-2 week or more onset (mechanism unclear, long term down regulation of receptors?)

can increase anxiety / patients who have been on BZ will refuse Buspar (can give both and taper off  / no sedation, may displace digitalis, slight problem with compliance

common:  GI upset, anxiety, insomnia

advantages: does not interact with alcohol

half-life 2-11 hrs

5-10 mg tid, add 5 mg every 3 days, to 15-60 mg/day / 60 mg has anti-D2 action (prolactinemia, EPS)

 

Hydroxyzine (Atarax, Vistaril)

Antihistamine anxiolytic, mild anticholinergic

Y uses: anxiety (only short-term therapy), acute agitation

adjunct to antipsychotics for increased sedation and decreased EPS effects

Common: dry mouth, dizziness, drowsiness, thickened bronchial secretions, hypotension, decreased coordination, GI disturbances

Hepatic impairment will increase levels

Drug interactions:  additive to other sedatives or anticholinergics, can potentiate opiates such as meperidine (Demerol), do NOT use within 2 weeks of MAO inhibitor

Available as: tablets, PO (Vistaril), syrup, IM (not IV)

Anxiety: 50-100 PO q 4-6 hrs

Acute agitation: 50-100 mg IM q 4-6 hrs

 

ANTI-PSYCHOTIC DRUGS

 

Typical                 Atypical

 

·        Grouped by Potency

·        Grouped by Class

·        Low Vs High Potency

·        Extrapyramidal Symptoms

·        Dopaminergic Pathways

 

Y indications:

Any condition with psychotic features (70% efficacy), acute impulsivity and aggression associated with MR, episodic dyscontrol, antisocial and borderline PD

Tourette’s (pimozide), Huntington’s, movement disorder, general nausea and vomiting

 

Mechanism:          D2 antagonist / mechanism for aggression may involve 5HT and other systems

 

Onset:       PO 2-4 hrs, oral solution less than 2 hrs, IM 30-60 mins

 

General side effects:

Hypersensitivity Reaction:  cholestatic jaundice, skin rashes

Other Dermatological:  photosensitivity, skin pigmentation

Agranulocytosis and other blood dyscrasias

Neuroleptic Induced Movement Disorders

Withdrawal syndrome, cardiac arrhythmias, hepatitis, seizures (lowers threshold)

weight gain, anti-emetic (except thioridazine), hypothermia, hyperthermia

 

Anti-a1:

orthostatic hypotension, light headedness, reflex tachycardia, sedation, sexual dysfunction

 

Anti-D2 (extrapyramidal):

acute dystonia, akathisia, Parkinson's like symptoms (tremor, gait), tardive dyskinesia (long term use of phenothiazides, anticholinergics), oculogyric crisis, hyperprolactinemia (disinhibition)

 

Anticholinergic:

orthostatic hypotension, sexual dysfunction (10%), dry mouth, blurred vision, constipation, urinary retention (↑ UTI), sedation (also from anti-histamine action)

 

Anti-H1: sedation, weight gain, fatigue

 

Other side-effects:

thioridazine and pimozide are noted for cardiotoxicity (can be fatal in overdose)

 

Drug interactions:

CNS depressants: can be fatal combined with overdose

Antacids and cimetidine: may inhibit absorption

Anticholinergics, antihistamines, antiadrenergics: additive effects

Antihypertensives: may potentiate hypotension (ACE inhibitors, alpha-methyldopa), may inhibit neuronal uptake of clonidine and alpha-methyldopa

Anticonvulsants, antidepressants: cyp2d6

Antipsychotics may increase levels of TCA’s

Barbiturates: reduce levels of antipsychotics; can cause respiratory depression

Beta-blockers: propranolol increases levels of antipsychotics

Bromocriptine, L-Dopa, stimulants: may worsen psychotic symptoms

Cigarettes: may increase metabolism and decrease level of antipsychotics

Digoxin: absorption may be increased

Isoniazid: may increase risk of hepatic toxicity

Lithium: possible risk of neuroleptic induced encephalopathic syndrome or neurotoxicity

MAO Inhibitors: will potentiate hypotensive effects of antipsychotics

Metrizamide: decreases seizure threshold (avoid combined use with antipsychotics)

Oral Contraceptives: may increase levels

Warfarin: may alter antipsychotic levels; Warfarin levels may be decreased causing decreased bleeding time

 

Contraindications:

Elderly: start with low dose atypical (risperidone) or if necessary, 0.5 mg Haldol

heart disease (use atypical other than clozapine), narrow angle glaucoma, enlarged prostate, leukopenia/agranulocytosis (avoid clozapine), severe liver disease, renal failure, Parkinson’s (use atypicals), seizure disorder (atypicals or possibly molindone, maybe haldol or mellaril are safer?)

pregnancy (class C teratogen), avoid breast feeding (high potency may have lower risk)

 

Overdose:

Mellaril, Serentil and Orap can produce fatal cardiotoxicity

Treatment may include gastric lavage, catharsis, IV diazepam, medical treatment of hypotension

 

Low Potency

High Potency

 

 

Fewer EPS                                          

More EPS

More sedation, postural hypotension

Less sedation, postural hypotension

Greater effect on SZ threshold             

Less effect on SZ threshold

EKG (especially Mellaril and Pimozide)

Less cardiotoxicity

More anticholinergic                                        

Less anticholinergic

More likely skin pigmentation & photosensitivity

Occasional photosensitivity

Occasional jaundice                                         

None

Rare agranulocytosis                                        

None

Decreased libido, retrograde ejaculation

Less

 

 

50 mg BID, add 50 mg/day and PRN (10-40mg/day)

5 mg qAM and/or qHS add 5 mg every 2-3days

 

 

Adverse Effect of Neuroleptics (Dopamine-related):

 

Early

 

50% in 48 hrs, 90% within 5 days (10% frequency) / more common under 30 (male > female) / hypocalcemia 2o to hypoparathyroidism increases risk / genetic component / children: generalized, adult: axial, arm

 

Note:  usually resolves with discontinuation of drug / anticholinergics or even diazepam usually helps [amantadine, benztropine, biperiden, diphenhydramine, ethopropazine, orphenadrine, procyclidine, trihexyphenidyl]

 

Late

 

rabbit syndrome, tardive – dyskinesia, akathisia, dystonia, Tourette, complex

 

 

Neuroleptic-induced acute dystonia

10% during first few hours/days / occurs mostly in extremities, neck, ocular muscles

Mechanism: DA hyperactivity during troughs

Treatment: anticholinergics (Cogentin), antihistamines (Benadryl), maybe diazepam

Prophylaxis: Cogentin 1-2 mg PO bid

 

Neuroleptic-induced acute akathisia

can appear at any time

Treatment: reduce neuroleptic dose (least common w/ thioridazine, low with risperidone)

anticholinergics less effective?, perhaps use propranolol, benzodiazepine (clonazepam 0.5 mg PO bid), clonidine

 

Neuroleptic-induced tardive dyskinesia

10-20% after one year of treatment (usually not before 2 months), risk increases 1%/year 5-40% remission / reduce dose or change to risperidone (less TD), can even try lithium or  benzodiazepines if pt cannot continue on neuroleptics

Vitamin E may be beneficial if given early

Risk factors: female, older (less remission), brain damage, children, mood disorder

 

Neuroleptic malignant syndrome (NMS) (see other)

 

Neuroleptic Hx: recent increase in neuroleptic use or withdrawal of dopa-agonists / 20-30% mortality / more in males, younger

Risk Factors: dehydration, heat exhaustion, poor nutrition

Presentation:

·        Severe muscle rigidity

not reversed by anticholinergics?, may also have tremor, dyskinesias, sialorrhea

·        High Fever: in the absence of infection

·        ANS Lability: hyper or hypotension, tachycardia, tachypnea

·        Copious diaphoresis: irrespective to temperature and behavior

·        Altered mental status: may reach coma (EEG slowness and Babinski +)

·        Myoglobinuria: elevated CPK (MM fraction) & renal failure (can use dialysis)

·        Leukocytosis:  may have low platelets & DIC

Treatment: can treat 5-10 days then restart with low potency neuroleptic or clozapine

·        Dantrolene (Dantrium) 0.8 - 2.5 mg/kg PO q 6hrs or 1-5 mg q 5 mins IV (up to 10 mg/kg/day, about 100-200 mg/day PO)

·        Bromocriptine (Parlodel) 20-30 mg day in 4 doses

·        Amantadine may also be given

 

Medication-induced movement disorders

postural tremor, cogwheel rigidity, festinating gait, other Parkinson’s-like symptoms)

also caused by lithium, antidepressants, valproate / reduce doses, minimize caffeine, take drug at night to minimize daytime tremor, propranolol (10-40 mg bid to qid)

 

Hyperthermia (see other)

 

Pathways of Dopaminergic Systems:

 

Mesocortical                negative symptoms (activity in frontal)    D3, D4

                                    2o negative symptoms (excessive blockade)

 

Mesolimbic                   positive symptoms (DA hyperactivity)   D2, D1, D5

 

Nigrostriatal               EPS (DA receptor blockade)             D2

 

Tuberoinfundibular        DA blockade increases prolactin                       D1, D2, D5

 

 

Chemical Categories of Neuroleptics:

 

Tricyclics:  phenothiazides (see below), thioxanthenes (Navane), dibenzodiazepine derivatives (Clozapine), dibenzoxepine derivatives (Loxapine)

Butyrophenones: Haldol, Inapsine

Diphenylbutylpiperidines: Orap

Indole: Moban

Benzisoxazole: Risperdal

 

Phenothiazides:

 

aliphatic (Prolixin)                                  piperazine                                 piperidine

 

chlorpromazine (Thorazine)                 perphenazine (Trilafan)           thioridazine (Mellaril)

triflupromazine (Vesprin)                     trifluoperazine (Stelazine)        mesoridazine (Serentil)

                                                            fluphenazine

 


Antipsychotics Grouped According By Potency

 

Low Potency                                        Medium Potency                      High Potency

Chlorpromazine (Thorazine)                  Loxapine (Loxitane)                  Perphenazine (Trilafan)

Thioridazine (Mellaril)                           Molindone (Moban)                 Trifluoperazine (Stelazine)

Mesoridazine (Serentil)                         Perphenazine (Trilafan)             Pimozide (Orap)

Prochlorperazine (Compazine)?            Quetiapine (Seroquel)               Thiothixine (Navane)

Promethazine                                                                                        Haloperidol (Haldol)

Clozapine (Clozaril)                                                                              Droperidol (Inapsine)

                                                                                                            Fluphenazine (Prolixin)

                                                                                                            Olanzapine (Zyprexa)

Risperidone (Risperdal)

Ziprasidone                                                                             

Typical Antipsychotics (see atypical)

 

Haloperidol (Haldol) (butyrphenone) 

more potent (50:1), severe EPS / sedation:1-2 anticholingergic:1 hypotension:1-2

may cause neuroleptic malignant syndrome

Y uses: anti-psychotic, Tourette's, Huntington's, anti-emetic

Pt Ed: stiffness (cogwheel, shuffling gate), blunted affect, restless, akathisia, NMS dry mouth, dry eyes, constipation, urinary symptoms (even more potent antipsychotics have some anticholinergic side effects)

Available as: tablet, concentrate, IM injection, depot formulation

haloperidol decanoate: IM every 4/5 weeks (10-15X normal dose, max 100 mg/day, rest 4-5 days later), TL is 5-20 ng/ml

Tourette’s: 0.05-0.1 mg/kg in 2-3 divided doses

onset: 7-14 days after injection (long half-life)

5-10 mg PO bid up to 5-20 mg/day / 5 mg IM PRN for acute agitation

elderly take 0.5-2 mg PO bid/tid

 

Fluphenazine (Prolixin)

more potent (100:1), severe EPS / sedation:1-2 anticholingergic:1 hypotension:1-2

Pt Ed:  see Haldol

Available as: tablet, concentrate, IM and depot formulation

fluphenazine decanoate: IM every 2-3 weeks (12.5 mg injection = 10 mg PO)

onset for depot: much faster than depot haldol due to shorter half-life (10-20 hrs)

more expensive than haldol

 

Droperidol (Inapsine)                        IV only

 

Pimozide (Orap)        

highest potency (100:1) / sedation: 1-2 anticholinergic: 1-2 hypotension:1-2

Tourette’s Syndrome (Haldol may be safer, HPD)

Serious side effects: cardiotoxicity [get EKG], overdose can be fatal

hepatic metabolism / half-life 55 hrs

Contraindications:  cardiac arrhythmia or drugs prolonging QT interval, use caution with history of hypokalemia

Tourette’s: 0.5-1 mg bid increase qod to 10 mg/day

2-10 mg / tablet

 

Thiothixine (Navane)

more potent (20:1) / sedation: 3 anticholingergic:1-2 hypotension:1-2

also used for anxiolytic properties

hepatic metabolism / half-life 55 hrs

other side effects:  may produce ocular pigmentary changes (periodic eye exam)

Available as: tablet, concentrate, IM injection

2-5 mg PO/IM tid, titrate to 15-60 mg, 5 mg IM q 45’ for acute agitation

TL suggested to be 2-57 ng/ml

 

Trifluoperazine (Stelazine)   

more potent (25:1), moderate-severe EPS

sedation:1-2 anticholingergic:1-2 hypotension:1-2

hepatic metabolism / half-life 10-20 hrs / associated with few ECG changes

Available as: tablet, concentrate, IM injection

2-5 PO bid, 20 – 50 mg/day divided doses / elderly 1-15 mg/day

1-2 mg IM q 4 hrs PRN (max 6 mg/day) for acute agitation

 

Loxapine (Loxitane) 

medium potency (7:1) / sedation: 3 anticholinergic: 3 hypotension:1-3

note: anticholinergic side effects may work like Cogentin to decrease acute EPS Sx

contraindications: may have higher seizure risk, avoid drugs which lower threshold

hepatic metabolism to active metabolite / half-life 5-15 hrs

Available as: tablet, concentrate, IM injection

10 mg PO bid, then 75-250 mg divided doses / elderly 5-25 mg/day

12.5-50 mg IM q 4-6 hrs PRN for acute agitation

 

Molindone (Moban) (indolic)

medium potency (12:1) / sedation: 3 anticholinergic: 3 hypotension:1-3

note: less weight gain [unique], amenorrhea, impotence, lower seizure risk

hepatic metabolism / half-life 10-20 hrs

Available as: tablet, concentrate

15-20 mg PO bid, then 40-225 mg

 

Perphenazine (Trilafan)        

medium potency (10:1) / sedation: 3 anticholinergic: 3 hypotension:1-3

Also has anti-emetic properties

hepatic metabolism / half-life 10-20 hrs

Available as: tablet, concentrate, IM

4-8 mg PO tid, then 20-64 mg

5-10 mg IM q 6 hrs PRN (max 30 mg/day) for acute agitation

 

Chlorpromazine (Thorazine)

low potency, sedation:3-5 anticholinergic:3-5 hypotension:3

these side effects are usually worse with IM formulation

increase LFT, severe photosensitivity, cardiac effects, leukopenia, agranulocytosis (rare)

hepatic metabolism to many metabolites

Contraindications: avoid in elderly due to orthostatic hypotension

Available as: tablets, concentrate, IM, suppository 10-50 mg PO bid/qid, 50mg BID, increase 50mg/day to 300-1000mg (2000 mg/day max)

intractable hiccups: 25-50 mg qid

nausea, vomiting: 10-25 mg PO qid, 25 mg IM qid, 100mg PR qid

 

Thioridazine (Mellaril)

low potency, sedation:3-5 anticholinergic:3-5 hypotension:3

photosensitivity:2-3 / more cardiotoxicity [get EKG], overdose can be fatal

dose-related retinal pigmentosa, more retrograde ejaculation, lower seizure risk?

only phenothiazide that has no anti-emetic action (CNS triggered)

hepatic metabolism to active metabolites (mesoridazine) / half-life 10-20 hrs

Contraindications: avoid in elderly due to orthostatic hypotension

Available as: tablet and concentrate

25-100 mg tid, then 300-750 mg

 

Mesoridazine (Serentil)

low potency (2:1), sedation:2-3 anticholinergic:2-3 hypotension:2-3

very low retinal pigmentosa, retrograde ejaculation

hepatic metabolism to many metabolites / half-life 24-48 hrs

Contraindications: avoid in elderly due to orthostatic hypotension

Available as: tablet, concentrate, IM

25-50 mg PO tid, then 75-300 mg

25-50 mg IM q 30’ PRN for acute agitation

 

Prochlorperazine (Compazine)

            anti-emetic, anti-psychotic / blocks D2 receptors in CTZ

 

Promethazine

            anti-emetic, anti-psychotic, pre-anesthetic

 

Atypical Antipsychotics

 

·        Clozapine has been shown to be more effective for positive symptoms in treatment resistant schizophrenia.  Studies are ongoing to determine if atypicals are as good as neuroleptics for acute psychosis as well. (7/99)

·        2nd line antipsychotic (works in 30% of non-responders to 1st line)

·        believed to be especially useful in patients with negative symptoms secondary to neuroleptic treatment; ongoing to determine efficacy on primary negative symptoms

·        Try to taper down other antipsychotic and/or anticholinergic to d/c within 30 days

·        Efficacy may require up to 4-6 weeks

 

Clozapine (Clozaril)                     

Y uses: refractory psychosis with failure from 2 classes (20mg/day haldol) for 6 weeks, or unable to tolerate other antipsychotics

mechanism: D1 >> D2, D4 and 5HT-2a receptor antagonist; blocks a-1, AChM, H1

sedation:4-5 anticholinergic:4-5 hypotension:4 / hypertension: 1-2 / EPS: low

Very low EPS, NO tardive dyskinesia (useful for Parkinson’s + psychosis)

note: M4 agonist (produces hypersalivation)

Less common: hypertension, leukopenia, agranulocytosis (2-3%) [weekly CBC for 6 months, than monthly], SZ (1-2%, 5% over 600mg/day)

hepatic metabolism CYP1A2 / half-life 11 hours

Pt Ed: sedation (40%), hypersalivation (30%), dizziness (20%)

constipation (15%, encourage fiber and fluids), headache, tachycardia, hyperthermia

Drug interactions:

Cimetidine (Tagamet) can increase levels [substitute with ranitidine (Zantac)]

Fluvoxamine can double Clozapine levels

TCA’s increase risk of seizures, cardiac changes, sedation

Contraindications:

absolute:  anaphylactic reaction, comatose state, concomitant use of epinephrine for shock

relative:  pregnancy, Hx of agranulocytosis, leukemia, NMS, narrow angle glaucoma, hepatic or renal dysfunction, prostatic hypertrophy, Parkinson’s, severe cardiovascular disease

avoid: drugs which can suppress bone marrow function: carbamazepine, sulfonamides, captopril

Clinical: Monitor hypotension and tachycardia more carefully in first month.  Agranulocytosis is more frequent than in younger adults and should be monitored even more carefully.  Discontinue at 3000/mcl (50% of normal) or absolute granulocytes drop below 1500/mcl.  May rechallenge after WBC’s return to normal, but call Clozaril National Registry 800-448-5938).  May rechallenge after seizure with concurrent use of Depakote.

Available as: tablet only

Overdose:  there are no specific antidotes for clozapine. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

25 mg bid, increase 25-50 mg every 2-3 days, then 300-900 mg divided doses, TL over 350 ng/ml

 

Risperidone (Risperdal)

      Potency N/A / 5-H2 and D2 receptor antagonist / blocks a-1

sedation:3 anticholinergic:1-2 hypotension:3 / Seizures: 1-2

Most common: insomnia and agitation

Less common: weight gain, increased prolactin, may prolong QT (rarely a problem)

drug of choice for private pay

dose-dependent EPS (over 6 mg/day, tardive dyskinesia frequency not determined)

Available as: tablet, concentrate (IM forthcoming)

1 mg bid, increase 1 mg every 2-3 days to 4-12 mg

elderly: 1-4 mg/day (may be a good choice)

hepatic metabolism to active metabolite, renal clearance / half-life 3-20 hrs

Clinical:  orthostatic hypotension and reflex tachycardia minimized with slow upward titration, can cause disinhibition in patients with underlying bipolar, aggression, impulsivity [check that 7/99]

 

Olanzapine (Zyprexa) [newer]

Potency N/D / 5-HT2, D1, D2, D3, D4 receptor antagonist / blocks a-1, ACh-M1, H1

No EPS / sedation:3 anticholinergic:3 hypotension:3

Most common: weight gain (especially when combined with mood stabilizers) drowsiness, dry mouth, akathisia, insomnia

Less common: orthostatic hypotension, lightheadedness, nausea, tremor

Other side effects: seizures (mild risk)

hepatic metabolism by CYP1A2 to active metabolite / half-life 21-50 hrs

Drug interactions: levels decreased by tobacco and carbamazepine

10 mg/day up to 5-15 mg / Available as: tablet

 

Quetiapine (Seroquel)

new, medium potency?

5-HT2 and D2 receptor antagonist / blocks a-1,2 and H1 receptors

seizures (mild risk) / lenticular opacity? / TD?

Common: orthostatic hypotension (temporary), sedation, weight gain (minimal), dyspepsia, abdominal and dry mouth

Other: lenticular opacity

Available as: tablet

Hepatic metabolism CYP3A4 / half-life 6 hrs

25 mg bid, increase 25-50 mg every 2-3 days, to 300-600 mg

Elderly: clearance reduced by 40%

 

Ziprasidone                                  

D2, D3 and 5-HT2a and 5-HT1a receptor antagonist / blocks monoamine reuptake

Side effects: somnolence, dizziness, nausea, postural hypotension

Other: prolactin elevation

Half-life 4 hrs

Available as: tablet, (IM forthcoming)

40-80 mg/day

 

Sertindole (Selerct)         

      changes in QTc interval (significance unknown) / is it any good?

 

 

STIMULANTS

 

 

Methylphenidate (Ritalin)

Y uses: covers all 3 symptoms of ADHD (hyperactivity, decreased attention) and narcolepsy, also used as antidepressant adjunct and in depressed AIDS patients

Mechanism: not known exactly, related to amphetamines

2-3 day onset

Metabolism: hydroxylation and renal excretion

Common side effects: nervousness, insomnia

Cardiac: Hypertension, tachycardia, arrhythmia

CNS: dizziness, euphoria, tremor, headache, precipitation ticks and early onset Tourette’s syndrome and psychosis (rare)

GI: decreased appetite, weight loss, reports of liver toxicity

Hematological: leukopenia and anemia reported

Growth Inhibition:  chronic administration associated but not conclusive

Overdose: agitation, tremors, hyperreflexia, confusion, psychosis, psychomotor agitation, tachycardia, sweating and hypertension.  Seizures, arrhythmias and coma can occur at very high doses.

Note: schedule II controlled substance, tolerance and intense psychological dependence can develop / abrupt cessation can precipitate severe depression, fatigue and suicide

Work-up: blood pressure and cardiac status (less cardiac risk than Dexedrine), leukopenia, anemia and elevated liver enzymes have been reported (get baseline CBC and LFT), screen for Tics and Tourette’s syndrome

Contraindications: hypertension, seizure disorder, symptomatic cardiac disease, not recommended for psychotic patients or history of substance abuse, pregnancy data not known (not recommended for pregnant or lactating women)

Drug interactions: may antagonize effects of antihypertensives (clonidine + ritalin may be fatal) / increases levels of TCA or tetracyclics, warfarin, phenytoin, phenobarbital, primidone, phenylbutazone

Available as: tabs or sustained release (should be swallowed whole)

Half-life: 3-4 hrs, 6-8 hrs for sustained release

Dose schedule:

ADHD: begin 5 mg bid/tid, increase 5-10 wk / dose x q 7am, 12noon, 0.5x 3pm,  60-80 mg/day (max 2mg/kg/day)

Depression (medically ill): 10-20 mg/day

Depression (augmentation): 10-40 mg/day

Clinical: take two 1 wk drug holidays per year / failure on one stimulant does not predict failure on another / Safety not established for children under 6 yrs, weight loss or growth inhibition are reasons for discontinuation

 

Dextroamphetamine (Dexedrine)

Mechanism:  sympathomimetic amine, causes release of NE, increased doses cause DA and 5HT release, some MAO inhibition

Common:  increases blood pressure, respirations, mydriasis, mild bronchial dilation

8-12 hr half-life

screen for movement disorder (can precipitate tics, Tourette’s)

Contraindications:  hypertension, hyperthyroid, cardiac disease, glaucoma, Hx of psychosis or substance abuse, children less than 3 yrs old

Pregnancy category C, avoid breast feeding also (premature, low birth weight)

Available as:  tablets, syrup, sustained release caps (dose bid)

Clinical: failure to respond to one does not preclude trying another stimulant

Schedule II / tolerance and intense psychological dependence / cessation may produce suicide / discontinue if weight loss or failure to grow occurs in children

ADHD: 2.5-5 mg bid/tid, then 40-60mg/day divided 7am, 12noon, 3 pm (1 mg/kg/day max for children) / 2-3 day onset

Narcolepsy: 10-60 mg/day

Adjunct for antidepressants: 5-20 mg/day

 

Pemoline (Cylert)

Y uses: ADHD / 2nd line for primary MS fatigue

Mechanism: unknown, 2-4 wk onset

Common: insomnia (may reside or decrease dose)

Serious: hepatic dysfunction and hepatitis (usually reversible)

CNS: tremor, headache, irritability, precipitation ticks and early onset Tourette’s, decreased seizure threshold and psychosis (rare)

GI: loss of appetite and weight loss (usually resolves in months)

Less cardiovascular effects compared with other stimulants

Overdose: nausea, vomiting, psychomotor agitation, tremor, hyperreflexia, sweating, headache, tachycardia, hypertension, confusion, hallucinations

Metabolism: hepatic with renal excretion (50% unchanged)

Half-life is 12 hrs

Note: reduced abused potential, but psychological dependence still possible

Work-up: frequent LFT’s and CBC, screen for tics and Tourette’s

Contraindications: pregnancy category B, not recommended for psychotic patients or history of substance abuse Safety not established for children under 6 yrs, weight loss or growth inhibition are reasons for discontinuation / also monitor for hepatic toxicity

Drug interactions: decreased seizure threshold (reported when given with anticonvulsants)

Dosing: 18.75-37.5 mg/day q 8am, increase by 18.75 until response achieved, usu. 18.75 mg qid (max 112.5 mg/day or 3 mg/kg/day

 

 D & L amphetamine (Adderall)

      adult drug of choice / 2 doses/day

 

 

Drugs Used For Substance Dependence or Reversal Agents

 

 

Buprenorphine [wiki]

μ agonist / κ antagonist / FDA approved for office-based therapy for opioid dependence (as opposed to methadone) / 8 to 32 mg daily 3 to 7 days/week / low potential for overdose (inherent limit on euphoria), easier detoxification

 

Methadone (Dolophine) [wiki]

blocks euphoria from heroin, decreases craving / used for maintenance of heroin addiction / must be prescribed from specialized clinic

 

Naloxone (Narcan) [wiki]

competitive antagonist for Mu receptor

Uses: reversal of over-sedation with narcotics / may have some other psyc uses (kleptomania, pruritis in PSC)

Pharm: IV only / short acting, half life is minutes, pt may relapse into depressed state

Side effects: can increase sympathetic tone precipitating MI in patients with coronary disease / otherwise, very safe, can be given every 5-10 minutes

 

Naltrexone (ReVia) (see naloxone)

            opioid antagonist / must be free of heroin 5 days or it will precipitate withdrawal

 

Flumazenil [wiki]

            BZ receptor antagonist / recovery from anesthetic use, BZ overdose

 

Clonidine (Catapres)

            for heroin withdrawal

 

Buproprion (Zyban)

            used in tobacco cessation

 

Disulfiram (Antabuse) [wiki]

inhibits acetaldehyde dehydrogenase / anti-ethanol conditioning / caution with CAD, HTN, CVA, DM / has not been consistently shown superior to placebo (naltrexone and acamprosate have conflicting results as well)

 

Aminocaproic acid

                        for heparin overdose (vitamin K for warfarin overdose)

 

Antiparkinsonian Agents Used in Psychiatry

 

Benztropine (Cogentin)                      systemic only (no sedation) / tablets and injection          

Triphexyphenidyl (Artane)                tablets

Biperiden (Akineton)

Procyclidine (Kemadrin)

Amantadine (Symmetrel)                   dopaminergic / capsule and syrup

Propranolol (Inderal)

Diphenhydramine (Benadryl)            sedation / capsule and injection

Tacrine (Cognex)                                old agent / not used anymore

 

Cholinesterase inhibitors

 

Donepezil (Aricept)

Galantamine

Rivastigmine

 

            Uses: dementia (often Alzheimer’s)

            Side effects: diarrhea, nausea, dizziness in 10-20%

Trends: 7/06 AIM says side effects often worse than benefit, so use less and at lower doses

 

ECT therapy

 

·        Patients must be over 18 years old (over 65 requires 2nd opinion)

·        Informed consent must be signed for each individual treatment

·        try to deliver charge to non-dominant hemisphere (usually right) to minimize cognitive side effects

·        bilateral creates more cognitive side effects

·        optimal Sz time 30-90 seconds (tonic, clonic, post-ictal)

·        6-9 or 9-12 treatments in series with follow-up drug therapy and/or ECT every 4-8 weeks

 

Complications:

death from anesthetic

fractures (not w/ modified ECT), soreness

memory loss

retro and anterograde amnesia surrounding treatment

biographical memory loss (no firm data according to Santos)

visuo-spatial memory loss (resolves w/in 1 month of treatment)

intractable Sz (anecdotal reports)

 

Drug Interactions (no absolute contraindications for ECT):

TCA – decrease dose, may cause conduction problems                                               

Heterocyclics - okay

SSRI – okay

Other class of AD?

Antipsychotics (typical) – lower Sz threshold might actually help

Antipsychotics (atypical) – decrease dose, potential problems, Sz threshold?

Lithium (d/c at least 1 day before, half-life is 24 hrs) – dangerous / disrupted BBB may allow influx and neurotoxic lithium levels

Anticonvulsants – decrease dose if needed to raise Sz threshold

Benzodiazepines - decrease dose if needed to raise Sz threshold

 

Drugs used for Modified ECT

1.      anticholinergics prevent vagal stimulation from causing bradycardia

2.      brevital – general anesthetic

3.      succinylcholine – short acting muscle relaxant

 

Cause Significant Weight Gain

Mood-stabilizers (except new ones)

Antidepressants (except SSRI, venlafaxine, bupropion)

Low and Medium Potency neuroleptics (except Moban)

Atypical antipsychotics (to an extent, especially olanzapine + depakote)

 

Clinical Strategy

AD for bipolar can cause manic switch

AS for mood disorder increases risk of tardive dyskinesia

 

Mechanisms

MAOI: MAOI

TCA: NE and 5HT reuptake

Amoxapine, Maprotiline: NE reuptake

Remeron: a-2 antagonist (and other)

SSRI: 5HT reuptake

Trazadone, Nefazodone: 5HT reuptake and 5HT2a antagonist

Venlafaxine: 5HT and NE reuptake

Bupropion: NE reuptake

Low Potency neuroleptic: D2

High Potency neuroleptic: D2

Clozapine: D1 > D2, D4 / 5HT2a antagonist

Quetiapine, Risperidone: D2 & 5HT2a antagonist

Olanzapine: D1, D2, D3, D4 / 5HT2a antagonist

Ziprasidone: D2, D3 / 5HT1a and 5HT2a / blocks monoamine reuptake

 

Decrease Seizure Threshold

 

TCA’s

Amoxapine (Asendin)

SSRI’s, Effexor (rare)

Bupropion (Wellbutrin)

Loxapine (Loxitane)

Clozapine (Clozaril)

Risperidone (Risperdal)

Olanzapine, Quetiapine (mild)?

 

Cardiotoxic

 

Thioridazine (Mellaril)

Pimozide (Orap)

Mesoridazine (Serentil)

Others?

 

Reduce Dose in Elderly

 

MAO

TCA

Tetracyclics

Atypical AD (except Venlafaxine)

Lithium

Benzodiazepines

Anticonvulsants?

Risperdal

 

Can be Given IM

 

lorazepam, diazepam

hydroxyzine

haldol, prolixin, thiothixine, stelazine, loxitane, trilafan, serentil, thorazine, ziprasidone?, risperdal

 

Can be Given IV

 

diazepam

droperidol (only form)

 

Dosages of Psychiatric Drugs

 

Antidepressants

 

Phenilzine (Nardil)  30-90 mg/day

Tranylcypromine (Parnate)  10-40 mg/day

Tertiary TCA  75-300 mg/day

Secondary TCA

            Desipramine (Norpramin) 75-300 mg/day

            Nortriptyline (Pamelor) 75-300 mg/day

            Protriptyline (Vivactil) 25-75 mg/day

Amoxapine (Asendin) 150-250 mg/day

Maprotiline (Ludiomil) 100-150 mg/day

Mirtazapine (Remeron) 15-45 mg/day

Fluoxetine (Prozac) 20-80 mg/day

Paroxetine (Paxil) 20-50 mg/day

Sertraline (Zoloft) 50-200 mg/day

Fluvoxamine (Luvox) 100-300 mg/day

Trazodone (Desyrel) 200-600 mg/day

25-150 mg/day (insomnia)

Nefazodone (Serzone) 300-600 mg/day

Venlafaxine (Effexor) 75-375 mg/day

Bupropion (Wellbutrin) 300-450 mg/day

 

Mood Stabilizers

 

Lithium 600-1200 mg/day

Carbamazepine (Tegretol) 1500 mg/day

Valproic Acid (Depakote) 750-3800 mg/day

Gabapentin (Neurontin) 900-3600 mg/day

Lamotrigine (Lamictal) 300-500 mg/day

Tiagabine () 32-56 mg/day w/ food

Clonidine 0.5 to 0.8 mg/day

 

Anxiolytic

 

Triazolam (Halcion) 0.25-0.5 mg PRN

Lorazepam (Ativan) 0.25-0.5 mg PRN

Alprazolam (Xanax) 0.5-5 mg

Oxazepam (Serax)

Clonazepam (Klonopin) 3-6 mg/day (anxiety), 0.25-10 mg/day (mania)

Chlordiazepoxide (Librium) 25-50 mg q 4 hrs (max 400 mg/day/day)

Diazepam (Valium)

Buspirone (Buspar) 15-60 mg/day

Hydroxyzine (Atarax, Vistaril) 50-100 mg/day

Verapamil 160-480 mg/day

Deprol 200-2000 mg/day

 

Sedative/Hypnotic

 

Temazepam (Restoril) 7.5-30 mg/day

Quazepam (Doral) 7.5-30 mg/day

Estazolam (ProSom) 1-2 mg/day

Flurazepam (Dalmane) 15-30 mg/day

Zolpidem (Ambien) 5-10 mg PO qhs

Chloral Hydrate 500-1000 mg/day

 

Antipsychotic

 

Haloperidol (Haldol) 5-20 mg/day

Fluphenazine (Prolixin) 5-20 mg/day

Pimozide (Orap) 1-10 mg/day

Thiothixine (Navane) 15-60 mg/day

Trifluoperazine (Stelazine) 20-50 mg/day

Perphenazine (Trilafan) 20-64 mg/day

Loxapine (Loxitane) 75-250 mg/day

Molindone (Moban) 40-225 mg/day

Chlorpromazine (Thorazine) 300-1000 mg/day

Thioridazine (Mellaril) 300-750 mg/day

Mesoridazine (Serentil) 75-300 mg/day

Clozapine (Clozaril) 300-900 mg/day

Risperidone (Risperdal) 4-12 mg/day

Olanzapine (Zyprexa) 5-15 mg/day

Quetiapine (Seroquel) 300-600 mg/day

Ziprasidone 40-80 mg/day

Methylphenidate (Ritalin) 60-80 mg/day

Dextroamphetamine (Dexedrine) 40-60 mg/day

Pemoline (Cylert) 60-80 mg/day

D&L amphetamine (Adderall)

Benztropine (Cogentin) 2-6 mg/day

Trihexyphenidyl (Artane) 4-15 mg/day

Diphenhydramine (Benadryl) 50-300 mg/day

Amantadine (Symmetrel) 100-300 mg/day

 

Anesthesia

 

 

 

T ½

Elimination

Metabolite

Midazolam (Versed)

0.5 to 5 hrs

hepatic/renal

yes

Lorazepam (Ativan)

15 to 20 hrs

glucuronidation /renal

no

Diazepam (Valium)

2 to 5 hours

hepatic/renal

multiple

 

Amides           

prilocaine < etidocaine < lidocaine, mepivocaine, bupivicaine (longer acting) / drug

interactions: cimetidine

 

Esters            

cocaine, procaine, tetracaine, benzocaine / rapidly metabolized in plasma

 

Dantrolene    

blocks SR Ca release / inhaled anesthetic

Uses: muscle relaxant, malignant hyperthermia (halothane + succinylcholine), malignant neuroleptic syndrome, reverses hypothalamic dysfunction caused by major tranquilizers

 

Thiopental     

fast onset / no analgesia / muscle relaxant / short acting, rapid redistribution / respiratory, CV depression / accumulates with long term use (liver metabolized)

 

Lorazepam (Ativan) (see above)

Diazepam (Valium) (see above)

Midazolam (Versed) (see above)

 

Dipravan (Propofol)

Mechanism: unclear but effect is same as benzodiazepines / smooth/immediate onset,

rapid metabolism (offset)

Uses: surgery, ICU setting

Side effects: decreases contractility (avoid with depressed EF), decreases BP, increased risk of

infection (because it’s stored/delivered in lipid emulsion), increased TG

 

Ketamine       

superficial pain reduction / amnesia / increases cardiac output bronchodilates (good for

asthmatics) / Side effects: CNS stimulant, hallucinations, increased ICP (PCP derivative) / used in

infants and children

 

Etomidate

minimal cardio/resp depression / rapid onset, metabolism / Side effects: pain at injection, myoclonic activity, steroidogenesis inhibition

 

 

onset

metabolism

Active metabolite

fentanyl

1 minute

renal

No

morphine

5 to 10 minutes

renal

Yes

demerol

3 to 5 minutes

renal

Yes

remifentanyl

1 minute

tissues

?

 

Morphine       

Side effects: potential for respiratory depression, cardiac depression (mild), histamine release / theoretically, high doses decrease TPR and actually increase C/O

 

Meperidine (Demerol)

cardiac depression, without the increase in C/O

 

Fentanyl         

#1 for cardiac patients / increases C/O

 

Remifentanyl

            Metabolized directly by tissues so great with liver/renal disease

 

 

Hormone pharmacology

 

Steroids, Estrogens, Fertility, Osteoporosis, Androgens, Other Hormones

 

Steroids (see other)

 

Prednisone     

            1:1 cortisol to aldosterone ratio

 

ß-dexamethasone

anti-inflammatory action is 30 x > cortisone, 5x > prednisolone)  / increased half-life, less Na retention (worse in older patients) / synthetic steroids do not bind CBG

 

Fludrocortisone (see other)

Mineralocorticoid – note: escape phenomenon prevents sodium retention beyond 15 days, but K excretion continues / aldosterone also promotes H ion excretion

 

GnRH analogs (leuprolide)    

continuous dosage inhibits pituitary release of FSH, LH

Uses: numerous – endometriosis, PCOD, prostate Ca (with flutamide, non-steroidal competitive

TR antagonist)

 

Estrogens

 

Conjugated Estrogens (premarin)

hormone replacement therapy / prevent ovulation, increase risk of clotting, decrease risk for many cancers, increase risk for breast Ca 1.5 x

Side effects: weight gain, nausea, gall bladder, mood changes

Contraindications: pregnancy, breast cancer, heart disease, stroke, liver disease, migraines

Drug interactions:  phenytoin/phenobarbital increase metabolism, rifampycin decreasing recyling (both increase clearance)

Dosing: 0.625 mg/d for replacement therapy

 

Tamoxifen     

estrogen receptor antagonist / agonist on bone, endometrium

Uses: adjunctive therapy in certain breast CA patients, secondary prevention of breast CA in high-risk patients

BCPT trial à tamoxifen 20 mg/d reduced by 50% risk of invasive and non-invasive breast cancer in women of all age-ranges, including prior LCIS (and now DCIS)

Side effects: increased risk of endometrial CA, 5x risk of DVT/PE and CVA, ?liver toxicity

 

Raloxifene

estrogen receptor agonist / similar profile as tamoxifen but supposed to not have increased risk for endometrial CA / STAR trial ongoing to compare tamoxifen vs. raloxifene head-to-head / still has 3x risk of thrombosis

 

            aromatase inhibitors

 

            exemestane

being used for estrogen receptor positive breast cancer adjunctive treatment similar to Tamoxifen / but may provide additional benefits (may even be better; also fewer adverse gynecological events and decreased incidence of venous thrombosis)

Side effects: increased osteoporosis, fractures, musculoskeletal complaints (versus SERMS)

 

 

Fertility / Obstetric

 

Oral Contraceptives

 

Drug interactions:

Efficacy of OCP’s reduced by penicillins, tetracyclines, rifampin, ibuprofen, phenytoin, barbiturates, sulfonamides

OCP’s reduce efficacy of folates, anticoagulants, insulin, hypoglycemics, methyldopa, phenothiazides, TCA’s

Contraindicated: see estrogen

           

Ethinyl estradiol        

mestranol is cleaved to EE by the liver / oral contraceptives

 

19-nor progestins (medroxyprogesterone, MPA)

variable effect on ovulation / impair transport and implantation

Side effects: edema, weight gain, HA, menstrual irregularities / ? avoid w/ liver disease

 

Intrauterine device (IUD)

very effective in preventing pregnancy, can be used in nulliparous women

           

Clomiphene (Clomid)

induces ovulation / competitive ER antagonist in pituitary / used to achieve ovulation in PCOD (given with GnRH? to induce FSH, LH surge) / Side effects: hot flashes, multiple gestation (usually twins)

 

Aromatase inhibitors

block conversion of androgens to estrogens

 

Mifepristone/RU-486

anti-progestin / given with prostaglandin to terminate pregnancy

 

 Osteoporosis

 

Bisphosphonates (PCP)

 

bind to bone, decrease turnover / taken PO

Uses:  patients at increased risk for fracture (osteoporosis, steroid use, prostate cancer receiving anti-androgen therapy), Paget’s (1-3 mo onset), neoplasms (given IV 1-3 day onset), trauma

Note: pt must stand up for 30 mins after taking oral formulations (take 30 mins apart from other meds, esp. antacids)

Contraindications: acute upper GI tract inflammation or other mechanical problems, osteomalacia, renal impairment, hypocalcemia, pregnancy or breastfeeding, < 18 yrs

Side effects:

·        Common: GI irritation to ulceration (e.g. contact stomatitis) [pic], with IV (can get short-lived influenza-like syndrome with fever, myalgia)

·        Rare: TMJ problems, severe rash, SJS/TEN, osteonecrosis of jaw [pic](are of exposed bone in mandible (⅔) or maxilla (⅓) [pic] which heals poorly or does not heal over 6-8 weeks; usually in higher doses (IV), longer duration, such as used in myeloma (5% incidence; usu. occurs with 1.5-3 yrs of use; dental procedures increase risk)

Metabolism: half-life of 10 years in bones, remainder excreted unchanged by kidney

Trends: 7/06 not cost effective for women with just osteopenia (T-score –1.5 to –2.4) and not osteoporosis // use vitamin D 800 IU/d + calcium

 

Alendronate (Fosamax) [wiki]                      

Dose: 70 mg q week or 10 mg qd

                       

            Residronate (Actonel) [wiki] 

                        daily or weekly

 

            Etidronate [wiki]        

                        more side effects / has been replaced by newer agents

 

            Pamidronate (Aredia) [wiki]

                        monthly IV

 

            Ibandronate (Boniva) [wiki]

                        Has Sally Field in T.V. ads.

 

SERMS (e.g. Tamoxifen, Raloxifene) (see above)

 

Mithramycin              

inhibit RNA synthesis (required for bone resorption) / treat Paget’s, hypercalcemia

Side effects: toxicity to bone, GI, blood dyscrasias

 

Fluoride         

may stimulate bone formation, decrease resorption / slow release NaF / Side effects: bone has less mechanical strength

 

Androgens

 

Careful with liver toxicity or liver disease

 

Testosterone esters

metabolite DHT is androgenic

Side effects: decreased HDL, jaundice, enanthate, decreased FSH/LH (spermatogenesis), “roid” rage, worsens

 

Propionate                 

prostate Ca

 

Methyl T                   

oral availability, but worse liver toxicity

 

Flutamide

non-steroidal competitive TR antagonist / sometimes used in combination with LHRH agonists for prostate cancer

 

Oxandrolone               increased anabolic : androgenic ratio

Oxymetholone

 

Danazol (Danocrine)             

weak androgen / treats endometriosis (negative pituitary feedback)

 

5α-reductase inhibitors (dutasteride, finasteride)

 

 

Thyroid

 

Levothyroxine (Synthroid)

Side effects: angina, arrhythmia // the symptoms of being hyperthyroid basically

Drug interactions: cholestyramine and iron (interfere with absorption; space out by 2 hrs), barbiturates (increase metabolism), displace plasma-bound drugs

long half-life: 6-7 days

 

Propylthiouracil (PTU) [wiki]

inhibits peroxidase (organification of I) and peripheral T4 to T3 conversion / may be immunosuppressive / accumulates in thyroid (serum levels not informative)

Side effects:

·        granulocytopenia (0.5%, obtain baseline WBC, onset is abrupt, sequential monitoring may not be useful) / can have mild leukopenia (and continue PTU) or can have severe agranulocytosis (usu. < 100 ANC); usu. recovers by 5-7 days after stopping PTU

·        aplastic anemia (rare)

·        skin rash (3-5%): purpura, dermatitis

·        subclinical hepatitis (common): usually transient/asymptomatic, can continue with caution

·        others: itching, arthritis, arthralgias, myalgias, lymphadenopathy, mouth ulcers

Pregnancy: both drugs cross placenta and inhibit fetal thyroid gland / use smallest does if pregnant

Course: response may take 2 wks due to stored T4 / euthyroid usually achieved within 2-4 months / continue treatment for 6 months to 1 yr and revisit (recheck TFT periodically)

 

Methimazole (Carbazole)

same without the T4 to T3 block

 

Carbimazole

Causes moderate thrombocytopenia (forms complex with platelet-endothelial-cell adhesion molecule 1)

 

Iodide             

high dose inhibits synthesis and release of T4/T3 / escape or tolerance within weeks limits to temporary use for hyperthyroidism (thyroid storm)

 

Radioiodine (I131)

Strategy: deplete stores of T4 with PTU (1 month), then stop PTU to allow uptake / usually takes 6-18 weeks to fully work, 30% become hypothyroid in first year after treatment, 3%/year after that / then requires lifelong HRT / steroids may reduce chance of exacerbation of Grave’s ophthalmopathy (which sometimes occurs upon I131 treatment)

Pregnancy: of course would be contraindicated for pregnancy but could be given if more than 6 months prior to conception

 

Other Hormones

 

Bromocriptine

            DA analog / hyperprolactinemia / decreases GH in acromegaly

 

Carbargoline             

newer agent for hyperprolactinemia

 

Octreotide     

Mechanism: somatostatin analog

Uses: acromegaly and other secretory tumors, given to reduce splanchnic blood flow in GI bleeding

Side effects: cholelithiasis, diarrhea, mild abdominal discomfort

 

Desmopressin           

            diabetes insipidus / more ADH action, less vasoconstriction