TCAs and hypotension

[i61164]

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I am told that TCAs work by blocking NE and 5HT reuptake. Eventually this causes downregulation of presynaptic alpha2 and postsynaptic beta receptors and upregulation of postsynaptic alpha1 receptors. Then they tell us that TCA cause "peripheral alpha1 blockage" which causes hypotension and I don't see how that relates to NE and 5HT reuptake inhibition. In fact, we were just told that alpha1 receptors are upregulated.

So let me get this straight. Alpha1 receptors are upregulated in the brain and blocked everywhere else? These just seem like bizarrely unrelated effects.

I think I need EMDR for studying related trauma.

 

[Anasazi23]

I am told that TCAs work by blocking NE and 5HT reuptake. Eventually this causes downregulation of presynaptic alpha2 and postsynaptic beta receptors and upregulation of postsynaptic alpha1 receptors. Then they tell us that TCA cause "peripheral alpha1 blockage" which causes hypotension and I don't see how that relates to NE and 5HT reuptake inhibition. In fact, we were just told that alpha1 receptors are upregulated.

So let me get this straight. Alpha1 receptors are upregulated in the brain and blocked everywhere else? These just seem like bizarrely unrelated effects.

I think I need EMDR for studying related trauma.

Tricyclic Antidepressants have five basic actions:
1. blocks reuptake of 5HT
2. blocks reuptake of NE
3. blocks alpha-1 adrenergic receptors
4. blocks H1 histamine
5. blocks muscarinic cholinergic receptors


The histaminic blockade is what causes weight gain and sedation, while the anticholinergic/antimuscarinic binding causes the anticholinergic side effects (dry mouth, sedation, blurry vision). Binding of the alpha-1 causes vasoconstricion and hypotension peripherally. Further, the antimuscarinic effects are seen at higher doses secondary to their central mechanism of action.

It's the peripheral blockade of Na channels in peripheral (cardiac) tissue that cause the arrythmia potential, and is also why they're lethal in overdose (degenerative arrythmia causes MI and death).

At least - that's the simple version.

 

[Solideliquid]

Tricyclic Antidepressants have five basic actions:
1. blocks reuptake of 5HT
2. blocks reuptake of NE
3. blocks alpha-1 adrenergic receptors
4. blocks H1 histamine
5. blocks muscarinic cholinergic receptors


The histaminic blockade is what causes weight gain and sedation, while the anticholinergic/antimuscarinic binding causes the anticholinergic side effects (dry mouth, sedation, blurry vision). Binding of the alpha-1 causes vasoconstricion and hypotension peripherally. Further, the antimuscarinic effects are seen at higher doses secondary to their central mechanism of action.

It's the peripheral blockade of Na channels in peripheral (cardiac) tissue that cause the arrythmia potential, and is also why they're lethal in overdose (degenerative arrythmia causes MI and death).

At least - that's the simple version.

Alpha-antagonist=vasodilation right?

 

[Anasazi23]

Alpha-antagonist=vasodilation right?

Think, young Jedi.

 

[Poety]

Alpha-antagonist=vasodilation right?

Sazi, I'm pretty sure Solid is right, alpha-1 antagonism causes vasodilation since unopposed it works as a vasoconstrictor. I think thats what causes the hypotension, excessive vasodilation.

 

[i61164]

Tricyclic Antidepressants have five basic actions:
1. blocks reuptake of 5HT
2. blocks reuptake of NE
3. blocks alpha-1 adrenergic receptors
4. blocks H1 histamine
5. blocks muscarinic cholinergic receptors


The histaminic blockade is what causes weight gain and sedation, while the anticholinergic/antimuscarinic binding causes the anticholinergic side effects (dry mouth, sedation, blurry vision). Binding of the alpha-1 causes vasoconstricion and hypotension peripherally. Further, the antimuscarinic effects are seen at higher doses secondary to their central mechanism of action.

It's the peripheral blockade of Na channels in peripheral (cardiac) tissue that cause the arrythmia potential, and is also why they're lethal in overdose (degenerative arrythmia causes MI and death).

At least - that's the simple version.

I'm glad you gave me the simple version. This is helpful (and I have an exam in three hours). As for the vasculature, blood vessels do have a sympathetic tone, so blocking alpha receptors should reduce vasoconstriction. However, even an alpha agonists like Clonidine can magically reduce blood pressure via the CNS somehow, so it's not always straight forward. What Solid is saying sounds right to me though.

 

[Solideliquid]

I'm glad you gave me the simple version. This is helpful (and I have an exam in three hours). As for the vasculature, blood vessels do have a sympathetic tone, so blocking alpha receptors should reduce vasoconstriction. However, even an alpha agonists like Clonidine can magically reduce blood pressure via the CNS somehow, so it's not always straight forward. What Solid is saying sounds right to me though.

Clonidine=alpha 2 agonist.

Alpha 2= reduce NE release in the synaptic cleft right? All that pharm is melding together, like paint in the rain 🙂

Double checked, I think I'm right A-2 agonist like Clonidine works in the pre-synaptic cleft in the CNS to reduce adrenergic agents thus reducing symphathetic action on the blood vessels.

 

[Anasazi23]

Alpha adrenergic stimulation results in vasoconstriction.

The muscarinic effect can result in tachycardia, which MAY lead to postural hypotension. The effects of the "dirty" drug (multiple receptor binding sites) can cloud what portion of the drug is causing the peripheral physiologic response.

Basically, we have to be careful in using terms like "blockade," "blocks," "stimulates", and the net effects in TCAs, which in some case is the blockade of reuptake. I think we're agreeing without realizing it.

i61164 is right, however, in that there are "first dose" effects of some of these meds, and can cause paradoxical effects in some cases through more complicated physiological mechanisms.

 

[sdn1977]

Alpha adrenergic stimulation results in vasoconstriction.

The muscarinic effect can result in tachycardia, which MAY lead to postural hypotension. The effects of the "dirty" drug (multiple receptor binding sites) can cloud what portion of the drug is causing the peripheral physiologic response.

Basically, we have to be careful in using terms like "blockade," "blocks," "stimulates", and the net effects in TCAs, which in some case is the blockade of reuptake. I think we're agreeing without realizing it.

i61164 is right, however, in that there are "first dose" effects of some of these meds, and can cause paradoxical effects in some cases through more complicated physiological mechanisms.

Agree with this! They are a difficult group of drugs to classify as having one resultant effect for all of them because of the different pharmacologic parameters of each sub group. The tertiary amines (amitriptyline, imipramine, etc) have predominately more anticholinergic effect & orthostatic hypotension than the secondary amines (nortriptyline, desipramine).

Generally, they all may increase the sensitivity of the postsynaptic alpha (a1) adrenergic & serotonin receptors & may decrease the sensitivity of the presynaptic receptor sites. The net effect depends on the degree to which each works on each site and the resultant physiologic response which predominates. The tachycardia can result from not only the change in the peripheral vessels, but some studies show a direct effect on the heart which some researchers think is a cause of the arrhythmias seen in overdose.

Clonidine is a selective a2 agonist. It was initially designed as a nasal decongestant, but during testing it was found to cause hypotension & bradycardia. IV & po effects are different. IV actually causes an acute rise in BP due to activation of postsynaptic a2 receptors in vascular smooth muscle. The affinity for these receptors is high, but it has relatively low efficacy since it is a partial agonist. This effect is not seen orally. The hypotension which follows is a result of decreased discharges in sympathetic preganglionic fibers in the splanchnic nerve & in postganglionic fibers of cardiac nerves & activation of a2 receptors in the lower brain stem. Some of the effects may also be mediated by activation of presynaptic a2 receptors that suppress norepi release from peripheral nerve endings. It may also stimulate parasympathetic outflow which contributes to bradycardia due to increased vagal tone.

Anyway...too much info prob & definitely too late for your exam - hope you did well! Anasazi's summary was a good, short summary of pertinent pharmacology of TCA's though!

 

[Solideliquid]

So...sazi you are saying TCAs block alpha receptors, which in turn cause vasoconstriction which causes the hypotension?

 

[Poety]

I've always been under the impression that alpha 1 is a vasoconstrictor. When you block its effects you get vasodilation? Is that wrong?

 

[Anasazi23]

I've always been under the impression that alpha 1 is a vasoconstrictor. When you block its effects you get vasodilation? Is that wrong?

So...sazi you are saying TCAs block alpha receptors, which in turn cause vasoconstriction which causes the hypotension?

Basically, yes.

I'll look in my Stahl book...he has a good way of simplifying concepts like these.

But, like SDN said above, this class of medications is quite dirty. So when we're talking about tricyclics (and some would argue 3-ring structured molecules in general) the exact mechanism of the hypotension per se is more muddy.

SDN's example of clonodine having different effects depending on dosing routes was the exact example I was thinking about - not to mention the rebound hypertension commonly seen after discontinuation of the blockade of vascular smooth muscle postsynaptic a2 receptors.

In TCA's specifically, the muscarinic effect (if I remember) is also a cause of the hypotension. I'll have to double check this.

So, is the hypotension due to the cardiac compensation secondary to the tachycardia, or a direct effect of smooth muscle relaxation of vascular smooth muscle? This is again tricky, since vasodilation can result in reflex hypertension.

The TCA's (and not all of them equally) have antagonistic binding to alpha-1 receptor sites. So in effect, we're right by saying that we're essentially blocking the alpha adrenergic blockade of these post-synaptic receptors. The end result is postural hypotension secondary to the blockade of the vasoconstrictive effect. This, however, is not dose related, and occurs unequally among drugs in the same class. Nortryptiline, for example, has reports that it causes LESS hypotension than the other cyclic antidepressants. There are even studies showing that the degree of depression is ALSO related to the amount of hypotension.

This is also why we see postural hypotension in some of the antipsychotics. Imipramine (a structural analog of chlorpromazine) was being studied in the 1950's for use as a neuroleptic. When it was being tested, it was disappointingly found to have no antipsychotic effect, but changes in BP, anticholinergic, antimuscarinic effects and elevation of mood were seen in their samples. Therefore, the cyclic antidepressant era was born.

 

[Surg Path]

So...sazi you are saying TCAs block alpha receptors, which in turn cause vasoconstriction which causes the hypotension?

I always thought TCA induced hypotension was caused by (a) minor reduction in cardiac contractility (high does and in elderly) and (b) reduced systemic vascular resitance due to alpha-1 antagonism.

Also, the constriction or dilation effect will depend on where, anatomically, you are blocking alpha 1 (eg smooth muscle, skeletal muscle, ect)

Not altogether sure, though. Can anyone verify this?

 

[sdn1977]

One thing to remember about drugs & comparing what they do to what you might observe in a physiology lab is the response to drugs said to block one or the other division of the autonomic nervous system is not necessarily the same as the response to extrinsic nerve section. Given that, we can only "predict" what inhibition of norepinephrine transport (or antagonism of a1 responses, etc.) might do...but, the body's compensatory mechanisms, particularly with a drug given orally, will always cloud the effect of what you are actually seeing.

Agreed - the primary mechanism of postural hypotension is due to the peripheral a-blockade on vascular smooth muscle. Arterioles in skeletal muscle are innervated both by adrenergic & cholinergic nerves, but venous smooth muscle is only adrenergic innervation (a&b). So, you not only have the catecholamine effect if you block the a1 in arterioles, you'll also have the b2 effect on venous smooth muscle which leads to venous pooling, consequent decrease in venous return, cardiac output & a compensatory reflex tachycardia. I really doubt you could tell which effect was primary and which effect is secondary to physiology when you give an oral drug - we can't tell in a lab.....I didn't even mention what effect TCA's have on the renin-angiotensin system - that is being looked at now in studies further complicating the issue.

The cardiotoxicity is due to a quinidine-like effect on conduction which decreases myocardial contractility, HR & coronary blood flow. But, these mechanisms should not be in play in any age of pt unless the dose is too high. At normal doses & in pts who don't have prexisting conduction disorders or recent MI, this should not be a reason for the hypotension which is a common side effect in all pts who take TCA's

Blocking

 

[Solideliquid]

I always thought TCA induced hypotension was caused by (a) minor reduction in cardiac contractility (high does and in elderly) and (b) reduced systemic vascular resitance due to alpha-1 antagonism.

Also, the constriction or dilation effect will depend on where, anatomically, you are blocking alpha 1 (eg smooth muscle, skeletal muscle, ect)

Not altogether sure, though. Can anyone verify this?

I agree with what you are saying, and the site of A-1 blockage (dec. vascular resistance)=Smooth MM on the arterial side.

 

[Surg Path]

One thing to remember about drugs & comparing what they do to what you might observe in a physiology lab is the response to drugs said to block one or the other division of the autonomic nervous system is not necessarily the same as the response to extrinsic nerve section. Given that, we can only "predict" what inhibition of norepinephrine transport (or antagonism of a1 responses, etc.) might do...but, the body's compensatory mechanisms, particularly with a drug given orally, will always cloud the effect of what you are actually seeing.

Agreed - the primary mechanism of postural hypotension is due to the peripheral a-blockade on vascular smooth muscle. Arterioles in skeletal muscle are innervated both by adrenergic & cholinergic nerves, but venous smooth muscle is only adrenergic innervation (a&b). So, you not only have the catecholamine effect if you block the a1 in arterioles, you'll also have the b2 effect on venous smooth muscle which leads to venous pooling, consequent decrease in venous return, cardiac output & a compensatory reflex tachycardia. I really doubt you could tell which effect was primary and which effect is secondary to physiology when you give an oral drug - we can't tell in a lab.....I didn't even mention what effect TCA's have on the renin-angiotensin system - that is being looked at now in studies further complicating the issue.

The cardiotoxicity is due to a quinidine-like effect on conduction which decreases myocardial contractility, HR & coronary blood flow. But, these mechanisms should not be in play in any age of pt unless the dose is too high. At normal doses & in pts who don't have prexisting conduction disorders or recent MI, this should not be a reason for the hypotension which is a common side effect in all pts who take TCA's

Blocking

Thanks, that clears things up as far as what we can predict as far as constriction/dilation in arterioles/venous system with regard to the observed hypotension, as well as the reflex tachycardia.

The fact that we can't sort out each mechanistic step which produces the physiological response makes sense, considering the complexity of each underlying biological system, and the many compensatory mechanisms involved.

thanks

 

[i61164]

Man you guys are scaring me. I can't even remember the simplified version that they teach us for the exam. Now I see that the truth/reality is much more complicated and difficult. Maybe it's all for the best. At least I won't remember all the lies they teach us. Come third year, the nerds that remember everything from the first two years should be just as ignorant as me.

There was a question on the exam about TCA's and postural hypotension. The answer was alpha 1. I'm glad we talked about because it helped me remember during the exam.

That was my last exam of first year. Next week I recieve a patient write-up and have to present it to a faculty panel (including giving them a lecture on the basic science stuff involved in the case). Then I shadow a family practice doc for two weeks 😴 and then I'm home free for 12 weeks.

 

[Surg Path]

Man you guys are scaring me. I can't even remember the simplified version that they teach us for the exam. Now I see that the truth/reality is much more complicated and difficult.

Sometimes I have the opposite problem- I remember all the exceptions but rule out the "basic" concepts too quickly on exams.

I remeber one question where tamoxifen was mentioned, and one was supposed to automatically think of tam as an estrogen receptor (ER) antagonist. After studying hormones in breast cancer in a lab for years, I recognozed tam as a SERM (selective ER modulator). It's an ER coactivator in bones and endometrium (hence increase in endometrial cancer and helps bone density like Evista), and corepressor in breast (blocks estrogen responsive IBC).

Sorry for the tangent, but I guess the conclusion is that biology always has exceptions. To me that's the intersting part.

 

[Anasazi23]

Man you guys are scaring me. I can't even remember the simplified version that they teach us for the exam. Now I see that the truth/reality is much more complicated and difficult. Maybe it's all for the best. At least I won't remember all the lies they teach us. Come third year, the nerds that remember everything from the first two years should be just as ignorant as me.

There was a question on the exam about TCA's and postural hypotension. The answer was alpha 1. I'm glad we talked about because it helped me remember during the exam.

That was my last exam of first year. Next week I recieve a patient write-up and have to present it to a faculty panel (including giving them a lecture on the basic science stuff involved in the case). Then I shadow a family practice doc for two weeks 😴 and then I'm home free for 12 weeks.

Congrats on finishing your first year academics. Let us know what you decide to do on your psych write-up case. Some people here might know something about that psych stuff to help you.

 

[Solideliquid]

So then do TCAs block alpha-1 receptors or are alpha-1 receptors downregulated as a result of excessive NE? Or is the hypotension a result of overcompensation because of the tachy/high NE affecting the cardio system?

And how does peripheral vasoconstriction result in hypotension?

All things being equal.

 

[Poety]

So then do TCAs block alpha-1 receptors or are alpha-1 receptors downregulated as a result of excessive NE? Or is the hypotension a result of overcompensation because of the tachy/high NE affecting the cardio system?

And how does peripheral vasoconstriction result in hypotension?

All things being equal.

Essentially its generalized sympathetic system depression solid 🙂

 

[sdn1977]

So then do TCAs block alpha-1 receptors or are alpha-1 receptors downregulated as a result of excessive NE? Or is the hypotension a result of overcompensation because of the tachy/high NE affecting the cardio system?

And how does peripheral vasoconstriction result in hypotension?

All things being equal.

Solid - I think the answer is both. Others may offer more recent experience with regard to research on the antidepressant effects of TCA's, but I believe the most recent evidence of this effect is the re-regulation of the abnormal receptor-neurotransmitter of NE you are referring to.

However, that is not the explanation for the side effect (hypotension) you observe. That results from not only the direct effect of the drug, but also the result of the autoregulatory capacity of the cardiovascular system.

The difference is the primary pharmacologic effect you might choose a drug for (antidepressant) & concomittant side effects which come along with the drug which may have their source somewhere other than the primary.

As for vasoconstriction & hypotension....a good drug to study for this is epinephrine (still used clinically - think crash cart & your dentist's local anesthetic). It acts as both a vasoconstrictor & vasodilator. The vasocontrictor action on superficial vessels is readily apparent - the skin blanches (& if infused peripherally, vessels constrict). But, it dilates arterioles in skeletal muscle to a greater degree. You might assume resistance = pressure divided by flow. But....total peripheral resistance is an approximate index of the sum of all vasomotor changes in all beds in either direction. TPR falls when epi is infused - it is a net vasodilator & pressure falls even though cardiac output is increased. It widens the pulse pressure & elevates systolic pressure by incresing stroke volume. But, the vasodilatory effects can actually lower diastolic bp. You also need to differentiate if you are referring to arteriolar or venous constriction. That is only what the drug does to blood vessels & pressure. It also has direct effects on the heart itself. In addition, all effects are dose dependent - low doses produce effects different from high doses. Your dentist uses a low dose of epi with the anesthetic to keep the anesthetic locally in tissues by vasoconstriction & not allow the anesthetic itself to enter the general circulation rapidly where it has undesired effects.

That is a much more complex mechanism than what goes on with TCA's, but is a good model for learning what drugs do to the ANS & how compensatory mechanisms work. Unfortunately, all things are not equal in this..

 

[i61164]

Congrats on finishing your first year academics. Let us know what you decide to do on your psych write-up case. Some people here might know something about that psych stuff to help you.

Thanks. I will get the case on Wednesday and have to master it by Friday. Even though we have just finished our psych block, I don't think it will be a psych case. They told us they like to give us something that we haven't studied yet. Supposedly they want to test our clinical reasoning. Anyway, I'll probably ask you guys anyway if I need help.

 

[i61164]

So here is the case:

CHIEF COMPLAINT: Headache

HISTORY OF PRESENT ILLNESS:Miss Jones is a 26 yr old Caucasian female with past medical history of headaches. These headaches have been off and on for several months but have become more frequent lately with at least a low-grade headache being present most of the time. She has not been awakened at night due to the headache. She did have one headache that occurred rather abruptly about three weeks ago that was accompanied by blurriness of her vision and some difficulty with her balance. It gradually resolved and she did not seek medical care for that event. Over the past month, she has noted problems expressing herself (words she says are not what she is trying to say). She denies any trauma, fevers, weight change or night sweats. She presents today for evaluation of the difficulty expressing herself. She is accompanied by her fiancé.

PAST MEDICAL HISTORY:
1. Asthma—on no meds
2. Left ovarian cyst—treated with birth control pills
3. Mild chronic headache

ALLERGIES: No known drug allergies

MEDICATIONS: Oral contraceptive pills for couple years

SOCIAL HISTORY:
Lives in Winston-Salem with her fiancé and her son (4 yrs old). Smokes ½ pack cigarettes per day and has been smoking for past year. Denies alcohol or illicit drug use. Has been tested for HIV in the past (3 yrs ago—negative) and denies any possible exposure to HIV since that time. Employed by local convenience store

FAMILY HISTORY:
Denies any history of stroke, coronary artery disease or cancer in a first degree relative.

REVIEW OF SYMPTOMS:
A complete review of systems is obtained and all are negative except as noted in the HPI.

PHYSICAL EXAMINATION:

Vital signs: Temp 96.1, blood pressure 132/67, pulse 88 and regular, respiratory rate 18

General: She is awake and alert and in no acute distress. Very thin and gaunt appearing female.

HEENT: Very poor dentition. Oropharynx clear. No palpable lymphadenopathy in head and neck. No gross abnormalities noted on the scalp. Thyroid not enlarged. No sinus tenderness

Cardiovascular: Regular rate and rhythm and no murmurs. Normal S1 and S2. No gallops. Carotid pulses full and no bruits.

Chest/lungs: Basilar crackles on the right base. Normal fremitus and percussion. No wheezes

Breasts: No masses

Abdomen: Normal bowel sounds. Soft, non-tender and not distended. No masses or organomegaly. No abdominal bruits.

Neurological: Affect appropriate. Alert and oriented x 4. Cranial nerves II-XII intact including normal fundoscopic exam. Difficulty with repeating sentences. Much perseveration while speaking and had paraphasic errors including calling a hand a knee, glove a sleeve, key a tea. She called feather a fillow. She named a chair as a car, the remote control was a camera or menu. She was able to count to 10 and give her home telephone number without difficulty. Strength rated as 5/5 and equal bilaterally in all extremities and all muscle groups. Coordination intact by finger-to-nose, rapid alternating movements and heel-to-shin testing. Her sensation was intact bilaterally to light touch, pin prick, vibratory and temperature sensation. Reflexes are 3+ and symmetrical throughout. Her plantar reflex is downgoing bilaterally and there is no clonus. Muscle tone normal but there was definite decreased bulk of the muscles. She had no pronator drift.

Skin: Warm and dry and no worrisome lesions

Psychiatric: Somewhat flat affect


So now I have to figure out what I think is wrong with her, order tests, and come up with basic science "learning issues" that I can research and present on friday. Right now I think she has had some kind of ischemic or hemorrhagic event or a mass lesion in her brain. I am also considered the possibility of a psychiatric illness. Actually it doesn't matter that much what I think the problem is right now. The question is which tests do I order and why. I am thinking CBC (infection), CMP (I don't know why but it seems like a good idea), blood glucose (just in case, but I think it might be covered in the CMP), Head CT, tox screen (maybe she's lying about not using drugs), Chest X-ray (because of some crackle in her right lung). By the way, they don't care if I spend a lot of money on tests as long as I have a good reason for ordering them. Do you think any of these tests are not indicated? Am I missing anything major? What is the significance of the ovarian cyst?

 

[Solideliquid]

So here is the case:

CHIEF COMPLAINT: Headache

HISTORY OF PRESENT ILLNESS:Miss Jones is a 26 yr old Caucasian female with past medical history of headaches. These headaches have been off and on for several months but have become more frequent lately with at least a low-grade headache being present most of the time. She has not been awakened at night due to the headache. She did have one headache that occurred rather abruptly about three weeks ago that was accompanied by blurriness of her vision and some difficulty with her balance. It gradually resolved and she did not seek medical care for that event. Over the past month, she has noted problems expressing herself (words she says are not what she is trying to say). She denies any trauma, fevers, weight change or night sweats. She presents today for evaluation of the difficulty expressing herself. She is accompanied by her fiancé.

PAST MEDICAL HISTORY:
1. Asthma—on no meds
2. Left ovarian cyst—treated with birth control pills
3. Mild chronic headache

ALLERGIES: No known drug allergies

MEDICATIONS: Oral contraceptive pills for couple years

SOCIAL HISTORY:
Lives in Winston-Salem with her fiancé and her son (4 yrs old). Smokes ½ pack cigarettes per day and has been smoking for past year. Denies alcohol or illicit drug use. Has been tested for HIV in the past (3 yrs ago—negative) and denies any possible exposure to HIV since that time. Employed by local convenience store

FAMILY HISTORY:
Denies any history of stroke, coronary artery disease or cancer in a first degree relative.

REVIEW OF SYMPTOMS:
A complete review of systems is obtained and all are negative except as noted in the HPI.

PHYSICAL EXAMINATION:

Vital signs: Temp 96.1, blood pressure 132/67, pulse 88 and regular, respiratory rate 18

General: She is awake and alert and in no acute distress. Very thin and gaunt appearing female.

HEENT: Very poor dentition. Oropharynx clear. No palpable lymphadenopathy in head and neck. No gross abnormalities noted on the scalp. Thyroid not enlarged. No sinus tenderness

Cardiovascular: Regular rate and rhythm and no murmurs. Normal S1 and S2. No gallops. Carotid pulses full and no bruits.

Chest/lungs: Basilar crackles on the right base. Normal fremitus and percussion. No wheezes

Breasts: No masses

Abdomen: Normal bowel sounds. Soft, non-tender and not distended. No masses or organomegaly. No abdominal bruits.

Neurological: Affect appropriate. Alert and oriented x 4. Cranial nerves II-XII intact including normal fundoscopic exam. Difficulty with repeating sentences. Much perseveration while speaking and had paraphasic errors including calling a hand a knee, glove a sleeve, key a tea. She called feather a fillow. She named a chair as a car, the remote control was a camera or menu. She was able to count to 10 and give her home telephone number without difficulty. Strength rated as 5/5 and equal bilaterally in all extremities and all muscle groups. Coordination intact by finger-to-nose, rapid alternating movements and heel-to-shin testing. Her sensation was intact bilaterally to light touch, pin prick, vibratory and temperature sensation. Reflexes are 3+ and symmetrical throughout. Her plantar reflex is downgoing bilaterally and there is no clonus. Muscle tone normal but there was definite decreased bulk of the muscles. She had no pronator drift.

Skin: Warm and dry and no worrisome lesions

Psychiatric: Somewhat flat affect


So now I have to figure out what I think is wrong with her, order tests, and come up with basic science "learning issues" that I can research and present on friday. Right now I think she has had some kind of ischemic or hemorrhagic event or a mass lesion in her brain. I am also considered the possibility of a psychiatric illness. Actually it doesn't matter that much what I think the problem is right now. The question is which tests do I order and why. I am thinking CBC (infection), CMP (I don't know why but it seems like a good idea), blood glucose (just in case, but I think it might be covered in the CMP), Head CT, tox screen (maybe she's lying about not using drugs), Chest X-ray (because of some crackle in her right lung). By the way, they don't care if I spend a lot of money on tests as long as I have a good reason for ordering them. Do you think any of these tests are not indicated? Am I missing anything major? What is the significance of the ovarian cyst?

OCPs+Smoking=blood clots check a D-Dimer, ultrasound the carotid aa's, and get a head CT with contrast.

 

[i61164]

OCPs+Smoking=blood clots check a D-Dimer, ultrasound the carotid aa's, and get a head CT with contrast.

In the interst of improving my clinical reasoning skills, what would you do first? I think a clot is likely, but she did have strong carotid pulses with no bruits, so is the carotid ultrasound indicated? Would you get a D-Dimer right away without doing a CBC (to look at the platelets)? I want to do a head CT but I'm not sure if I should do it right away or wait for other test results.

 

[Solideliquid]

In the interst of improving my clinical reasoning skills, what would you do first? I think a clot is likely, but she did have strong carotid pulses with no bruits, so is the carotid ultrasound indicated? Would you get a D-Dimer right away without doing a CBC (to look at the platelets)? I want to do a head CT but I'm not sure if I should do it right away or wait for other test results.

About the carotid ultrasound, I would still do it as it's cheap test. Though I did overlook that part in the PE. As to the D-dimer, yes still do it and the CBC I was just adding that to your lab orders. I would still do a head CT after drawing the blood and a quick U/S of the neck. I might even U/S the lower EXT while I was at it to look for a DVT.

 

[i61164]

About the carotid ultrasound, I would still do it as it's cheap test. Though I did overlook that part in the PE. As to the D-dimer, yes still do it and the CBC I was just adding that to your lab orders. I would still do a head CT after drawing the blood and a quick U/S of the neck. I might even U/S the lower EXT while I was at it to look for a DVT.

What about a metabolic panel? I've heard that pretty much everyone gets one of these, but what would I be ruling in or out? Do you think a BMP is enough or would you go for the CMP? Fasting or non-fasting?

Right now I think I am going to do the CBC, D-Dimer, and CMP (maybe), followed by the cranial CT (with infusion).

 

[Doc Samson]

OCPs+Smoking=blood clots check a D-Dimer, ultrasound the carotid aa's, and get a head CT with contrast.

So much for Socratic method 😉

 

[i61164]

So much for Socratic method 😉

I interpret this to mean that you agree with Solid (since you imply that he is giving me the answer instead of me figuring it out on my own).

 

[i61164]

Ok, I took the plunge. I decided to try to order the CBC, D-Dimer, and head CT. This was the result:

5/3/2006, 10:29:15 PM
Test: CBC with Differential
Result: WBC 9.9 X 1000 (4.8-10.8), RBC 4.17 X 1,000,000 (4.2-5.4), Hgb 13.3 G/DL (12.0-16.0), Hct 37.5 % (37.0-47.0), MCV 89.9 FL (81.0-99,0), MCHC 35.4 G/DL (33.0-37.0), MCHB 31.8 PG (27-31), CV OF MCV 12.8 % (11.5-14.5), Platelet count 236,000 (160-360,000), DIFFERENTIAL ( Segs 75%, lymphs 18%, Monos 5% , Basos 0%, Eos 2 % ==differential is NORMAL)
Cost: $29.25

Test: D-Dimer Test
Result: test not performed
Cost: $51.50

5/3/2006, 10:34:54 PM
Test: CT Cranial - with infusion
Result: test not performed
Cost: $748.35


So now I'm starting to get worried. The CBC isn't telling me anything and I was sure that they would have done the CT. I think it's time for the CMP.

 

[i61164]

So here is the result of the CMP:

5/3/2006, 11:04:14 PM

Test Results:

Test: Comprehensive Metabolic Panel (Na, K, Cl, CO2, GLU, BUN, Creat, Calcium, Total Prot, Alb, T. Bili, Alk P'tase, AST (SGOT) and ALT (SGPT)) - Fasting
Result: test not performed
Cost: $36.50
TOTAL COST: $36.50

At the risk of being a complainer, I'm an F'ing first year and I don't even know what most tests are for. Out of CBC, CMP, D-Dimer, and head CT, I get one result (CBC) and all the values are normal? What am I supposed to do with that? Right now I would like to just click on every test and see which ones they did, but they discourage that by lowering your grade. The only other tests I can think to do are UA and EEG but at this point I'm grasping at straws.

 

[i61164]

Ok there is one other test that I can think of and I think it might be "The One." Lumbar puncture. We shall see.

 

[Solideliquid]

So here is the result of the CMP:

5/3/2006, 11:04:14 PM

Test Results:

Test: Comprehensive Metabolic Panel (Na, K, Cl, CO2, GLU, BUN, Creat, Calcium, Total Prot, Alb, T. Bili, Alk P'tase, AST (SGOT) and ALT (SGPT)) - Fasting
Result: test not performed
Cost: $36.50
TOTAL COST: $36.50

At the risk of being a complainer, I'm an F'ing first year and I don't even know what most tests are for. Out of CBC, CMP, D-Dimer, and head CT, I get one result (CBC) and all the values are normal? What am I supposed to do with that? Right now I would like to just click on every test and see which ones they did, but they discourage that by lowering your grade. The only other tests I can think to do are UA and EEG but at this point I'm grasping at straws.

Well, didn't you say money wasn't an issue? Why would they not do a CT for a neuro case?

 

[Solideliquid]

Ok there is one other test that I can think of and I think it might be "The One." Lumbar puncture. We shall see.

BEFORE you do an LP you need to either do a head CT/MRI OR a fundoscopic exam to rule out increased intracranial pressure.

 

[i61164]

They don't care how much money we spend in make-believe land. Unfortunately, I can't get results for tests that they didn't do in real life and I have no way of knowing which tests those were until I try them. Right now it looks like my clinical reasoning sucks.

I shouldn't have been surprised, but the LP "test was not performed." Actually, I couldn't find LP on the list of tests but I think CSF cytology is the same thing (am I right?). It was the only one that sounded like LP.

CBC 👍 (but didn't get me anywhere)
D-Dimer 👎
head CT 👎
CMP 👎
CSF cytology 👎

Anybody think I should try the UA and/or the EEG? What have I got to lose at this point? There are about 430 available tests, but I really don't know why I would do most of them.

 

[i61164]

BEFORE you do an LP you need to either do a head CT/MRI OR a fundoscopic exam to rule out increased intracranial pressure.

The fundoscopic exam was normal so I assumed it was safe to do the LP (no papilledema).

 

[Solideliquid]

They don't care how much money we spend in make-believe land. Unfortunately, I can't get results for tests that they didn't do in real life and I have no way of knowing which tests those were until I try them. Right now it looks like my clinical reasoning sucks.

I shouldn't have been surprised, but the LP "test was not performed." Actually, I couldn't find LP on the list of tests but I think CSF cytology is the same thing (am I right?). It was the only one that sounded like LP.

CBC 👍 (but didn't get me anywhere)
D-Dimer 👎
head CT 👎
CMP 👎
CSF cytology 👎

Anybody think I should try the UA and/or the EEG? What have I got to lose at this point? There are about 430 available tests, but I really don't know why I would do most of them.

The more I think about it, this is a pretty hard task for a first year.

 

[i61164]

The more I think about it, this is a pretty hard task for a first year.

Supposedly, they don't care if I come to the right diagnosis. They want to see my clinical reasoning skills. However, due to the lack of test results (which I find unrealistic), I have no way to revise my hypotheses. I thought that clinical reasoning was coming up with mechanistic hypotheses, testing them, and revising them as necessary. Right now I can't seem to get past step 1.

 

[i61164]

Finally I chose a test that was actually done! I decided to try to order all the tests that are similar to the ones I wanted. Guess which test they did...






























Test: MRI Brain - (With/Without Contrast)
Result: Conclusion: 1) Gyriform inhancement involving the left temporal lobe with adjacent T2 and FLAIR hyperintensity is most consistant with subacute infarct with petechial hemorhage. Viral encephalitis and neoplasm remain in the differential, but are less likely. 2) Focal area of T2 hyperintensity within the thalamus is most consistant with a prior lacunar infarct. 3) Punctate restricted effusion in the high right parietal cortex is consistant with an acute cortical infarct.


I knew something wasn't right in this patient's head. It looks like Solid was right about the blood clots. Since the D-Dimer didn't come back, I'm not sure if there are any other tests that I should do. It looks like it's time to start reading up on brain anatomy and physiology so I can give my presentation tomorrow.

 

[Anasazi23]

That's a little bit of a tough case for a MS I. The natural assumption is to think of more complicated brain pathology, since we normally don't consider stroke in 26 year-olds. However, they are giving you clues in the sense that she is on OCPs (they have a slightly increased risk of ischemic infarcts in themselves), then couple that with the smoking history, which causes coagulopathies. Still though, this is not garden variety.

Solide was good with his suggestions. The labs I would have ordered would be MRI brain, CBC, BMP, D-dimers, spiral CT chest if money doesn't matter to rule out a saddle, CBC, BMP. CSF cytology isn't a bad idea in chronic headache with this presentation, but the symptoms are more focal, suggesting this may be more useful later. Others argue that all cases like these should be tapped. LFTs and Coags are also needed to rule out a factor deficiency. Poor dentition mentioned in the case points to either poor self care, poor compliance, or drug abuse - something to keep in mind.

Good luck.

 

[i61164]

But I think she is clotting too much and a factor deficiency would cause the opposite (too much bleeding) so why would I check for that?

 

[i61164]

Hang on. By factor deficiency do you mean a rare disorder that causes the complete absence of a coagulation factor, or lower than normal levels of coagulation factors. The latter makes sense to me because if she is doing too much coagulating, that would deplete the coag factors.

 

[i61164]

Well, I ordered a prothrombin time test:

Test Results:

Test: Prothrombin Time (PT)
Result: 10.0 sec (8.9-12.1)
Cost: $22.75
TOTAL COST: $22.75

😕

 

[i61164]

5/4/2006, 12:49:12 PM

Test Results:

Test: Partial Thromboplastin Time-PTT
Result: 23.2 sec (less that 30sec)
Cost: $27.00
TOTAL COST: $27.00


😕 😕

23 seconds looks low to me, but according to the test results anything under 30 is normal.

 

[Solideliquid]

That's a little bit of a tough case for a MS I. The natural assumption is to think of more complicated brain pathology, since we normally don't consider stroke in 26 year-olds. However, they are giving you clues in the sense that she is on OCPs (they have a slightly increased risk of ischemic infarcts in themselves), then couple that with the smoking history, which causes coagulopathies. Still though, this is not garden variety.

Solide was good with his suggestions. The labs I would have ordered would be MRI brain, CBC, BMP, D-dimers, spiral CT chest if money doesn't matter to rule out a saddle, CBC, BMP. CSF cytology isn't a bad idea in chronic headache with this presentation, but the symptoms are more focal, suggesting this may be more useful later. Others argue that all cases like these should be tapped. LFTs and Coags are also needed to rule out a factor deficiency. Poor dentition mentioned in the case points to either poor self care, poor compliance, or drug abuse - something to keep in mind.

Good luck.

Darn..forgot about the spiral CT chest. Hopefully I won't make TOO much of a fool out of myself during intern year. Although I guess intern year would be the best time to make a fool out of yourself, because at least you are learning...

MRI for stroke, CT for masses..

 

[Solideliquid]

That's a little bit of a tough case for a MS I. The natural assumption is to think of more complicated brain pathology, since we normally don't consider stroke in 26 year-olds. However, they are giving you clues in the sense that she is on OCPs (they have a slightly increased risk of ischemic infarcts in themselves), then couple that with the smoking history, which causes coagulopathies. Still though, this is not garden variety.

Solide was good with his suggestions. The labs I would have ordered would be MRI brain, CBC, BMP, D-dimers, spiral CT chest if money doesn't matter to rule out a saddle, CBC, BMP. CSF cytology isn't a bad idea in chronic headache with this presentation, but the symptoms are more focal, suggesting this may be more useful later. Others argue that all cases like these should be tapped. LFTs and Coags are also needed to rule out a factor deficiency. Poor dentition mentioned in the case points to either poor self care, poor compliance, or drug abuse - something to keep in mind.

Good luck.

BTW Sazi,

How common is this anyway? What I mean is, most of the time people throw clots into the lung, but the clots don't get to the brain unless there is a heart/septal wall defect right?

 

[i61164]

BTW Sazi,

How common is this anyway? What I mean is, most of the time people throw clots into the lung, but the clots don't get to the brain unless there is a heart/septal wall defect right?

Could this be anything other than clots? I wonder because my PT and PTT were normal.

 

[worriedwell]

totally interesting stuff, doing this case.

couple thoughts,

the point about DVTs due to ocp plus smoking NOT causing stroke is a good one, and I'm surprised people are implying that people are entertaining this diagnosis. DVTS cause PE, but they do not flip across to the brain. On the other hand, coagulopathies, etc, can cause strokes and maybe ocps and smoking have some effect on this (but I don't think they have much, and plus the coags were normal).

Its also weird because headache is not a classic presentation of stroke, single or multiple. It may be as a result of poor vision, but this case is fascinating.

By way, as a psychiatrist, one should be aware that poor dentition in a young women can be the result of bulemia because they are rotting away their teeth when they vomit. Bulemia can be fatal usually due to electrolyte imbalances, but they didn't run a CMP and because I can't figure out how that would cause a stroke.

The other thing to think about is drug use (I'm thinking like a shrink here) because iv drug abusers can get bacterial endocarditis, have a valve in their heart with something growing on it, and then flip clots sporadically into their brain. But they'd likely be sicker and I doubt it is that. But it may be a good idea, given a patient has a few lacunes and stroke looking things of different ages, to image the heart (and possibly carotids but this person is too young for carotid stenosis.

Before the MRI I was also considering MS as a presentation but doesn't seem to be that.

I'm curious what this is though, and still trying to put it together...pertinent positives to me as follows:

difficulty with repeating and naming
decreased muscle bulk diffusely
flat affect
poor dentition
multiple clots of different ages in the brain.

You could probably explain the affect and the speaking difficulty by strokes, but dentition and decreased muscle bulk are weird.

 

[i61164]

Test: Echocardiogram (2D and M Mode)
Result: Normal left atrium size, left ventricle size, left ventricular wall thickness, right atrium and right ventricular size. Inferior vena cava not well seen; Intra-atrial septum show definite patent foramen ovale; no pericardial effusion; normal valves, left ventricular function normal; ejection fraction 56%



Worriedwell, every time I read a post of yours, my respect for you increases. When the coags came back normal, I was stuck. I would like to blame that on my MS1 infopenia. You have breathed new life into me.