Hepatic Encephalopathy or Psychosis?

We received a really interesting nonformulary consult for risperidone this week. Pt on lactulose, rifaximin, risperidone, omeprazole, lasix, codeine/APAP. Just looking at the meds, you know the pt is probably in end stage cirrhosis (needing lasix to keep the fluid out, acid reflux issues…). Plus, of course, he’s on lactulose and rifaximin. Pharmacy was consulted on what to do with the risperidone. Now the detective work begins…The following is the SOAP note I wrote up regarding this issue.

S)
70 y/o male patient with PMH significant for chronic hepatitis, cirrhosis, RA, osteoporosis, delirium, and unspecified psychosis. Current medications include codeine/APAP, omeprazole, KCl, Lasix, Risperidone, lactulose, Rifaximin, loratidine, and sertraline. Pt in for outpatient appt on 01/04/2012 – he was at baseline, but fatigued in the mornings. Relative is requesting dose decrease. Denied delusions/hallucinations at this visit. Clinical pharmacist consulted for continued use of nonformulary risperidone.

Previous hospitalizations:

2009: Pt admitted to ED after falling in the shower. He was given 80mg prednisone, and became profoundly agitated (required restraints). His agitation improved, but psychosis emerged. Risperidone started. Prior to D/C, pt’s mental status improved and risperidone dose decreased to 1mg in AM and 2mg at HS with hopes of further decreasing dose in future. Ammonia 95 at this visit.

2010: Pt admitted to hospital d/t being unresponsive. Started Rifaximin by GI, and showed improvement. Gained 20lbs over a few days, mostly responded to Lasix. Pt discharged with rifaximin. Ammonia 180 at this visit.

2011: Pt’s CC was AMS. Found that this was likely d/t pt running out of rifaximin and his constipation. Negative for SBP, ascites, and blood culture x2.

O)
10/23/2011: Glucose 106, SCr 0.77, Alk phos 182 H, AST 49 H, ALT 33, bilirubin 1.9 H
BP range last year: 91/50 to 150/88, Mostly 120s/70s.
Pt did not get lipids done during last visit and has not been updated since 2009.

A)
1. Mental health sx may be d/t hepatic related encephalopathy. Pt has never tried rifaximin alone without risperidone. Also, pt’s 2011 admit for AMS was d/t running out of rifaximin – this may be the medication that is alleviating MH sx.

2. March 2011 MH note states: “Pt appears to have dementia and Parkinson-related symptoms.” Dementa-related psychosis is a black box warning for risperidone d/t increased mortality risk in elderly dementia pts – most deaths d/t CV or infectious events. Also, Parkinson-related symptoms may be d/t risperidone.

P)
1. D/C risperidone – rifaximin alone may be controlling his MH sx, and risperidone has a black box warning for dementia-related psychosis.  
2. F/U lipids, since risperidone is associated with metabolic syndrome and can elevate cholesterol.

For mental health patients – it’s so important to look at when the start date of the medication was, and see why it was started, and what the situation was. This is a great example of why.

Short post today - getting prepared for residency interviews...first one in San Diego tomorrow!

TCA's AKA the "dirty" SNRI's

The VA and Department of Defense have an extensive document about the treatment of Major Depressive Disorder (MDD). The first half of the document is about the appropriate diagnosis of MDD – I don’t think it’s important for clinical pharmacists to know all the details of this, since diagnosing is in the physician’s scope of practice. However, I do think it’s important for pharmacists to skim over this portion and at least be familiar with the symptoms to look out for. For example, if the mental health pharmacist (my preceptor) gets a consult on what to do with a pt’s antidepressant (d/t ADR’s, etc), then she will read the pt’s chart thoroughly. What if it turns out that the pt’s current symptoms don’t totally correspond to MDD, and just mild symptoms of depression? Does the pt really need the antidepressant? Can the dose significantly be lowered? Questions like these pop up, and it helps to at least be familiar with how various disease states are diagnosed. When I’m in practice, I really won’t be questioning diagnoses since that is not in my scope of practice unless I see something really wrong/dramatically affects my medication therapy recommendations. So…

1.       Diagnosis of MDD is made.

2.       Many 1^st line options.

a.       Selective Serotonin Reuptake Inhibitors (SSRI’s) – Paxil (paroxetine), Celexa (citalopram), Prozac (fluoxetine), and Zoloft (sertraline) – increase serotonin in synapse.

                                                               i.      Paroxetine: not for pregnant patients – category D related to CV malformations. Others are category C, but caution needed d/t pulmonary HTN in the baby. Plus, RISK of miscarriage, preterm labor.  Paroxetine also associated with increased D/C rates, increased weight, and increased sexual dysfunction.

                                                             ii.      Sertraline: increased diarrhea (mostly selective for 5HT3).

                                                            iii.      Fluoxetine: associated with decreased D/C rates. This one is also particularly activating – so consider in patients who are lethargic, etc. Has a LONG half life, and if need to D/C this drug, self-tapering is an option.

                                                           iv.      Citalopram: This was the “Step 1” therapy used in the Star*D trial (huge, pivotal study for treatment of non-psychosis depression). About 37% of study participants reached remission after just citalopram alone.

b.      Serotonin & Norepinephrine Reuptake Inhibitors (SNRI’s) – Cymbalta (duloxetine), Effexor (Venlafaxine) - increase serotonin and norepinephrine in synapse.

                                                               i.      Duloxetine: don’t use if pt has liver dysfunction or alcohol abuse. There’s no evidence of duloxetine being better than SSRI’s, but there is evidence for venlafaxine being about as efficacious as SSRI’s.

                                                             ii.      Venlafaxine: you don’t get a norepinephrine effect until at doses >200mg/day. So, until this dose, mostly going to be working on 5HT.

c.       Norepinephrine & Dopamine Reuptake Inhibitors (NDRI’s) – Wellbutrin (buproprion)  - increase norepinephrine and dopamine in synapse.

                                                               i.      Increased aggregion d/t the increased DA levels. This drug can be associated with weight loss, and not for pt’s with a history of an eating disorder like anorexia or bulimia. Also can decrease seizure threshold, so avoid in seizure pts. If pt is looking to quit smoking, this medication could be a “2 for 1” deal and help with depression and smoking cessation. Bupropion has also been well studied as an adjunct therapy if other antidepressants were working , but just short of remission.

d.      Remeron (Mirtazapine)

                                                               i.      Major mechanisms of action are H1 blocker and alpha2 antagonist. When I think of a H1 blocker now, I automatically think of sedation and weight gain. In fact, mirtazapine is one of the strongest H1 blockers out there – even stronger than our antihistamines (Benadryl, etc.). Which means it’s also associated with lots of sedation and weight gain. It also acts as an antagonist to alpha2. Remember clonidine? Alpha2 agonist, which tells alpha2 there’s enough NE in the body, and to signal to stop production. Decreased NE then causes less vasoconstriction, and leads to tx of HTN. Well mirtazapine is just the opposite – alpha2 antagonist >> more NE >> tx for depression. So, makes sense that one of the ADRs is HTN. Mirtazapine is a great example of how the maximum dose of an antidepressant should be tried (as long as pt can tolerate) before claiming a treatment failure. If a pt is on a 15mg dose, then most of the drug is hitting the H1 receptor…and pt will feel sedated most of the time – great for sleep if pt is also having trouble sleeping, but not excellent for the depression. However, at a higher dose, more drug is able to inhibit the alpha2 receptor, and increase NE production. This is an activating neurotransmitter, antidepressant properties can be more apparent now. Of course every pt is different though, and some may just require the 15mg dose.

3.       TCA’s AKA “dirty” SNRI’s. They are SNRI’s as well as anticholinergic, alpha1 blockers, and histamine blockers – amitriptyline, nortriptyline, imipramine, desipramine, doxepin

a.       Contraindications: post MI, hypersensitivity to the class of drugs, angle closure glaucoma, CVD (CHD with abnormal EKG), orthostatic hypotension, suicide, cognitive impairment (especially in elderly).

b.      ADRs: anticholinergic effects,  CV (OH, syncope, arrhythmia), CNS (sedation, confusion), weight gain (especially amitriptyline and doxepin), sexual dysfunction, decreased seizure threshold.

c.       If NEED to use a TCA in the elderly, notriptyline or desipramine first line. But only if you NEED to.

d.      Clomipramine is also a TCA, but only approved for OCD.

4.       Monoamine Oxidase Inhibitors – isocarboxazid, phenelzine, tranylcypromine, selegiline (transdermal).

a.       Last line.

b.      Pt needs to be well educated about avoiding tyramine-containing food (ex. cheese, wine, etc.), stimulants, and vasoconstrictors d/t risk of HTN crisis.

c.       Cannot take with antidepressants, triptans, meperidine, tramadol, propoxyphen, dextromethorphan d/t risk of 5HT syndrome.

The picture that shows up on Wikipedia's MDD page. Artist - Van Gogh. No, I didn't use Wikipedia to get any of the clinical information - just the picture ;)!

Other Drugs Facts

·         TCAS’s: question – would increasing the dose provide better treatment for sleep? No, since a low dose should be hitting and saturating the H-receptors.

·         SSRI – should be taken in the AM because it can cause insomnia (^5HT in the body).

·         Amitriptyline most associated with anticholinergic effects out of the TCA’s.

·         Imipramine mostly affects 5HT, not very anticholinergic and alpha blocking, but fairly high histamine block.

·         Doxepin – STRONG histamine blocker.

·         As you increase the dose of the above 3 meds, starts becoming less selective for the receptor it acts on the most.

·         SSRI and TCA combination – SSRIs increase TCA concentration about 3 to 4-fold d/t blocking CYP2D6. Fluoxetine is most notorious for blocking 2D6.

My Published Article!

Serving those who served our country – By Neha Giridharan

Veterans Affairs - A Colorful History

1918 (end of WWI): Military hospitals were too burdened to keep all veterans through recovery.

1921: Veterans’ Bureau created.

1930: Budget included $786 million and served 4.6 million veterans.

1944:  GI Bill of Rights was passed to benefit WWII veterans with home loans and education.

1946: Under leadership of Major General Paul Hawley, resident and teaching fellowships were created in VA hospitals in addition to hospital-based research programs.

1975: Vietnam veterans came home to underfunded, run down hospitals.

1995: Transformation of VA system included a shift to outpatient care from inpatient care, and an emphasis on measuring health-care performance on the outcome of patient treatment.

1997: VA began establishing community-based outpatient clinics across the country.

2005: VA’s 75^th anniversary, and a budget of $63.5 billion serving nearly 25 million veterans. Currently, there are roughly 909 ambulatory care and community-based outpatient clinics, 135 nursing homes, 47 residential rehabilitation treatment programs, 232 Veterans Centers and 108 comprehensive home-care programs.

Past newspaper headlines referring to the U.S. Department of Veterans Affairs (VA) have read, “Third-Rate Medicine for First-Rate Men,” “The VA’s War on Health,” and “The Worst Health Care in the Nation.” The latter two were from the 1990s. Today, the VA system is a model for 21^st-century health care reform. How did that happen?

One of many important changes was the implementation of the Veterans Health Information Systems and Technology Architecture (VistA). Built to combine patients’ different forms of information into one electronic health record, VistA enhanced technology systems at the VA and improved communication between providers.

Through VistA, health care professionals such as pharmacists and nurses were, able to access complete patient information to provide better care. This helps the growing number of clinical pharmacists who are incorporated into medicine teams at VA hospitals. With the goal of providing optimal patient care, the medicine team includes the attending physician, medical resident, medical intern(s), medical student, social worker, case manager, pharmacist, and the student pharmacist. I was on rotation on one of these medicine teams from May to August.

From “Zero to Hero”

My professo’s parting words were, “You can consider yourselves professional 1-year-olds, so don’t be too hard on yourselves initially, and let your skills develop with experience.” His warning was appropriate because at the beginning of my rotation, I definitely felt like a professional “infant.”

Initially during rounds, when I was asked questions, I would recognize that I had learned the answer at some point during my coursework. The didactic learning environment of a classroom is very different from the clinical world, however, I eventually created a routine for myself every morning and gained the confidence I needed to participate actively in patient discussions. Also, with the guidance of my excellent preceptors, I was comfortable offering drug therapy recommendations to the medicine team.

I was consulted on many topics, including the need to bridge a patient with heparin, drug-drug interactions, length of treatment for complicated urinary tract infections, appropriate medication regimens for various disease states, medication dosages, mechanism of action of drugs, and much more. Over time, I felt like I was really contributing to the team effort.  

Blogging My Experiences

As I researched certain topics throughout my rotation, I feared that I would quickly forget the details. Thus, I started a blog to capture everyday experiences while on my rotation. The blog is also serves as a good learning tool for other students whose rotation sites are not geared towards treating an elderly population. The blog is a great learning tool for me as well; it allows me to review at home what I learned during the day. You can read my blog at http://pharmdrotations.blogspot.com.

Future Directions

The VA healthcare system is one of servereal practice settings leading pharmacy toward patient-centered care. I hope that in the near future, patients will be assigned to their own pharmacists, just like any other clinician. Whatever new ways the pharmacy profession incorporates itself into the VA healthcare system, I am sure that pharmacists will stay true to the VA motto spoken by President Abraham Lincoln: “Care for him who shall have borne the battle and for his widow, and his orphan.”

References

1. “VA History in Brief.” Department of Veterans Affairs.     

2. Longman, Phillip (2010). Best care anywhere (2^nd ed.). Sausalito, CA: PoliPointPress.

3. My Blog - http://pharmdrotations.blogspot.com/

Pepsi*Root Beer*Coke*Gingerale*Dr. Pepper

I’m already thankful for this rotation – it’s making the 1.5-hour drive round trip more bearable. My preceptor is really good at grilling me with questions, and doesn’t give in and help me out – she patiently waits while my mind fumbles through all the notes and lectures from class :). I’m understanding what my preceptor meant when she said she wanted me to be able to recognize what a medication does clinically as well as its ADRs just by knowing which receptors the drug acts on. Honestly, I feel like I had forgotten most of my pscyh drug knowledge by the end of that respective semester. I’m glad I have this rotation towards the end, since psych meds are important – A LOT of people here are on them, and it comes up a lot, even in the acute setting.

PTSD

I was working on a fairly complicated patient last week with PTSD from witnessing multiple suicides and burning bodies during the war. He even wakes up to the smell of burning flesh :(. I was taking a look at his chart because there was a nonformulary consult for Seroquel (quetiapine). We ended up denying it, since there were definitely other options for the patient – trialing another SSRI, trying venlafaxine, retrialing prazosin at a higher dose (had it before at a max dose of 6mg/day) for his nightmares, or D/C’ing the atypical antipsychotic altogether – since he has a history of drug abuse, and his psychotic sx could have been from that (he is clean now). When it comes to PTSD, there are 3 groups of sx you would look for: hyperarousal (does usually respond to meds), avoidance (usually does not respond to meds, but is most important to treat, since it’s linked to suicide), and flashbacks/nightmares. SSRI’s have shown to help with the hyperarousal sx.

Receptors

NE: is an activating neurotransmitter, and causes vasoconstriction

5HT: is an activating neurotransmitter, can cause insomnia, headaches

5HT2A: too much of it causes sexual dysfunction

5HT3: too much of it causes nause/diarrhea

DA: activating neurotransmitter

Ach: too much causes everything to become “more wet” – increased salivation, diarrhea, urinary frequency, N/V, sweating.

Alpha1: blocking this causes orthostatic hypotension

Alpha2: centrally acting adrenergic receptor. Agonizing this causes a negative feedback in the brain, and signals body to stop producing NE (mainly). Think of how clonidine works…agonizes alpha2, less NE, less vasoconstriction, tx for HTN.

H1: blocking histamine1 causes sedation and weight gain

About SSRI’s

My preceptor and I had an awesome discussion about this class of medications. My question to her was, “I realize that a pt with depression needs to be treated with an SSRI for an adequate amount of time (~4-6 weeks) before saying pt failed therapy. So, if increasing the dose of an SSRI, would the 4-6 weeks start over, or continue?” This led us to a discussion about how SSRI’s work…and this is illustrated by the picture. So what’s the connection between the picture and my question? Wish I had a more definite answer, but as always – depends on the patient! Although, as long as the patient is tolerating the medication but hasn’t completely reached remission, I would consider upping the dose at around 4 weeks. 

Fun facts:

*My grandpa always used to chew on this stuff called “Paak” in India after meals. He always told me it aided in digestion, and I tried it a few times (it’s not bad, but not really good either). It’s also known as “betel nut.” Apparently, arecoline is the active ingredient in this stuff, and it’s also a cholinomimetic alkaloid, which means increased acetylcholine! It causes extensive salivation, and also causes a mild euphoria ;).

The dark stuff is the betal nut.

 *Pepsi, Root beer, Coke, Gingerale, and Dr. Pepper were all invented by PHARMACISTS!! Back in the day, a pharmacist was someone who owned a drug store and sold medications (of course we know it’s so much more than that today). It was customary to also have a soda fountain in the store…so my guess is that these pharmacists experimented with a variety of concoctions and came up with these very popular drinks :).

Caleb Bradham - Pepsi

John Pemberton - Coke

ABC's "Revenge" & Pharmacy

Every Wednesday, the specialty clinical pharmacist in mental health has

a clozapine clinic day. Basically, patients on clozapine come to see the

physician, then the pharmacist for further discussion, and then the

pharmacy to pick up their medication. In light of “clozapine days,” I read

the clozapine patient management protocol that the VA has, and also some

basic background information on the drug. Here it goes…

Clozapine

o        Blocks DA2, 5HT2, and cholinergic receptors (ADR of the latter mechanism

think blind as a bat, dry as a bone, red as a beet, and mad as a hatter,

hot as a hare…)

o        Black box warnings for: agranulocytosis, seizures, myocarditis

(especially during the first month), CV/Respiratory dysfunction (Benzo

drug-drug interaction), dementia.

o        Agranulocytosis is defined as an ANC < 500/mm3, most frequent in first 6

months of clozapine use.

o        Other ADRs: cardiac toxicity, GI hypomotility, hypersalivation (you

would think the patient would have a dry mouth d/t anticholinergic

effects, but the hypersalivation is actually d/t the patient not being

able to swallow appropriately), metabolic syndrome, EKG abnormalities.

o        Therapeutic range at steady state: 0.35-0.60mg/L.

o        Other DDI’s: cisapride and dronedarone causes additive QT prolongation

if either is used with clozapine, and concomitant potassium-salts cause

delay in potassium passage through the GI tract (which causes increased

risk for ulcerative lesions).

o        Limitations of clozapine – it’s reserved for severe schizophrenia

(treatment resistant or treatment intolerant) and in schizophrenia with

emergency suicidal ideations. The ADRs associated with this medication

prevent it from being first line.

o        Off label uses: schizoaffective disorder, bipolar affective disorder,

tremor, and Parkinson’s.

o        Max dose is 900mg/day.

o        May take 8 weeks to see initial effect, and up to 6 months for full effect.

o        For discontinuation, taper must be over 1-2 weeks, and need to monitor

o        WBC and ANC for four weeks after D/C.

When I see something pharmacy-related in pop culture, I tend to get pretty excited. 

The antagonist of my new favorite ABC show was taking clozapine, and when the 

protagonist took his medication bottle, he started experiencing withdrawal symptoms 

(since it wasn’t tapered over how many weeks? That’s right, 1-2 weeks). 

And this is Tyler from ABC's "Revenge" great actor!

In other news, we had a patient call in today asking about sexual dysfunction with his 

newly prescribed SSRI (citalopram). The 5HT2A receptor plays a big role in sexual 

dysfunction. Basically, agonists of this receptor contribute to sexual dysfunction and 

antagonists don’t have this effect. This is a common ADR of SSRI’s, about a 40% 

chance of happening. I called the patient back to find out more about it. Unfortunately, 

he wasn’t at home, but I did have a list of questions prepared: have you noticed any 

benefit from the citalopram? When did these new sx begin? Have you been compliant 

with the medication? Have you ever had an antidepressant in the past? My plan was to 

start off with these questions and then take the conversation wherever it went. Some 

solutions to this ADR include:

o        If patient is on Prozac (the SSRI most associated with sexual dysfunction), 

then consider switching to another SSRI (citalopram or sertraline are least associated 

with this).

o        Decrease the dose – this however may not be acceptable if this affects control of 

depression. This could be a possibility if a patient is already on the maximum dose of 

an SSRI, and is aware enough to correlate the ADR with the last increased taper up. 

o        Change drug to mirtazapine, buproprion, nefazodone, or trazodone – these have 

the lowest incidence of adverse sexual side effects. These have action as a 5HT2A 

antagonist – so it makes sense why there would be fewer incidents. 

o        Add Viagra to patient’s medications. 

That closes out week #1. I’ve pulled all my psych lectures from school (I realize I 

had some pretty amazing pharmacology professors). I’m working on putting together

 presynaptic/synaptic cleft/post synaptic diagrams for all the main neurotransmitters 

for psych medications. I will share as soon as I finish! 

New Year, New Rotation

Tuesday was the first day of my mental health rotation, after 2 months of vacation! 

It’ll take some getting used to having a set schedule again, but I’m ready to be back. 

Psych medications in general are weakness for me, so I’m looking to get the most 

out of this rotation. I’ve already learned a few things today.

• Olanzapine and quetiapine are FDA approved for bipolar, but not PTSD.This 

is important when looking at nonformulary consults for atypicals andverify whether 

or not the patient has either disease state.

• Ziprasadone – one side effect of antipsychotics in general is the metabolic syndrome. 

This medication needs to be taken with a high fat meal in order to absorb…so metabolic 

syndrome + high fat meal? Not the best combination. Plus this medication is dosed BID, 

which can affect compliance.

• Symptoms to be looking for for bipolar vs PTSD: With bipolar, the patient will 

experience manic episodes, and can go without sleep for days and then crash and 

sleep for days. For PTSD, The patient will have nightmares and feel the need to 

“sleep with a gun” for example, and will want to go to sleep, but can’t. These are subtle 

differences to watch out for.

• Citalopram: can prolong QT interval, and the max dose was recently changed

 to 40mg/day.

• Tramadol: can cause seizures.

• Bupropion: high seizure risk, has a black box warning for this. Not for patients 

with history of seizures, head trauma, alcoholics (d/t seizing during withdrawal), 

and bulimic patients (d/t electrolyte imbalances).

• 5 traditional mood stabilizers: if a patient needs a mood stabilizer, then one or 

a combination of the following should be tried before anything else: lithium, 

valproic acid, carbamazepine, oxcarbamazepine, and lamictal. The latter 4 are also 

anti-seizure medications.

• New medical abbreviations: SI/HI: suicidal ideation or homocidal ideation. 

MST: military sexual trauma (form of PTSD)

• DSM-IV Multiaxial Classification
          o  Axis I: Diagnosis of psych issue as an infant, child, or adolescent. 

Examples include delirium, dementia, amnesia, substance-related, schizophrenia, 

mood disorders, anxiety, sexual/gender identity disorders, eating/sleep/impulse-control/

adjustment disorders.
          o  Axis II: Mental retardation and personality disorders. Examples include: 

paranoia, antisocial/narcissistic/avoidant/dependent/and obsessive compulsive disorders.
          o  Axis III: General medical conditions
          o  Axis IV: psychosocial and environmental problems – things that affect 

diagnosis and treatment of Axis I and II problems.
          o  Axis V: Overall function, noted as the GAF (global assessment of function).

• Delusion – a false belief that one firmly holds.
          o  Bizarre: a delusion a patient has that would be culturally implausible.
          o  Delusional jealousy: delusion that sexual partner is unfaithful.
          o  Erotomanic: delusion that someone (usually of higher status) is in love with individual.
          o  Grandiose: delusion of inflated worth, etc.
          o  Persecutory: delusion that patient is being attached or conspired against.
          o  Somatic: delusion dealing with function of body.
          o  Thought broadcasting: delusion that thoughts are being broadcasted.
          o  Thought insertion: delusion that thoughts are being inserted into patient’s head.

• Hallucination – sensory perception of reality.
          o  Auditory
          o  Gustatory
          o  Olfactory (usually of decaying fish or burned rubber)
          o  Somatic
          o  Tactile (ex. Formication – something is crawling under skin).
          o  Visual

• Mood ~ climate as affected ~ weather