NPLEX Combination ReviewNeurology

Paul S. Anderson, ND

Medical Board Review Services

Copyright MBRS

Computerized Tomography (CT Scan)• Produces X-rays similar to conventional X-ray,

but produces cross-sectional images (“slices”) of anatomic structures without superimposing tissues on each other.

• CT is formerly the imaging study of choice to differentiate tissue structures within solid organs.

• Used in trauma situations due to speed and superiority over plain film

• Used in many initial CVA / Neurological studies• “CAT – FAT – BLACK”

SPECT

• Single Positron Emission CT– Used as a more functional CT scan of the

brain– Often used in the Dx of dementia

Magnetic Resonance Imaging (MRI)

• Nonionic, Noninvasive technique that produces cross-sectional images of human anatomy – very effective in visualizing soft-tissues, especially CNS and PNS.

• Image of choice for most neurologic and many interarticular orthopedic procedures.

CNS Imaging

• Imaging is the procedure of choice for CNS diagnosis – Except for potential Meningitis – then it is Lumbar Puncture.

• MRI is the CNS image of choice.

Neurological Pharmacology

Neurotransmitter PhysiologyNeurotransmitter If Decreased: If Increased:

Acetylcholine Decreased memory, Delirium, Delusions

Aggression, Depression

Dopamine Dementia, Movement disorders

Depression

Psychoses, Anxiety, Confusion, Aggression

Serotonin Depression, Aggression Anxiety

Norepinephrine Depression, Dementia Anxiety, Aggression, Inattention

GABA Anxiety Affective decrease, Lethargy

Glycine Anxiety Affective decrease, Lethargy

Nitrous Oxide Vasospasm, Potential hyperactivity

Sedation, Vasodilatation, Visual Hallucinations

Histamine Mania Depression

Neurosteroids Allows down regulation of GABAa receptors via a-4 subunit proliferation

Potentates GABAa receptor activity

Brain Chemistry BalanceDOWNERS:

GABA

Glycine

NO

Histamine

Neurosteroids

UPPERS:

Serotonin

Ach

DOPA

NE

BALANCE / LEVELING NEUROTRANSMITTERS:

Serotonin

Acetylcholine

(Glycine)

General and Autonomic Agents

Cholinergic Agonist

MOA Uses Adverse Effects Other

Pilocarpine Acts upon Muscarinic Receptors

GlaucomaAcute closed angle glaucoma

Myopia, blurred vision, bronchoconstriction and pulmonary edema

CholinesteraseInhibitor

MOA Uses Adverse Effects Other

Physostigmine Competes with ACh for active site of enzyme

GlaucomaMyasthenia Gravis

Seizures, restlessness, excitability, bronchospasm, diarrhea, excessive salivation

Contraindicated in obstruction of intestine or GU tract, diabetes, asthma or CV disease

Nicotinic Agonist MOA Uses Adverse Effects Other

Nicorette GumNicoderm PatchNasal Spray

Binds to nicotinic receptor Stop smoking protocols

Headache, insomnia, N/V. Tachycardia.Patch may cause local rash

** Don’t confuse with withdrawal Sx.

** If patient is having NIGHTMARES they may be toxic.

Gum is contraindicated during pregnancy

Oral: Leathal in kids.

Induces CYP1A2INTERACTS WITH:Caffeine / Theophylline . TCA’s / Warfarin

Psychoses

Neuroleptic drugs

• The neuroleptic drugs are competitive inhibitors of a variety of receptors.

• The anti-psychotic effect of these drugs is attributed in large part to competitive blockade of dopamine receptors.

• This class of drugs does not cure the underlying disease but at best, permits the psychotic patient to function in a supportive environment.

Neuroleptic drugs

The neuroleptic drugs can be divided into five major classifications bases on the structure of the drug. These classes are:

1. Phenothiazine class

2. Benzisoxazole class

3. Butyrophenone class

4. Dibenzodazepine class

5. Thienobenzodiazepine class

Neuroleptic drugs

Phenothiazine class includes:

• Chlorpromazine - Thorazine

• Fluphenazine - Prolixin

• Prochlorperazine - Compazine

• Thioridazone – Mellaril

• Trifluoperazine - Stelazine

Neuroleptic drugsBenzisoxazole class

• Respiradone – Risperdal

Butyrophenone class

• Haloperidol – Haldol

Dibenzodazepine class

• Clozapine – Clozaril

• Quetiapine fumarate – Seroquel

Thienobenzodiazepine class

• Olanzapine – Zyprexa

Neuroleptic drugs

• Adverse effects commonly observed with the use of neuroleptics include:– Tremors/ Parkinsonian effects– Tardive dyskinesia– Postural hypotension– Blurred vision, dry mouth, constipation, and

urinary retention– Sexual dysfunction– Drowsiness

Neuroleptic drugs

• An additional side effect that occurs only rarely is termed neuroleptic malignant syndrome.

• Neuroleptic malignant syndrome is characterized by catatonia, fluctuating blood pressure, dysarthria and fever.

• This syndrome may be fatal if the anti-psychotic drug is not immediately discontinued and the patient receives treatment with a dopamine agonist such as Bromocriptine.

Neuroleptic drugs

• Most of the neuroleptic drugs have anti-emetic effects that are mediated by blocking D2 dopaminergic receptors in the chemoreceptor trigger zone of the medulla.

• Several neuroleptics are useful in the treatment of nausea due to cancer chemotherapy.

Antipsychotics MOA Uses Adverse Effects

Other

PhenothiazinesChlorpromazine, Thioridazine, Prochlorperazine

Complex: seems to block post-synaptic dopamine receptors in the brain.

Psychosis, N/V and hiccoughs

Extrapyramidal reactions, tardive dyskinesia, sedation, orthostatic hypotension, dry mouth, constipation and urine retention.

Contraindi-cated in depressed patients, patients with bone marrow suppression.

Haloperidol Mechanism similar to that of phenothi-azines PLUS H1 blockade.

Psychosis, Tourette’s syndrome, Huntington’s Disease.

Severe extrapyramidal reactions, seizures, blurred vision, and tardive dyskinesia.

Enhances actions of CNS depressants, alcohol, and anti-convulsants.

Chlorpromazine/ ThorazineClass: Phenothiazine• Indication: Psychosis, mania,

schizophrenia as well as nausea and vomiting and intractable hiccoughs.

• MOA: Chiefly D2 dopaminergic receptor site blockade.

• Dose: PO/IM/PR. Half life ~20-40 hours. Metabolized by liver to inactive metabolites. Generally has more extrapyramidal side effects then do the newer agents.

Chlorpromazine/ Thorazine

• Side effects: As noted in prior slides, a signifigant side effects is onset of Parkinsonian symptoms and extrapyramidal signs such as tardive dyskinesia. Increased release of prolactin often occurs as a result of dopamine blockade. Increased prolactin can result in galactorrhea, amenorrhea and infertility.

Prochlorperazine/ CompazineClass: Phenothiazine• Indication: Psychosis as well as nausea and

vomiting.• MOA: Primarily H1-histamine receptor antagonist

as well as alpha-adrenergic receptor antagonist and D2 dopaminergic receptor antagonist.

• Dose: Oral only. Less orthostatic hypotension and fewer extrapyramidal signs then chlorpromazine. Better anti-emetic agent.

Prochlorperazine/ Compazine

• Side effects: As noted previously. Signifigant drowsiness, dry mouth, constipation and urinary retention.

Respiradone/ Risperdal

Class: Benzisoxazole• Indication: Psychosis• MOA: Exact mechanism of action is

unknown yet presumed to be a combination of dopamine and serotonin receptor blockade.

• Dose: PO. Metabolized in liver by P450 enzyme and metabolites are active. Reduce dose in patients with liver dysfunction.

Respiradone/ Risperdal

• Side effects: Extrapyramidal effects, tardive dyskinesia, constipation, sedation. Slow withdrawal is recommended to reduce the incidence of acute psychosis.

Haloperidol/ Haldol

Class: Butyrophenone

• Indication: Psychosis, Tourette’s syndrome, Huntington’s disease, acute agitated behavior.

• MOA: Chiefly D2 dopaminergic receptor site blockade.

• Dose: PO/IM/IV. Careful administration so as to reduce excessive sedation and tardive dyskinesia.

Haloperidol/ Haldol

• Side effects: Chiefly Parkinsonian and extra-pyramidal effects, which may be very dramatic. Tremors very common. Less blockade of the muscarinic and the -adrenergic receptors relative to other neuroleptic agents such as Chlorpromazine (Thorazine).

Clozapine/ Clozaril

Class: Dibenzodazepine• Indication: Schizophrenia, especially when

other anti-psychotic agents have failed or have produced undesirable side effects.

• MOA: Multiple receptor site blockade yet greatest effects at D2 and S (serotonin) receptor sites.

• Dose: PO. Rapid absorption and extensive metabolism

Clozapine/ Clozaril

• Side effects: Relative diminished extra-pyramidal side effects compared to other neuroleptic agents. Potent anti-muscarinic effects. Agranulocytosis has been reported in 1-2% of patients. Therapy should be withheld if granulocyte count is <1,500.

Aripiprazole

[Abilify]

An atypical antipsychotic:

Treatment of Schizophrenia,

manic or mixed episodes associated with Bipolar I Disorder as monotherapy or adjunctive to lithium or valproate Adjunctive treatment of Major Depressive Disorder in adults

Adult patients with Schizophrenia: akathisia

Pediatric patients (13 to 17 years) with Schizophrenia: extrapyramidal disorder, somnolence, and tremor

Adult patients (monotherapy) with Bipolar Mania: akathisia, sedation, restlessness, tremor, and extrapyramidal disorder

Adult patients (adjunctive therapy with lithium or valproate) with Bipolar Mania: akathisia, insomnia, and extrapyramidal disorder

Pediatric patients (10 to 17 years) with Bipolar Mania: somnolence, extrapyramidal disorder, fatigue, nausea, akathisia, blurred vision, salivary hypersecretion, and dizziness

Adult patients with Major Depressive Disorder (adjunctive treatment to antidepressant therapy): akathisia, restlessness, insomnia, constipation, fatigue, and blurred vision

Adult patients with agitation associated with Schizophrenia or

Bipolar Mania: nausea.

Atypical Antipsychotics

Some information courtesy of Drugs.com

Movement Disorders

Anti-Parkinson

MOA Uses Adverse Effects Other

Levodopa Decarboxylation reaction takes place in the brain to convert to Dopamine

Parkinson’s Disease

N/V, aggressive behavior, seizures, dystonia, dyskinetic, dementia, delirium, hallucinations, suicidal tendencies

Contraindicated with MAO inhibitors

Carbodopa

Carbi-Levodopa [Sinemet]

BromocriptinePergolide

Pramipexole [Mirapex]Ropinirole [Requip]

Improves effect of Levodopa

Dopamine Agonists

Adjunct to Parkinson’s Disease

Adjunct to Parkinson’s Disease

No effects when used alone. Does not diminish side effects of Levodopa except may decrease N/V

N/V, Psych. Changes

Pills contain fixed amounts of Levodopa and Carobdopa(Sinemet)

Ergot derivative

Non-Ergot

Major Treatment Directions

Depression• Catecholamine

Theory– Need ‘uppers’

• Serotonin Theory– Need leveling

• Combination?– Need both

Anxiety / Sleep• GABA• Glycine

• NMDA antagonism

• NO

• Histamine

Depression - 1

Catecholamines

ADRENERGIC (Epi. / NE) RECEPTORS

SAM-E

(S-Adenosyl-L-methionine)

SAMe [L-Methionine Adenosyltransferase] Methionine Homocysteine

(B6)

Cystathionine (B6)

Sulfite Cysteine (Mg) Glutathione

(Toxic-S) (B3)

(Mo)

(B6)

Sulfate (Helpful-S)

Taurine

Diet / Toxin:

B-12 and Betaine

SAMh

The Catecholamines

• Generally excitatory

• Include mainly Dopamine and Norepinephrine in the CNS

• Produced from dietary Phenylalanine and Tyrosine

• Involved in neuropharmacology for movement disorders, depression, ADD/ADHD…

Tyrosine / Phenylalanine Metabolites

Thyroid Hormone Synthesis

Phenylalanine [Phenyl-Hydroxylase] Tyrosine TCA Cycle

[Tyrosine Hydroxylase]

L-DOPA

[DOPA-decarboxylase]

Dopamine

CO-FACTORS:

B3 / Fe / Biopterin

CO-FACTORS:

SAMe / B12 / Folate

Stimulated by cold & stress

Inhibited by NE

B-6, B-1

Stimulated by:Copper, Vit. C

Inhibited by: Glutathione, Cystiene, B-5

NE Epi.

[N-Methyl-Transferase]

(Adrenal Medulla)[Dopa-Beta-Hydroxylase]

Dopamine Synapse

Tyr.

DOPA

DA

DA

DA

DA

Reserpine inactivates storage granules

DA - Receptor

Reuptake Blocked by: Cocaine, Buproprion, Benzatropine, Amphetamine.

NE Pathway

NE Synapse (CNS)

Tyr.

DOPA

DA

NE

NE

NE

Reserpine inactivates storage granules

Alpha - Receptor

Reuptake Blocked by: Tricyclics & Amphetamine.

MAO

COMT MAO Sulfotransferase

Monoamine Oxidase Inhibitors

Phenelzine (Nardil)

Isocarboxazid (Marplan)

Action:

Block the metabolism of dopamine, norepinephrine, and serotonin. Suppresses REM sleep.

RARE USE NOW!

Used for:Depression, narcolepsy, phobias and Parkinson’s.

Interact with almost all antidepressants, 5HT, and many medications which effect catecholamines.

Bupropion [Wellbutrin]

[Zyban] NE & Dopa Activity: So can be used with an SSRI

Depression

Stop-Smoking

Lowers SEIZURE THRESHOLD!

If these meds are working, consider catecholamine augmentation prior to tapering.

Catecholamine Metabolism

NE [MAO] 3,4OH2-MA [MAO] EPI

[COMT] [COMT] [COMT]

COMT re

N-MET [MAO] VMA [MAO] MET

[Hepatic Glucuronidation / Sulfation]

Glucuronide / Sulfide=NE Glucuronide / Sulfide=Epi.

VMA

COMT requires Magnesium and SAMe to operate properly.

MAO requires B-6 to operate properly.

Depression – 2

Serotonin

Serotonin

• Major target of neuropharmacology for the past 25 years

• Provides calming effect to the brain, as well as some cross receptor regulation

• Has CNS and peripheral effect

• Multiple receptor sub-classes discovered

• Produced from dietary Tryptophan

Tryptophan Metabolism

Tryptophan

[Tryptophan Hydroxylase] [Tryptophan pyrolase]

5-Hydroxy-tryptophan Kynurenine

(B6) (B6)

Serotonin Niacinamide (B5)

(B12/Folate)

Melatonin

Inhibited by Niacinamide

Stimulated by: Cortisol, Tryptophan, Estradiol

Biopterin / B3 / Fe

N-Acetyl Serotonin

P

I

N

E

A

L

Degradation by MAO and Aldehyde

Dehydrogenase

Note: Serotonin can not cross the BBB.Tryptophan uptake is via an active AA transporter at the BBB, which has competition from Tyr-Phe-Leu-Isoleu-Val-Met-His

Serotonin (5HT) Synapse

Tryp

5HTP

5HT

5HT

5HT

5HT

5HT Receptor

MAO

LSD: -+

SSRI -

Reserpine inactivates storage granules

SSRI’s:Fluoxetine (Prozac)Sertraline (Zoloft)Paroxetine (Paxil)Citalopram [Celexa]Excitalopram [Lexapro]

Block the uptake of Serotonin to increase the amount of serotonin in the synaptic clefts.

Tapering may be slower or faster, depending on the dose and duration of treatment.

Tryptophan, and its cofactors and metabolites are key to success in lowering or removing these drugs.

Be wary of latent suppressed mental and emotional pathology, which will often present itself upon tapering off these drugs.

SSRI’s

Trazadone

[Desyrel]

Nefazodone

[Serzone]

Serotonin Transporter Inhibition

Depression

Insomnia

Clinically, treat like other serotonin manipulating drugs. Can be very hard to wean patients off if long term user.

Rebound insomnia is a common withdrawal effect.

OTHER (Non-SSRI) AGENTS - 1

Serotonin AugmentationTryptophan

[Tryptophan Hydroxylase] [Tryptophan pyrolase]

5-HTP (B6)

Serotonin

(B5)

(B12/Folate)

Melatonin

Inhibited by Niacinamide

Stimulated by: Cortisol, Tryptophan, Estradiol

Biopterin / B3 / Fe

P

I

N

E

A

L

1. Tryptophan or 5HTP with B62. Niacinamide may be added to REDUCE Tryp. / 5HT

dose3. In depression with insomnia, add Pantothenic acid

(1/2 to 3 grams / day), B12 / folate, and 3 – 12 mg Melatonin and taper off Melatonin after 2 to 4 months.

4. In combination med responsive depression add Tyrosine or Phenylalanine.

Note: Serotonin can not cross the BBB.Tryptophan uptake is via an active AA transporter at the BBB, which

has competition from Tyr-Phe-Leu-Isoleu-Val-Met-His

(B6)

Niacinamide

Serotonin Agent Management

• If patient is on any serotonin agent, the addition of another may cause serotonin syndrome.

• Careful patient monitoring and slowly tapering on (nutrients) and off (meds) will prevent most significant side effects.

• Also, consider the dose range for the agent, patients size and length of treatment. All these factors will give input regarding how much nutrient support you can begin prior to tapering the meds.

• Dream state is often first to show increased serotonin – as dreams become more memorable or intense often the drug can be tapered more.

Drug taper (off)

Nutrient taper (on)

Serotonin Agent Management-2

1. Look at the dose of SSRI the patient is on2. Look at the patient size (BMI) and see where

they fall in the range; i.e. high dose, medium or low dose.

3. The lower in the range they are the faster you can introduce Serotonin type nutrients / herbs.

Drug taper (off)

Nutrient taper (on)

Serotonin Agent Management-3Example-1

1) Look at the dose of SSRI the patient is on1) Fluoxetine (Prozac) 80mg daily

2) Look at the patient size (BMI) and see where they fall in the range; i.e. high dose, medium or low dose.

1) Fluoxetine (Prozac) range 20-80mg daily avg. human2) Average dose is for 150# person between 18-65 yo3) This patient is a 160# male, 45 yo4) This patient is at the UPPER end of dose range = easy to overdose!

3) The lower in the range they are the faster you can introduce Serotonin type nutrients / herbs.

1) In this case one should consider basic nutrient support while tapering the SSRI SLOWLY, and then start Serotonin specific nutrients once the patient is at 60mg or less.

Drug taper (off)

Nutrient taper (on)

Serotonin Agent Management-4Example-2

1) Look at the dose of SSRI the patient is on1) Fluoxetine (Prozac) 20mg daily

2) Look at the patient size (BMI) and see where they fall in the range; i.e. high dose, medium or low dose.

1) Fluoxetine (Prozac) range 20-80mg daily avg. human2) Average dose is for 150# person between 18-65 yo3) This patient is a 90# female, 25 yo4) This patient is at the Middle end of dose range (<150#)

3) The lower in the range they are the faster you can introduce Serotonin type nutrients / herbs.

1) In this case one should consider basic nutrient support and slowly increasing specific serotonin nutrition while tapering the SSRI SLOWLY.

Drug taper (off)

Nutrient taper (on)

Why all the worry about tapering and monitoring?

SEROTONIN SYNDROME

• FEVER

• HYPERREFLEXIA

• B.P. CHANGES

• COMA

• DEATH

Serotonin Enhancement Rx:

• B6 / Niacinamide– Use together– B6 100-300mg / Niacinamide 1000 – 3000 mg Daily

• Tryptophan– 500mg – 6000mg daily. Less with the above.

• 5HTP– 50mg – 1000mg

So - I’ve heard that St. Johns Wort is bad for your liver?

LIVER DETOXIFICATION PATHWAYS

Phase-1 CYP450

(-OH added)

Phase-2

Enzymatic Conjugation

Excreted derivativesFat –

Soluble Compounds

Water – Soluble compounds

Natural creation of Hydroxyl and Superoxide Radicals leading to Lipid Peroxidation.

Glycine Hippurates

Glutathione Mercapturates

Glucuronic Acid Glucuronides

PHASE-1 (Cytochrome P450) Pathways:

Generally render Non-polar (Lipid Soluble) substances Polar

Reactions: Oxidation, Reduction, Hydrolysis, Hydration…

Co-factors / Substrates: B2,3,6,12,Folate, GSH, AA’s…

PHASE-2 (Conjugation) Pathways:

Take intermediary (more-polar) P450 metabolites and conjugate them with Amino Acids.

Hepatic Detoxification Pathways:

EXCRETION:

BILE SERUM URINE

This process creates NATURALLY peroxide and superoxide free radicals!

INDUCERS INHIBITORS

BarbituratesCarbamazepine Dexamethasone EfavirenzGlucocorticoids ModafinilNevirapinePhenobarbital Phenylbutazone Phenytoin PioglitazonePrimidone Rifabutin Rifampin

St. John's WortSulfinpyrazoneTroglitazone

AmiodaroneAnastrozole ChloramphenicolCimetidine CiprofloxacinClarithromycin Clotrimazole Danazol Delavirdine Diltiazem Erythromycin Fluconazole Fluoxetine Fluvoxamine Grapefruit juice Indinavir Itraconazole Ketoconazole Metronidazole MibefradilMiconazole Nefazodone Nelfinavir Nevirapine NorfloxacinNorfluoxetine Omeprazole Paroxetine Propoxyphene Quinidine Ranitidine

Substances having effect on the Cytochrome P450 3A4 system

Depression – 3

Combination

Tricyclic Antidepressants

Amitriptyline

Imipramine

Desipramine

Nortryptyline

Clomiprimine

Protriptyline

Doxepin

Amoxapine

Action:Block reuptake of MAO and increase amount of NE and serotonin.

Used for:DepressionNeuropathyInsomniaMigraine

1: Hard to get patients off if taking higher (50 + mg.) doses. ****Watch for rebound INSOMNIA

2: Must replace neurotransmitters NE & 5HT if trying to taper.

3: Generally require very slow, gradual tapering. Often best after other therapy for underlying condition is started.

MSE’sVenlafaxine (Effexor)

Mirtazapine [Remeron]

Block the uptake of Serotonin to increase the amount of serotonin in the synaptic clefts.

Added effect on NE receptors!

Effect on NE as well as being a 5HT-2&3 Blocker (No Serotonin SE’s)

Tapering may be slower or faster, depending on the dose and duration of treatment.

Tryptophan cofactors along with SOME DOPA augmentation are key to success in lowering or removing these drugs.

Be wary of latent suppressed mental and emotional pathology, which will often present itself upon tapering off these drugs.

Modified 5HT Effectors

Memory and Cognition

Acetylcholine

• Multiple sites of action in the body– Acts as a neurotransmitter (PNS / CNS)– Acts as a hormone (Cornea)

• Peripherally acts at the neuromuscular junction, and elsewhere via Nicotinic and Muscarinic receptors

• Centrally seems to be involved in memory and other neurological counter regulation

Acetylcholine Metabolism

SERINE

Pyruvate[Folate / B3 / B6]

Acetate[B2 / B5 / B6]

Acetyl-CoA[Choline Acetylase]

Acetylcholine (ACh)Diet [Acetylcholine esterase]

Choline Acetate

Phosphatidylethanolamine

Phosphatidylcholine

Choline

Betaine

SAMe

SAMh

Acetylcholine Synapse

AcCoA

Choline

ACh

ACh

AChCholine

Acetate

Release blocked by:

Mg / Botox

Stimulated by:

Black Widow Venom

Acetylcholine Receptor

Cell Membrane

ACh

Na+Receptor:

Blocked by: Atropine, Rabies, Curare.

Stimulated by Anti-Cholinesterase agents.

Cell Activation

Cognitive Agents – Acetylcholine Sparing

• Aricept– Generic: donepezil

• Cognex– Generic: tacrine hydrochloride

• Razadyne – Generic: galantamine

• Exelon – Generic: rivastigmine

Cognitive Agents – NMDA / Glutamate blockers

• Namenda• Generic: memantine hydrochloride

– Orally active NMDA receptor antagonist.• Persistent activation of central nervous system N-methyl-

D-aspartate (NMDA) receptors by the excitatory amino acid glutamate has been hypothesized to contribute to the symptomatology of Alzheimer's disease.

• Memantine is postulated to exert its therapeutic effect through its action as a low to moderate affinity uncompetitive (open-channel) NMDA receptor antagonist which binds preferentially to the NMDA receptor-operated cation channels.

• In vitro studies have shown that memantine does not affect the reversible inhibition of acetylcholinesterase by donepezil, galantamine, or tacrine.

“Depression Hurts”And other

Reasons to have centralacting pain controllers

FMS

• Many FMS Rx strategies use antidepressants.

• Most are used to raist Serotonin, NE, DOPA or all three.

• One is an atypical anti-seizure medication:

pregabalin

[Lyrica]

Lyrica is indicated for:•Neuropathic pain associated with diabetic peripheral neuropathy •Post herpetic neuralgia •Adjunctive therapy for adult patients with partial onset seizures •Fibromyalgia

Lyrica (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's antinociceptive and antiseizure effects in animal models. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of calcium channel function.

WARNINGS AND PRECAUTIONS

Angioedema (e.g. swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Lyrica should be discontinued immediately in these cases.

Hypersensitivity reactions (e.g. hives, dyspnea, and wheezing) can occur. Lyrica should be discontinued immediately in these patients.

Increased seizure frequency may occur in patients with seizure disorders if Lyrica is rapidly discontinued. Withdraw Lyrica gradually over a minimum of 1 week.

Lyrica may cause peripheral edema. Exercise caution when co-administering Lyrica and thiazolidinedione antidiabetic agents.

Lyrica may cause dizziness and somnolence and impair patients' ability to drive or operate machinery.

ADVERSE REACTIONS

Most common adverse reactions (≥ 5% and twice placebo) are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention).

FMS Pain – Central Drug

Some information courtesy of Drugs.com

Anxiety and Sleep

Drugs with somnolence as a side effect – not necessarily

calming to neurotransmission

Tricyclic Antidepressants

Amitriptyline

Imipramine

Desipramine

Nortryptyline

Clomiprimine

Protriptyline

Doxepin

Amoxapine

Action:Block reuptake of MAO and increase amount of NE and serotonin.

Used for:DepressionNeuropathyInsomniaMigraine

1: Hard to get patients off if taking higher (50 + mg.) doses. ****Watch for rebound INSOMNIA

2: Must replace neurotransmitters NE & 5HT if trying to taper.

3: Generally require very slow, gradual tapering. Often best after other therapy for underlying condition is started.

Trazadone [Desyrel]

Nefazodone [Serzone]

Serotonin Transporter Inhibition

Depression

Insomnia

Clinically, treat like other serotonin manipulating drugs. Can be very hard to wean patients off if long term user.

Rebound insomnia is a common withdrawal effect.

H1 Blockers(* = Non-Sedating)• Diphenhydramine (Benadryl)

– 12.5, 25 and 50 mg

• Loratadine * (Claritin)– 5 and 10 mg

• Desloratadine * (Clarinex)– 2.5 and 5 mg

• Cetirizine * (Zyrtec)– 5 and 10 mg

• Levocetirizine (Xyzal)– 5 mg

• Promethazine (Phenergan)– 12.5, 25 and 50 mg

• Fexofenadine * (Allegra)– 30, 60 and 180 mg

Tryptophan Metabolism

Tryptophan

[Tryptophan Hydroxylase] [Tryptophan pyrolase]

5-Hydroxy-tryptophan Kynurenine

(B6) (B6)

Serotonin Niacinamide (B5)

(B12/Folate)

Melatonin

Inhibited by Niacinamide

Stimulated by: Cortisol, Tryptophan, Estradiol

Biopterin / B3 / Fe

N-Acetyl Serotonin

P

I

N

E

A

L

Degradation by MAO and Aldehyde

Dehydrogenase

Note: Serotonin can not cross the BBB.Tryptophan uptake is via an active AA transporter at the BBB, which has competition from Tyr-Phe-Leu-Isoleu-Val-Met-His

Inhibitory Neurotransmission

GABA

• Main (most well known) inhibitory neurotransmitter

• Formed from Glutamine in the CNS

• Two separate receptor subtypes

• Target of neuropharmacology for over 50 years

• Target of self medication for centuries

The GABA Target:

Benzodiazepines

Barbiturates

BOOZE

GABA Metabolism in the CNS

Glucose Alanine Glutamine

Pyruvate Glutamic Acid

alpha-oxoglutaric acid B-1 / [Glutamic Acid Decarboxylase]

GABA

TCA

GHB

Succinate

G

A

B

A

Synapse

GABA Synapse

Glutamate(B-1)[glutamic acid

decarboxylase]

GABA

GABA

GABA

GABA

GABA-T

GABA Receptor

Depakote blocks:

GABA a Receptor

Cell Membrane

Cl-

1

3

2

4

Receptor Agonists:

1: Benzodiazepine

Increases channel opening frequency.

2: Barbiturate

3: Alcohol

4: Neuro Steroid

2,3&4 all increase the duration of channel opening.

CNS: Neurosteroid Effect

Progesterone

[3-alpha-HSD] (Stimulated by SSRI’s)

Tetrahydroprogesterone (aka. THP, Allopregnanolone)

Alpha-4-sub unit (inhibitory)

GABAa Receptor

-+

GABA b Receptor

Cell Membrane

GABA

Calcium

K

No Chloride activity.

Increased Potassium conductance.

Decreased Calcium conductance

PhenobarbitalAmobarbitalPentobarbital

Results in lengthening of Cl- channel opening. Barbiturates and Benzodiazepines

have high tolerance and addiction potential.

Slow tapering is essential or patients may have psychotic episodes.

Effecting the GABA complex in multiple ways if the key to successful removal of the drug.

Diazepam [Valium] Alprazolam [Xanax]Halazepam [Paxipam] Triazolam [Halcion]

Chlordiazepoxide [Librium]Clorazepate [Tranxene]

Benzodiazepine: Binds to GABA receptor.

Lorazepam [Ativan]Oxazepam [Serax]

“The Benzo’s to the elderly”(Short t ½ ) .

Buspirone

[Buspar]

Serotonin / Dopa / NE Activity

Anxiolytic without sedation and euphoria.

Takes 3-4 weeks to be effective

Anti Anxiety

Generic Name Brand Name Available Doses (mg)

Approximate EliminationHalf-life (hr)[9,12,13] DEA Schedule

** Benzodiazepine receptor agonists

Immediate-release benzodiazepine

   Estazolam Prosom (Abbott) 1, 2 8-24 IV

   Flurazepam Dalmane (Valeant) 15, 30 48-120 IV

   Quazepam Doral (MedPointe/Questcor)

7.5, 15 48-120 IV

   Temazepam Restoril (Mallinckrodt) 7.5, 15, 22.5, 30 8-20 IV

   Triazolam Halcion (Pharmacia & Upjohn)

0.125, 0.25 2-4 IV

Immediate-release non-benzodiazepine

   Eszopiclone Lunesta (Sepracor) 1, 2, 3 5-7 IV

   Zaleplon Sonata (Monarch/King) 5, 10 1 IV

   Zolpidem Ambien (sanofi-aventis) 5, 10 1.5-2.4 IV

Modified-release non-benzodiazepine

   Zolpidem ER Ambien CR (sanofi-aventis)

6.25, 12.5 2.8-2.9 IV

** Selective melatonin receptor agonist

   Ramelteon Rozerem (Takeda) 8 1-2.6 None

Phenytoin(Dilantin)

Reduce Na+, Ca+ and K+ across neuronal membranes

Carbamazepine(Tegretol)

Phenobarbital

Resembles Phenytoin

Enhance GABA

Clonazepam (Klonopin)

Unknown probably effects GABA, similar to benzodiazepines

Other Calming Drugs: Seizure DisorderAnti seizure properties, some off label uses as well.

Many patients will be using this for insomnia, anxiety, and occasionally during drug detox.

Anti-Seizure MOA Uses Adverse Effects Other

Phenytoin(Dilantin)

Reduce Na+, Ca+ and K+ across neuronal membranes

All seizures except absence seizures

Ataxia, slurred speech, confusion, incoordination, pancytopenia, hepatitis, gingival hyperplasia, N/V, nystagmus,

Numerous drug interactions

Phenobarbital Enhance GABA General seizures

Depresses CNS, drowsiness, lethargy, hangover, respiratory depression, angio-edema,

Decrease effect of MANY other drugs

Clonazepam (Klonopin)

Unknown probably effects GABA, similar to benzodiazepines

Status epilepticus.

Drowsiness, ataxia, disturbance in behavior, thrombocytopenia, respiratory depression

Contraindicated in hepatic disease, or acute closed-angle glaucoma

Carbamazepine(Tegretol)

Resembles Phenytoin

All seizures except absence seizures

Dizziness, drowsiness, vertigo, ataxia, worsening of seizures, N/V, aplastic anemia, agranulocytosis, thrombocytopenia, Steven Johnson syndrome, hepatitis, and CHF

May decrease effectiveness of oral contraceptives and doxyclycline. Do not use with MAO inhibitors

Effective drugs used to treat absence seizures include ethosuximide, valproate, clonazepam and trimethadione.

Remember Diazepam and Calcium Gluconate Given IV in acute seizure!

pregabalin

[Lyrica]

Lyrica is indicated for:•Neuropathic pain associated with diabetic peripheral neuropathy •Post herpetic neuralgia •Adjunctive therapy for adult patients with partial onset seizures •Fibromyalgia

Lyrica (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's antinociceptive and antiseizure effects in animal models. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of calcium channel function.

WARNINGS AND PRECAUTIONS

Angioedema (e.g. swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Lyrica should be discontinued immediately in these cases.

Hypersensitivity reactions (e.g. hives, dyspnea, and wheezing) can occur. Lyrica should be discontinued immediately in these patients.

Increased seizure frequency may occur in patients with seizure disorders if Lyrica is rapidly discontinued. Withdraw Lyrica gradually over a minimum of 1 week.

Lyrica may cause peripheral edema. Exercise caution when co-administering Lyrica and thiazolidinedione antidiabetic agents.

Lyrica may cause dizziness and somnolence and impair patients' ability to drive or operate machinery.

ADVERSE REACTIONS

Most common adverse reactions (≥ 5% and twice placebo) are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention).

Seizure – Central Drug

Some information courtesy of Drugs.com

Non-Scheduled Anxiolytics

• Buspirone [Buspar]– 5,10,15 and 30mg oral

• Initial dose 7.5-10 mg bid ramped up over 2-3 weeks to average of 20 – 30 mg total daily dose.

• Do not exceed 60 mg daily

– Normally requires 3 weeks to fully work

• Hydroxyzine [Anx, Vistiril]– 10, 25, 50 and 100 mg (oral)

• Anxiety 50 – 100mg po qid daily

– 25 or 50 mg/mL (injection – IM ONLY)• 25-100mg DEEP IM

Glutamate and Glycine: CNS Metabolism

Glutamine

Succinate

Glutamic acid a-keto-glutarate

(glutamate) (TCA)

Glyoxylase Glycine

5,10,Methyl-THF

Serine

TetraHydroFolate

ATP

B-6

Glycine Receptor

• Receptor agonist: Glycine– Glycine is also agonist to NMDA receptor– Glycine receptor is probably a major cross

regulatory mechanism for the excitatory receptor class

• Receptor opens Chloride channel

• Inhibitory / calming effect, like GABA

• Easy to target nutritionally

Glycine Receptor

Cell Membrane

Cl- Glycine

Cellular down-regulation

Glycine

– Low toxicity

– Extreme caution in Bipolar patients• Due to potential NMDA receptor agonist activity and

triggering of mania

– Helpful for: • Anxiety• Wound healing • Muscle spasticity

NMDA Receptor

• Primary excitatory receptor complex

• Often categorized with other excitatory “Glutamate” class receptors– N-methyl-D-aspartate (Na/Ca/K)– Kainate (Na/K ?)– AMPA (Na/K)– AP4 (Presynaptic inhibition)– ACPD (IP3 / DAG)

NMDA Receptor

Cell Membrane

Na Ca

1 2 3

45

3a

Excitatory

1: Glutamate

2: Zinc

3: Glycine (Acts as inhibitory transmitter at Glycine receptors)

Inhibitory

3a: Kynurenate (Tryptophan metabolite)

4: Magnesium

5: PCP / Ketamine

Blocked by ETOH

Nitric Oxide

Arginine

[NO Synthase] N=O

Citrulline

Cytoplasmic Cyclase

cGMP GTP

Cellular Activity

+

Retina: Photoreception

Vascular Smooth Muscle: Vasodilatation

AMPA (Excitatory) receptors: probable desensitization

Tetrahydrobiopterin, Ca2+, NADPH, o2

Hyper Catecholamine Patients

• Consider:– MAO support

– Liver support

– Rauwolfia / Reserpine in extreme cases

But doesn’t Rauwolfia and Reserpine use make people

kill themselves?

Lets go through this now:

Peripheral anti-adrenergic

MOA Uses Adverse Effects Other

Reserpine Depletes catecholamine stores in PNS [and maybe CNS]

Essential hypertension

These are RARE in hyper-catecholamine patients.Drowsiness, sedation, nervousness, depression, Decr. HR, nasal congestion, nausea / diarrhea Parasympathetic Predominance

Do NOT administer MAO inhibitors and Reserpine within two weeks of each other

Rauwolfia and Reserpine

• Reserpine Tablets:– 0.1 and 0.25mg available– Dose is 0.1 – 0.25 qd - bid

• Rauwolfia:– Watch tincture concentration– Average dose 1-3 mL qd - bid

Bipolar Spectrum Disorder

BIPOLAR MOA Uses Adverse Effects

Other

Lithium

Gabapentin [Neurontin]

Valproic Acid [Depakote]

Interferes with sodium ions in the brain.

GABA Agonist

Incr. GABA ?

Mania

Mania

Mania

Coma, seizures, arrhythmias, polyuria, headache, drowsiness, lethargy, tinnitus, blurred vision, abdominal pains, pruritus and etc.

Care in Ki. Dz.

Li. TOXICMonitor Levels!

Blood levels must be closely monitored.

NO low Na diets!

NO Liver metabolism

(OTHER – Many newer seizure drugs (Lamotrigine [Lamictal]) are used for mania)

Mania

• Mania is another affective disorder, characterized by elevated, expansive or irritable moods accompanied by increased activity, rapid speech, thoughts and feelings of grandiosity, distractibility and decreased need for sleep.

• Patients that cycle between periods of depression and mania carry the diagnosis of bipolar disorder.

Lithium salts

• Lithium salts are used prophylactically in treating bipolar disorder and in the treatment of manic episodes.

• Lithium is widely distributed in the central nervous system and interacts with a number of neurotransmitters and receptors, decreasing noradrenaline release and increasing serotonin synthesis.

Lithium salts

• The exact MOA of lithium as a drug is not known but it may serve to dampen transmission by norepinephrine as well as acting to increase second messenger concentration of inositol triphosphate (ITP or IP3) which further serves as an inhibitor of neurotransmission.

Lithium carbonate/ Eskalith

Class: Lithium salt

• Indication: Bipolar disorder and manic episodes. Lithium has also being used in the treatment of schizophrenia.

• MOA: As previously noted.

• Dose: PO. Cleared by kidneys. Very small therapeutic index such that therapeutic serum levels may be extremely close to toxic levels. Blood levels of lithium must be frequently checked.

Lithium carbonate/ EskalithSide effects: A major problem with lithium

treatment is lack of compliance, especially due to the side effects of weight gain, cognitive impairment and short-term memory deficits.

• The most common renal effect of lithium is impaired concentration capacity due to reduced renal response to antidiuretic hormone (ADH).

• The incidence of polyuria due to nephrogenic diabetes insipidus is approximately up to 20% of patients receiving chronic treatment.

Lithium carbonate/ Eskalith

• Hypothyroidism may occur in 5% to 35% of patients on long term lithium therapy.

• Signs that lithium levels may be too high include: lethargy, confusion, diarrhea, abdominal pain, nausea and vomiting ataxia and severe tremors.

• As lithium levels increase, seizures develop and cardiotoxicity can occur.

Infectious Disease

• Routes of Spread of Infection: – Blood: via arteries or veins of face– Direct injury or trauma– Extension of other infection (Spinal cord, Sinus, Mastoid…)– PNS Herpes, Rabies, Other

• Bacterial Meningitis: – E. coli, H. flu, Meningococcus– Headache– Purpuric rash on trunk (Meningococcal)– Nuchal rigidity (not always present in pediatric patients)– Obtundation– Toxic appearance

• Brain Abscess: – Strep & Staph – Increased risk in orbital infections!!, bacterial endocarditis,

bronchiectasis, congenital heart dz.

• TB meningitis: – Mycobacterium TB, – Well formed granulomas with caseous necrosis & giant

cell infiltrates– Seen with acid fast stain

• Neurosyphilis: tertiary; – Asymptomatic meningitis; – Paralytic = brain atrophy from cell death– Tabes Dorsalis

• spirochete destroys dorsal roots = impaired sensation & ataxia, absent DTR’s

Encephalitis• Severe:

– Headache with systemic sn/sx (fever, n/v…)– Often focal neurological deficit

• Sub-acute:– Like a severe viral illness.– Headache PERSISTS even as the systemic

sn/sx wane.

Severity

Time

Headache

Other Sn/Sx

• Encephalitis: – EEE, (Togaviridae, genus Alphavirus) arthropod borne; birds

reservoir not horses• Mosquito – bird transmission / reservoir (people and horses get the

disease) • 35% of humans die, another 35% have residual neurological sx.

– Measles, mumps, chicken pox, rubella can cause autoimmune encephalitis

– HSV I & II (why C-section for positive mothers in the past)

• Rabies: – via dog or wild carnivore,

• virus from bite ascends to brain, • Negri bodies in hippocampus & cerebellum,

– Paresthesias around wound, spasms, hydrophobia

• Poliomyelitis: – Non-specific gastroenteritis

• secondary invasion of lower motor neurons, • flaccid paralysis, hyporeflexia;

– Post polio syndrome• progressive weakness 25-35 yrs later, muscle wasting, pain;

virus not found

• Herpes Zoster: – Recurrence of varicella virus in dermatomes

• Often mistaken for vertebral back pain

– Shingles; itching, burning, sharp pain, radiculo-neuritis

• Tumors Clinical Signs: – Drowsiness, lethargy, obtundation, personality changes, psychosis,

seizures, headache, vomiting, papilledema• In adults tend to occur above the tentorium cerebelli• In children tend to occur below the tentorium

• Neuroglial: – Astrocytoma (grades 1-4) Grade 1-2 = benign, Grade 3 = malignant– Glioblastoma Multiforme

• (GBM = grade 4 Astrocytoma) most common primary brain tumor of adults. Most aggressive / highly malignant.

• Neural Tissue Origin: neuroblastoma; gangliocytoma• Peripheral Nerve Tumors:

– Schwannomas=benign;– Acoustic neuroma=CN 8; – Neurofibromas=benign if solitary; potentially malignant if multiple; – Neurofibromastosis=Von Recklinghausens, autosomal dominant &

mutations

• Demyelinating disorders:– (CNS) : MS: Female

• Risk by location lived first 15 yrs (Northern climates); familial• Optic neuritis, glove and stocking parasthesias• Autoimmune demyelination: usual triggers

– (PNS) : Guillain-Barre Syndrome: • Acute idiopathic polyneuritis; polyradicuolneuropathy; • 2/3 preceded by acute flu-like illness; • ascending paralysis; • DTR’s disappear; sensation intact

• Dysmyelination disorders (CNS)– AKA: Leukodystrophies – caused by inborn enzyme

deficiencies that create abnormal myelin.• Adrenoleukodystrophy• Metachromic leukodystrophy (most common)• Krabbe’s disease

Nutritional Disorders:• Wernicke-Korsakoff syndrome:

– Thiamine (B1) deficiency due to alcoholism• ETOH metabolism uses up B1 (among other nutrients)

– Confabulations / no short term memory• Tx. With B1 IV reverses many Sn/Sx

• Pellegra/Niacin def.: – Many psychiatric hospitalizations historically– Dementia, Dermatitis, Diarrhea (death)

• Vitamin B12 Def.: – Macrocytic anemia– Degeneration of spinal cord

• Spasticity, weakness, dementia, loss of proprioception.

– Some PNS Sx.– Not cured by Folate supplementation

• Although the macrocytic anemia will clear up.

Ischemic cerebrovascular disease

• 25% of pts with carotid-middle cerebral artery ischemia and 50% with vertebrobasilar insufficiency have new, recurrent, nondescript headache

• Headaches often occur before event

• New headaches in patients > 50 should be investigated

• Increased Intracranial Pressure: – Leads to papilledema (swelling of disk) & brain

herniation.

• Cerebral Edema: – Brain has no lymphatics, blood brain barrier

controls fluid transport – Edema secondary to increased vascular

permeability, altered regulation of fluid or transudation

– Common after injury, radiation, long term HTN

• Hydrocephalus: – Enlarged ventricles

• Increased CSF produced in choroid plexus• Lateral third and fourth ventricles swell

• Hypoxia/Ischemia: – Damage from low pH or low O2 (Remember, CO2 =

Carbonic Acid)• Encephalomalcia = necrosis

• Cerebral Infarction/Stroke: – Thrombotic from athersclerosis– Embolic from cardiac thrombi to middle cerebral arteries– Hemorrhagic secondary to:

• hypertension, rupture of berry aneurysm, • women who smoke & take OBC;

– Liquifaction necrosis in both

• Intracranial Hemorrhage: (Larger structure hemorrhage)– Hypertension; rupture of aneurysms (Charcot-Bouchard); – Confusion, drowsiness, h/a, nausea

• Vascular malformations/Berry Aneurysm: – AVM = Congenital, may occur anywhere, cause chronic HA– Berry = Congenital; anterior middle, & posterior communicating

arteries• Sudden excruciating h/a with rupture

• Hypertensive Encephalopathy: – Diastolic pressure over 120

• Grade 4 retinal changes

– Confusion, drowsiness, h/a, nausea• May lead to rupture and hemorrhage

• Spinal Cord Vascular Lesions: – Various neurologic deficits can be caused by vascular compromise. – Most often from vascular compression (e.g. tumors, acute disk

compression)– Occlusion from remote causes (aortic surgery, dissecting aneurysm)

Neurological Event Types:

• TIA– Sn/Sx of stroke that last LESS than 24 hrs.

• RIND– Sn/Sx of stroke that last longer than 24 hours,

BUT resolve completely!

• Stroke!

Transient Ischemic Attack (TIA)

• Focal neurological abnormalities of sudden onset and brief duration secondary to transient ischemia of the brain

• Acute onset; last 2-30 min; abate with no permanent sequelae

• 90% affect carotidipsilateral blindness/contralateral hemiparesis that are temporary

• Neurological exam is normal when seen

Stroke

• Infarction of brain tissue manifested by neurologic deficits of varying severity

• Atherothrombotic: sudden, gradual, stepwise or fluctuating.

• Cardiac embolus: sudden onset. High Risk-atrial fibrillation, prosthetic valve, mural thrombus, dilated cardiomyopathy, M I in previous 4 wks.

• Risks:– Hyperlipidemia; smoking

Features of stroke

• Speech not impaired in R. cortical stroke• Inattention = cortical stroke• Impaired cognition = large cortical or

bilateral stroke• Total hemiplegia = sub cortical stroke• Lower cranial nerves involved = sub

cortical stroke• Cerebellar signs = sub cortical stroke

Cortical strokes

Middle cerebral artery Contralateral hemiparesis /sensory loss, more on face and upper extremities; aphasia

Anterior cerebral artery

Contralateral hemiparesis /sensory loss, lower extremities more involved

Posterior cerebral artery

Contralateral hemianopsia with macular sparing

Ulnar palsy

• Ulnar nerve compression at elbow or wrist

• Involves ½ of ring finger and 5th finger on palm surface

• Atrophy of hypothenar eminence and interosseous muscles of hand claw hand.

Thoracic outlet syndrome

• Involves brachial plexus

• Compression from cervical rib, occupation, lymphoma, vascular malformation.

Bell’s palsy

• Unilateral facial paralysis of sudden onset• Usually due to viral inf with swelling of the

7th nerve• Pain behind ear may precede paralysis• No sensory loss, except taste• Treatment is difficult; involves steroids,

physical therapy and eye patching.

Guillain-Barrė Syndrome (GBS)

• Symmetric weakness with paresthesias, beginning in legs and moving upward

• DTR’s lost, sphincter control maintained• 50% have facial involvement• 90% reach maximum paralysis in 2 to 3

wks• Lab shows CSF protein• DDX: botulism

Botulism

• Neuromuscular poisoning from Clostridium botulinum toxin, an anaerobic bacterium– Spore forming bacteria reactivates

• Found in contaminated home canned food, wounds and in the intestine of susceptible infants.

• Sudden onset in a previously healthy person usu within 18-36 hrs of ingestion

Symptoms of Botulism

• Dry mouth, diplopia, ptosis, loss of accommodation and pupillary light reflex– G.I. Sx precede neuro sx and include n/v, cramps and

diarrhea

• No fever• Descending paralysis (the reverse of G.B.)

– Sensation is normal

Infant Botulism

• Most often seen at 2-3 mos/age– Caused by colonization of gut– Honey (some cases recorded) is common

source of infection, plus soil or spore contaminated foods.

• Constipation may precede other sx

• May progress to “floppy baby”– Stool analysis confirms dx.

Headache Comparison

Feature Cluster Migraine Tension

Gender male female equal

Age/onset 20-50 yrs 10-40 yrs Any age

Frequency 1-8/d 1-8/mo daily

Duration ½-4 hrs 4-72 hrs. steady

Intensity severe moderate Dull ache

Location unilateral Unilat/bilat bilateral

Headache Comparison

Feature Cluster Migraine Tension

Nasal con 70% none none

Teary eye common none rare

N and V rare common rare

nocturnal common rare rare

Behavior restless hibernates hibernates

Family Hx 7% 90% + with stress

Tension headache

• Most common type of headache– Muscle tension of scalp and neck– Steady vice-like pain– Usually bilateral, starting in occiput and

spreads to frontal/temporal areas

• Can recur daily more in p.m.– May last for days to months– Not associated with nausea/vomiting– May overlap with / trigger migraines

Migraine headaches - 1• Common:

– without prodrome

• Classic: – with prodrome

• Complicated: – associated with sensory or motor neurological defects

• Diagnosis made clinically– Look for + F.H.– Exclude other causes,

• e.g. tumor, sinusitis, glaucoma, temporal arteritis, etc.

Migraine headaches - 2

• Paroxysmal disorder characterized by recurrent attacks of headache, with or without associated visual, neuro or G.I. symptoms

• Associated with vasodilatation and vasoconstriction of intracranial arteries

• Intracranial a/v malformations, tumor, heredity, estrogens, foods are triggers

Migraine headaches

• Lateralized throbbing headache, some times preceded by a prodrome

• Prodrome may include depression, irritability, scintillating scotomas, visual field defects, paresthesias, paralysis

• Last for several hours

Migraine

• Goal generally is vasoconstriction

• Triptans are specific 5HT effectors

• Ergot drugs are alpha effectors

“Triptans” ; Sumitriptan

Mechanism of Action• Sumatriptan is an agonist for a vascular 5-

hydroxytryptamine1 receptor subtype having only a weak affinity for 5-HT1A, 5-HT5A, and 5-HT7 receptors.

• The vascular 5-HT1 receptor subtype that sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction. – This action in humans correlates with the relief of migraine

headache. – In addition to causing vasoconstriction, experimental data from

animal studies show that sumatriptan also activates 5-HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels.

– Such an action may also contribute to the antimigrainous effect of sumatriptan in humans.

“Triptans” ; SumitriptanIndications and Usage for Imitrex• Imitrex Tablets are indicated for the acute treatment of migraine attacks with or without

aura in adults.– Imitrex Tablets are not intended for the prophylactic therapy of migraine or for use in the

management of hemiplegic or basilar migraine.– Safety and effectiveness of Imitrex Tablets have not been established for cluster headache,

which is present in an older, predominantly male population.Contraindications• Imitrex Tablets should not be given to patients with history, symptoms, or signs of

ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. In addition, patients with other significant underlying cardiovascular diseases should not receive Imitrex Tablets. Ischemic cardiac syndromes include, but are not limited to, angina pectoris of any type (e.g., stable angina of effort and vasospastic forms of angina such as the Prinzmetal variant), all forms of myocardial infarction, and silent myocardial ischemia. Cerebrovascular syndromes include, but are not limited to, strokes of any type as well as transient ischemic attacks. Peripheral vascular disease includes, but is not limited to, ischemic bowel disease.

– Because Imitrex Tablets may increase blood pressure, they should not be given to patients with uncontrolled hypertension.

– Concurrent administration of MAO-A inhibitors or use within 2 weeks of discontinuation of MAO-A inhibitor therapy is contraindicated.

– Imitrex Tablets should not be administered to patients with hemiplegic or basilar migraine.– Imitrex Tablets and any ergotamine-containing or ergot-type medication (like

dihydroergotamine or methysergide) should not be used within 24 hours of each other, nor should Imitrex and another 5-HT1 agonist.

– Imitrex Tablets are contraindicated in patients with hypersensitivity to sumatriptan or any of their components.

– Imitrex Tablets are contraindicated in patients with severe hepatic impairment.

Ergot Alkaloids

Ergonovine

DHE or

Methyl-ergonovine[Methergine]

Vasoconstriction,Induce contractions of the uterine smooth muscle

Migraine;

Prevention and treatment of postpartum or post abortion hemorrhage

Hypertension, seizures,

may cause infant mortality if given before delivery

Acute dosing is Sub-Q injection;

Not for labor induction

Ergot Migraine Medications / Uterine Stimulants

MOA Uses Adverse Effects Other

Cluster headache

• Lasts 15 to 180 min, severe, unilateral, located periorbitally, can occur 6-8x’s/day, associated with tearing, red eye, stuffy nose or miosis

• More in men 30-60 yrs• Etoh, stress, lack of sleep can trigger• Usually occurs in spring and fall• Rapid onset, often at night; pain is severe• Unlike migraines, no n/v

Infection (meningitis, encephalitis)

• Usually gradual onset of headache, severe,

nuchal rigidity present with meningitis

• Diagnosis made by L.P.– MRI, CT

• Fever usually present, plus other findings of infection

Encephalitis• Severe:

– Headache with systemic sn/sx (fever, n/v…)– Often focal neurological deficit

• Sub-acute:– Like a severe viral illness.– Headache PERSISTS even as the systemic

sn/sx wane.

Severity

Time

Headache

Other Sn/Sx

Trigeminal neuralgia• Shooting pain in face from 5th C. nerve

– Lower 2 divisions of 5th usually involved

• Attacks occur in spring and fall

• Pain is lancinating; can be triggered by touch, drafts, brushing teeth

• No sensory loss or motor weakness

Giant cell arteritis

• Symptoms include malaise, proximal muscle pain, jaw claudication, tender scalp arteries

• Untreated, blindness results in 50% of pts who present with headache

• Lab shows ESR over 100/+ biopsy of artery

Multiple Sclerosis (MS)

• Chronic remitting dis characterized by demyelination of patches in the brain and spinal cord that result in multiple neurological symptoms– Onset between 20 and 40– Weakness, numbness, tingling, unsteadiness,

spasticity, diplopia, sphincter disturbance

• MRI best test to show plaques– Paraventricular white matter lesions

Muscular Dystrophy

• Progressive noninflammatory muscle fiber degeneration.– Can have CK/ aldose (levels of CK >2000 in

Duchenne’s from ages 4-8 from muscle necrosis.– EKG changes due to muscle necrosis; Duchenne’s:

70% have wide Q waves, tall R waves and arrhythmias.

• Muscle biopsy is definitive– For the most severe type, Duchenne’s type,

identification of female carrier and genetic counseling are crucial

Myotonic dystrophy

• Variation of MD; more common– Stiffness, unable to release a grasp, thick speech,

muscle atrophy in face and neck swan neck deformity

• Autosomal dominant; slowly progressive– Onset in 20’s– Cataract, frontal baldness, testes atrophy, diabetes,

cardiac and intellectual changes.

Cerebral Palsy

• Motor manifestations of nonprogressive brain damage sustained during prenatal/postnatal life.

• 1-3/1,000 births (5x more common than MD)– Etiology: low birth weight, anoxia at birth

– Spastic (70%): may be quadraplegic (most severe, IQ, paucity of movement, dysarthria, poor feeding), hemiplegic (1/3 have seizures, motor milestones delayed), diplegic (bilat spasticity of arms or legs, clumsy, normal IQ)

Amyotrophic Lateral Sclerosis ALS - 1

• Characterized by progressive degeneration of corticospinal tracts and/or anterior horn cells and/or bulbar motor nuclei

• Disease of mid and later life– Progressive; 50% die in 3 yrs; 90% in 6

ALS

• Lower motor neuron involvement—atrophy, weakness of arms/legs, normal sensation, DTR’s, fasciculations of muscles, dorsal interosseous spaces become hollow

• Upper motor neuron involvement—spasticity, clonus, DTR’s, + Babinski

• Bulbar involvement—dysarthria, dysphagia, tongue atrophy

• Sensation and gait are maintained– Muscle biopsy will show neurogenic process– CK may be very high (>1000)

Myasthenia gravis - 1

• Autoimmune disorder caused by antibodies to the acetylcholine receptor of skeletal muscle– Women mostly in their 20’s; – Men mostly in 40-50’s

• DDX: Myasthenic Syndrome: Basically same Dz with different autoimmune target (sub class of Ca channel).

• Primary symptoms:– weakness, particularly of ocular, bulbar, pharyngeal,

respiratory, proximal extremities– Weakness on exertion!

Myasthenia gravis - 2• Onset may be gradual or sudden Weakness

worse after exercise; helped by rest.• No sensory loss

– 1/3, usually those patients with symptoms limited to ocular muscles, improve spontaneously and have protracted remissions

– Those with generalized MG may develop potentially fatal respiratory failure

• Edrophonium (Tensilon) test is pos if a in muscle weakness occurs after this cholinesterase inhibitor is given iv

Benign Essential Tremor

• Etiology unknown• No known pathology• Most common movement disorder

– FH found in 50% of cases– Increased with skilled movements and made worse

with tension

• Absent at rest– Tremor of head and voice also common

Parkinson’s Disease -1

• Idiopathic, slowly progressive degenerative dis of CNS with 4 characteristic features:– Slow movement (bradykinesia)– Muscular rigidity– Resting tremor– Postural instability

Parkinson’s Disease -2

• Caused by of dopamine in brain– Slow onset that is progressive

• Resting tremor (pill rolling) that: – disappears with sleep and – made worse with excitement or fatigue

• Difficulty initiating movement; cogwheeling– Rigidity affects the face mask-like features

• Stooped posture, loss of balance, stiff shuffling gait, no arm swing– Mild intellectual deterioration / depression

Huntington’s Disease

• Each child of an affected parent has a 50% chance of inheriting the disease

• Does not become manifest until 3rd or 4th decade– Movement disorder starts as a fidgeting or

restlessness, eventually progressing to writhing, purposeless movements

• Dementia follows– Disease progresses over 15-20 yrs to death

Alzheimer’s dementia

• Most common cause of dementia in the elderly (75% of cases of dementia)

Diagnostic criteria for A.D.

• Clinical exam and M.M.S.E.– Deficits in 2 or more areas of cognition

• SPECT Scanning becoming more common in AD diagnosis.

• Progressive worsening

• No disturbance of consciousness

• Absence of systemic or other brain disease to account for symptoms

Clinical findings in A.D.

• Delusions: (false beliefs) affect 30-70%; usually simple ones, e.g. persecution (someone wants to kill me); theft (items got stolen); phantom boarder (intruder in house)

• Depression very common; frequent is debated due to problem in applying formal testing

• Suicide is rare

Behavior problems in A.D.

• Personality change: apathetic or more impulsive

• Anxiety: apprehension over upcoming events

• Aggression: physical or verbal• Wandering : can be dangerous• Screaming• Sundowning / sleep disruption

Diagnosis of epilepsy

• Best tool is the history• Attacks are rarely witnessed by the doctor

• CT / MRI / LP can rule out secondary causes – MRI is image of choice

• Must be done to r/o tumor or other organic disease

– LP may be done in some cases

• EEG may help, but 20% of pts will be normal (AND 5% of normal people have abnormal EEG)

Carbon monoxide exposure

• Dull, diffuse headache

• Worse on awakening and eased when patient gets up and goes outside

• Seen in impoverished circumstances with improper heating units

PainPharmacology

Central acting Pain Medications

Pain and CNS / Pain Medications

• Central Pain Control– Central Muscle Relaxants – non-DEA– Central Pain Control

• DEA Scheduled• Non-DEA Scheduled

• Peripheral Pain Control– Non-DEA Scheduled

ANALGESICS AND ANTIINFLAMMATORIES

• D.E.A. Classifications (Class I – V)– A classification of drug agents (analgesic, and other categories) based on potential for

abuse and addiction.

• Specific Drugs, as classified:– C-1: Heroin, L.S.D., Peyote, Marijuana

– C-2: Dronabinol (Marinol), Morphine, Oxycodone(Percodan / Percocet), [**Hydrocodone and Codeine – plain form] Fentanyl (and all its family), Methadone, Meperidine (Demerol), Hydro & Oxymorphone.

– C-3: Codeine + ASA or APAP (Tylenol 1,2,3,4), Hydrocodone + APAP or Ibuprophen (Vicodin, Vicoprophen), Codeine or Hydrocodone antitussive syrups (Hycodan, Robitussin AC, DAC). [Testosterone]

– C-4: Pentazocine (Talwin), Propoxyphene (Darvon, Darvocet), Butorphanol (Stadol [NS or Inj.]). [Diazepam…Barbital…Chloryl Hydrate]

– C-5: Buprenorphine inj., Dilute forms of Codeine / Hydrocodone

– No DEA designation: Tramadol (Ultram), Nalbuphine inj.

Muscle Relaxants

MOA Uses Adverse Effects Other

Methocarbamolcarbamate derivative of guaifenesin

Unknown; may modify central pain perception without changing reflexes

Muscle pain and tetanus management

Drowsiness, syncope, headache, hypotension, diplopia, nystagmus, GI upset and anaphylactic reactions

Do not inject in patients with impaired renal function or seizure disorder

Carisoprodol(Soma)

Modify perception of pain by blocking activity in descending RAS

Acute painful musculo-skeletal conditions

Drowsiness, dizziness, orthostatic hypotension, N/V, irritability, headache, rash and anaphylaxis

Avoid CNS depressants including alcohol

Cyclobenzaprine hydrochloride(Flexeril)

UnknownTricyclic derivative

Muscle spasm Drowsiness, dizziness, seizures, dry mouth, syncope and tachycardia and GI upset

Do not use with MAO inhibitors

LONG t ½

Methocarbamol Dosage and Administration

• 500 mg – Adults: Initial dosage, 3 tablets q.i.d.; maintenance dosage, 2 tablets t.i.d.

• 750 mg – Adults: Initial dosage, 2 tablets q.i.d.; maintenance dosage, 1 tablet q.4h, or 2 tablets t.i.d.

• Six grams a day are recommended for the first 48 to 72 hours of treatment. (For severe conditions, 8 grams a day may be administered.) Thereafter, the dosage can usually be reduced to approximately 4 grams a day.

Carisoprodol Dosage and Administration

• The usual adult dosage of Carisoprodol Tablets, USP is one 350 mg tablet, three times daily and at bedtime.

• Usage in patients under age 12 is not recommended.

Cyclobenzaprine Dosage and Administration

• For most patients, the recommended dose of Cyclobenzaprine HCl tablet is 5 mg three times a day. – Based on individual patient response, the dose

may be increased to 10 mg three times a day. Use of Cyclobenzaprine HCl for periods longer than two or three weeks is not recommended.

• (see INDICATIONS AND USAGE). • Less frequent dosing should be considered for

hepatically impaired or elderly patients (see PRECAUTIONS, Impaired Hepatic Function, and Use in the Elderly).

Cinchonism!• Quinine AND Quinidine:• Tinnitus / Hearing Loss• Headache / Nausea• Dizziness / Vertigo• Visual changes

Quinine Affects calcium distribution within muscle fibers to decrease excitability of motor-end plate

Prevention of nocturnal leg muscle cramps

Seizure, cardiac arrest, cardiotoxic, and chinchonism

Contraindicated in tinnitus, optic neuritis, G6PD deficiency, thrombocyto-penia or hypersensitivity to quinine

Opioid MOA Uses Adverse Effects Other

Morphine Opiate receptor agonist Severe pain Constipation, respiratory depression, orthostatic hypotension, nausea, vomiting, euphoria, shock, cardiac arrest

Physical dependence high

Codeine [Tylenol-3]

Opiate receptor agonist, suppresses cough reflex

Mild to moderate pain and non-productive coughs

Sedation, light-headedness, nausea, vomiting, constipation, dry mouth, respiratory depression, diaphoresis

Prescribed with aspirin or acetaminophen to strengthen pain relief

Oxycodone [Percocet / Percodan]

Hydrocodone [Vicodin / Vicoprophen]

Opiate receptor agonist Moderate to severe pain

Sedation, dizziness, nausea, vomiting, constipation, respiratory depression, diaphoresis, hypotension

Tolerance may developPercocet = oxycodone + acetaminophenPercodan = oxycodone + aspirinVicoprophen = Hydrocodone + Ibuprophen

Acetaminophen MOA Uses Adverse Effects Other

[Tylenol][Paracetamol]“APAP”

Exact MOA unknown. Weak analgesic, anti-pyretic.

Thought to elevate pain threshold and act in the hypothalamic temperature center.

Fever and pain.

Adult dose threshold is 4 Grams / 24 hours.

Single dose liver toxicity 7-10 grams (140mg/kg).

Toxic dosages can cause hepatic necrosis – ETOH increases hepatotoxicity at 3 drinks / day.

Acetylcysteine (NAC – Mucomyst) assists in acetamino-phen excretion.

Normally used if dose > 140mg/kg

Acetaminophen with Codeine• # 2 Codeine Phosphate USP 15 mg

Acetaminophen USP 300 mg

• #3 Codeine Phosphate USP 30 mg Acetaminophen USP 300 mg

• #4 Codeine Phosphate USP 60 mg Acetaminophen USP 300 mg– Versions of each available with ASA in place of APAP

Single Doses   24 Hour Dose

(Range) Maximum

Codeine Phosphate 15 mg - 60 mg 360 mg

Acetaminophen 300 mg - 1000 mg 4000 mg

Codeine / Guaifenesin Cough Syrup

(Robitussin A-C)

10 mg Codeine;100 mg Guiafenesin / 5 mL

• Antitussive / Mucolytic

• Sig: 5 to 10 mL q-4h PRN Cough

Pseudoephedrine, Codeine, and Guaifenesin

(Robitusin DAC)

30mg Pseudoephedrine; 10mgCodeine; 100mg Guaifenesin

• Antitussive / Decongestant / Mucolytic

• Sig: 5 to 10 mL q-4h PRN Cough

Promethazine Phenylephrine and Codeine Cough Syrup

• 5 mL contains: Codeine phosphate 10 mg; promethazine hydrochloride 6.25 mg; phenylephrine hydrochloride 5 mg. Alcohol 7%.

• The average effective dose for adults (16 years of age and over) is 1 teaspoonful (5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

Non-Controlled Pain Drug

• Ultram (tramadol HCl)– Centrally acting synthetic opioid analgesic

• Seizure risk in normal and above normal doses. Elevated in patients taking SSRI’s, Tricyclics and other Opioids.

– Immediate Release• 50 mg tablets• Sig. 50 to 100 mg q. 4-6 hrs up to 400 mg/d dose

– Extended Release• 100, 200 and 300 mg ER tablets• Sig. 100 to 300 mg ONCE daily, up to 1- 300mg ER

tablet daily.

Peripheral Pain Control

• NSAIDS

• Steroids

• Gout Medications

EICOSANOIDS

MEMBRANE PHOSPHOLIPID

ARACHADONATE

LEUKOTRIENESPROSTAGLANDINS /

THROMBOXANES

Lipoxygenase Cyclooxygenase

Phospholipase A2

Stimulated by: Angiotensin - 2 / Bradykinin / Epinephrine / Thrombin

Inhibited by: CORTICOSTEROIDS

Inhibited by:

NSAID’S

NSAIDS MOA Uses Adverse Effects Other

Aspirin Blocks prostaglandin synthesis

Anti-inflammatory, anti-thrombotic

Salycism: tinnitus, hearing loss, vertigoAlso: GI upset, nausea, thrombocytopenia, occult bleeding, dyspepsia, rash, anaphylaxis and Reye’s syndrome

Stops production of histamine 2 to decrease the amount of mucus produced in stomach

Ibuprofen Unknown, possibly blocks prostaglandin synthesis

Inflammatory conditions

Headache, dizziness, GI distress, peripheral edema, tinnitus, acute renal failure, peptic ulcer, occult blood, bronchospasm, Stevens-Johnson syndrome

Monitor blood levels for toxicity when used with digoxin, lithium or anticoagulants

Naproxen[Naprosyn]

Unknown, possibly blocks prostaglandin synthesis

Inflammatory conditions, mild to moderate pain

GI distress, Headache, drowsiness, dizziness, edema, tinnitus, nephrotoxicity, rash

Better tolerated than aspirin

Cox 2 Inhibitors

Rofecoxib[Vioxx]

Celocoxib[Celebrex]

Blocks Cyclooxygenase-2 Activity

Inflammatory conditions

Less GI distress than aspirin, indigestion, gas, diarrhea, abdominal pain

Expensive

Toradol (ketorolac tromethamine)

• Moderately severe to severe pain only.– NSAID– Not for use over 5 days in duration– No pediatric use.– Dose adjusted in patients over age 65 or with

impaired GFR

• IV/IM form as well as 10 mg tablets– Dosage:

• IM: 60 mg; IV 30 mg single dose • Oral: 10 – 20 mg loading dose, then 10 mg q. 4-6 hrs

– not to exceed 40 mg daily

Steroids MOA Uses Adverse Effects Other

Hydrocortisone(Physiologic oral dose (35) 25-80 mg.)

Prednisone(Physiologic oral dose (7.5) 5-20 mg.)

Act by binding to cortisol receptor sites

Inflammation, adrenal insufficiency (replacement), immunosu-pression

Adrenal suppression, osteoporosis, skin atrophy, glucose intolerance, growth suppression, osteopenia

Prednisone longer acting than hydrocortisone

Abrupt withdrawal may be fatal

Other steroids: Triamcinolone, Dexamethasone…Cortisone: Hydrocortisone USP

Same as above (also a glucocorticoid)Bio-identical to human cortisolREMEMBER: dose from Prednisone to Cortisone conversion is a 4 to 1 ratio. 5 mg. Prednisone = 20 mg CortisonePhysiologic dose of Cortisone is 25 to 40 mg. orally.

Oral Steroids

• Methylprednisolone 4mg pack [Medrol DosePak]– Pre set does of 24 mg day 1 – tapering over 1

week– Easy to use, and LOW dose

• Other:– In some urgent cases you may need a

starting dose of 60, 80 or higher mg, then a taper over 3-6 weeks.

Gout Pain

Antigout MOA Uses Adverse Effects Other

Colchicine Unknown, reduces inflammation

Gout: acute or maintenance therapy

GI upset, nausea, vomiting, gastric pain, with long term use: aplastic anemia

Contraindicated in patients with CV, hepatic, renal or GI disease

Allopurinol Inhibits xanthine oxidase which reduces uric acid production

Gout, hyperuricemia

GI upset, hepatitis, hepatic necrosis, renal failure, rash, Stevens-Johnson syndrome

Monitor blood levels for toxicity when used with digoxin, lithium or anticoagulants

Use of oral prednisolone or naproxen for the treatment of gout arthritis: a double-blind, randomised equivalence trial.Lancet. 2008; 371(9627):1854-60 (ISSN: 1474-547X)

Rx either prednisolone (35 mg once a day; n=60) or naproxen (500 mg twice a day; n=60), for 5 days

“Oral prednisolone and naproxen are equally effective in the initial treatment of gout arthritis over 4 days.”

Local Anesthetics

MOA Uses Adverse Effects Other

Lidocaine Reduces permeability of sodium influx into neuronal membranes.

Topical anesthesia, sedation, arrhythmia’s

Drowsiness, dizziness, may cause heart block and arrhythmias.

Rapid onset and medium duration.Amide prototype.

Bupivacaine Same as lidocaine.

Nerve block, spinal and epidural.

Same as lidocaine.

Slow onset and long duration.Amide.

NO I.V.

Procaine Same as lidocaine.

Ester prototype.Metabolizes to PABA

Types of seizures

Simple Partial

• Limited to a single part of the body or one limited aspect of behavior

• Consciousness is preserved

• Symptoms include focal motor (convulsive jerks) or somatosensory (paresthesia or tingling)

Jacksonian Seizures

• Spread or “march” to different parts of limb or body

• Sensory symptoms: light flashes, smells, buzzing, songs

• Autonomic symptoms: flushing, sweating, epigastric sensations

Complex Partial

• S/S may change during attack (hallucinations change into complex motor acts)

• Change in, or loss of, consciousness

• Déjà vu (intense familiarity), fear, pleasure, anger are psychic symptoms

Generalized seizures

• May evolve from partial seizures

• The paroxysmal neuronal discharge is generalized to both sides of the brain

• Usually has an alteration or loss of consciousness

• Two major kinds – Absence (petit mal) seizures– Tonic-clonic (grand mal) seizures

Absence (petit mal) seizures

• Usually begin from age 2-12

• + FH

• Two Types:– Simple absence– Complex absence

Absence (petit mal) seizures

• Simple absence attacks– last 1-2 seconds, characterized by blank stare– child will “space out”, often in middle of a

sentence and come back without being conscious of the lapse

Absence (petit mal) seizures

• Complex absence– last 15-30 seconds; head drops/ arms may

jerk rhythmically– Freq of attacks may vary from 10-100/d– Hyperventilating may trigger attack– 30-50% of childrengrand mal seizures

Tonic-clonic (grand mal) seizures

• Most extreme form of seizure

• May begin at any age

• May be triggered by fatigue, fever, Ca, glucose, magnesium

• May be preceded by a prodrome of mood change, apprehension, loss of appetite

Grand mal seizures

• Begins with tonic phase lasting for 10-20 seconds (body stiffens and arches); may stop breathing and become cyanotic; pt may cry out at onset; tachycardia, hypertension, sweating, salivation

Grand mal seizures

• As the tonic phase relaxes, the person begins the clonic phase of series of jerks of neck, limbs and trunk; loss of sphincter control is common as is biting of tongue; person can injure themselves in this phase.

Grand mal seizures

• Postictal phase starts when contractions end; flaccid relaxation, heavy breathing, heavy salivation

• In a few minutes, patient may regain consciousness, drift off to sleep for several hoursrs or begin a new convulsion (status epilepticus).

Inhibitory Neurotransmission

GABA

• Main (most well known) inhibitory neurotransmitter

• Formed from Glutamine in the CNS

• Two separate receptor subtypes

• Target of neuropharmacology for over 50 years

• Target of self medication for centuries

The GABA Target:

Benzodiazepines

Barbiturates

BOOZE

GABA Metabolism in the CNS

Glucose Alanine Glutamine

Pyruvate Glutamic Acid

alpha-oxoglutaric acid B-1 / [Glutamic Acid Decarboxylase]

GABA

TCA

GHB

Succinate

G

A

B

A

Synapse

GABA Synapse

Glutamate(B-1)[glutamic acid

decarboxylase]

GABA

GABA

GABA

GABA

GABA-T

GABA Receptor

Depakote blocks:

GABA a Receptor

Cell Membrane

Cl-

1

3

2

4

Receptor Agonists:

1: Benzodiazepine

Increases channel opening frequency.

2: Barbiturate

3: Alcohol

4: Neuro Steroid

2,3&4 all increase the duration of channel opening.

CNS: Neurosteroid Effect

Progesterone

[3-alpha-HSD] (Stimulated by SSRI’s)

Tetrahydroprogesterone (aka. THP, Allopregnanolone)

Alpha-4-sub unit (inhibitory)

GABAa Receptor

-+

GABA b Receptor

Cell Membrane

GABA

Calcium

K

No Chloride activity.

Increased Potassium conductance.

Decreased Calcium conductance

PhenobarbitalAmobarbitalPentobarbital

Results in lengthening of Cl- channel opening. Barbiturates and Benzodiazepines

have high tolerance and addiction potential.

Slow tapering is essential or patients may have psychotic episodes.

Effecting the GABA complex in multiple ways if the key to successful removal of the drug.

Diazepam [Valium] Alprazolam [Xanax]Halazepam [Paxipam] Triazolam [Halcion]

Chlordiazepoxide [Librium]Clorazepate [Tranxene]

Benzodiazepine: Binds to GABA receptor.

Lorazepam [Ativan]Oxazepam [Serax]

“The Benzo’s to the elderly”(Short t ½ ) .

Buspirone

[Buspar]

Serotonin / Dopa / NE Activity

Anxiolytic without sedation and euphoria.

Takes 3-4 weeks to be effective

Anti Anxiety

Phenytoin(Dilantin)

Reduce Na+, Ca+ and K+ across neuronal membranes

Carbamazepine(Tegretol)

Phenobarbital

Resembles Phenytoin

Enhance GABA

Clonazepam (Klonopin)

Unknown probably effects GABA, similar to benzodiazepines

Other Calming Drugs: Seizure DisorderAnti seizure properties, some off label uses as well.

Many patients will be using this for insomnia, anxiety, and occasionally during drug detox.

Anti-Seizure MOA Uses Adverse Effects Other

Phenytoin(Dilantin)

Reduce Na+, Ca+ and K+ across neuronal membranes

All seizures except absence seizures

Ataxia, slurred speech, confusion, incoordination, pancytopenia, hepatitis, gingival hyperplasia, N/V, nystagmus,

Numerous drug interactions

Phenobarbital Enhance GABA General seizures

Depresses CNS, drowsiness, lethargy, hangover, respiratory depression, angio-edema,

Decrease effect of MANY other drugs

Clonazepam (Klonopin)

Unknown probably effects GABA, similar to benzodiazepines

Status epilepticus.

Drowsiness, ataxia, disturbance in behavior, thrombocytopenia, respiratory depression

Contraindicated in hepatic disease, or acute closed-angle glaucoma

Carbamazepine(Tegretol)

Resembles Phenytoin

All seizures except absence seizures

Dizziness, drowsiness, vertigo, ataxia, worsening of seizures, N/V, aplastic anemia, agranulocytosis, thrombocytopenia, Steven Johnson syndrome, hepatitis, and CHF

May decrease effectiveness of oral contraceptives and doxyclycline. Do not use with MAO inhibitors

Effective drugs used to treat absence seizures include ethosuximide, valproate, clonazepam and trimethadione.

Remember Diazepam and Calcium Gluconate Given IV in acute seizure!

pregabalin

[Lyrica]

Lyrica is indicated for:•Neuropathic pain associated with diabetic peripheral neuropathy •Post herpetic neuralgia •Adjunctive therapy for adult patients with partial onset seizures •Fibromyalgia

Lyrica (pregabalin) binds with high affinity to the alpha2-delta site (an auxiliary subunit of voltage-gated calcium channels) in central nervous system tissues. Although the mechanism of action of pregabalin is unknown, results with genetically modified mice and with compounds structurally related to pregabalin (such as gabapentin) suggest that binding to the alpha2-delta subunit may be involved in pregabalin's antinociceptive and antiseizure effects in animal models. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulation of calcium channel function.

WARNINGS AND PRECAUTIONS

Angioedema (e.g. swelling of the throat, head and neck) can occur, and may be associated with life-threatening respiratory compromise requiring emergency treatment. Lyrica should be discontinued immediately in these cases.

Hypersensitivity reactions (e.g. hives, dyspnea, and wheezing) can occur. Lyrica should be discontinued immediately in these patients.

Increased seizure frequency may occur in patients with seizure disorders if Lyrica is rapidly discontinued. Withdraw Lyrica gradually over a minimum of 1 week.

Lyrica may cause peripheral edema. Exercise caution when co-administering Lyrica and thiazolidinedione antidiabetic agents.

Lyrica may cause dizziness and somnolence and impair patients' ability to drive or operate machinery.

ADVERSE REACTIONS

Most common adverse reactions (≥ 5% and twice placebo) are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and thinking abnormal (primarily difficulty with concentration/attention).

Seizure – Central Drug

Some information courtesy of Drugs.com

Syncope• “Partial or complete loss of consciousness with interruption of

awareness of oneself and ones surroundings. When the loss of consciousness is temporary and there is spontaneous recovery, it is referred to as syncope or, in nonmedical quarters, fainting. Syncope accounts for one in every 30 visits to an emergency room.” (medterms.com)

– Most causes are NON-CARDIAC – but, because the cardiac causes have significant mortality and morbidity they must be worked up.

• Cardiac causes include:– Abnormal heart rhythms. – Abnormalities of the heart valves (aortic stenosis or pulmonic

valve stenosis). – High blood pressure in the arteries supplying the lungs

(pulmonary artery hypertension). – Tears in the aorta (aortic dissection). – Widespread disease of the heart muscle (cardiomyopathy).

Recreational Drugs / Drugs of Abuse

Cannabis

In the reward circuit, just as in the case of other drugs, more dopamine is released.

As with opiates, this paradoxical increase is explained by the fact that the dopaminergic neurons in this circuit are normally inhibited by GABA neurons. The cannabis removes this inhibition by the GABA neurons and hence activates the dopamine neurons.

In chronic consumers of cannabis, the loss of CB1 receptors in the brain’s arteries reduces the flow of blood, and hence of glucose and oxygen, to the brain. The main results are attention deficits, memory loss, and impaired learning ability.

Cocaine

Acts by blocking the reuptake of the neurotransmitters Dopamine, Norepinephrine, and Serotonin.

The group of neurons thus modified produces

Euphoria (from dopamine),

Confidence (from serotonin),

Energy (from norepinephrine)

Ecstasy

Like amphetamines and cocaine, ecstasy blocks the reuptake pumps for certain neurotransmitters.

While ecstasy also potentiates the effects of Norepinephrine and Dopamine, it is distinguished from other psychostimulants by its strong affinity for serotonin transporters.

The initial effect of ecstasy is thus an increased release of serotonin by the serotonergic neurons. The individual may then experience increased energy, euphoria, and the suppression of certain inhibitions in relating to other people.

Mental Status Examination

MSE

Indications

• Documentation of subsequent cognitive function decline

• Cognitive Function Assessment

Role of the mental status exam

• Able to see patient along a continuum of human experience and expression

• Able to gauge patient’s ability to give a reliable history

• Monitor progress of treatment for patients with mental disorders

Role of the mental status exam

• Used to evaluate disability

• Assess benefit of referral to mental health professional

• Able to make immediate/emergency assessment of level of damage

Items included in the MSE

• Appearance, behavior, and attitude

• Characteristics of speech

• Affect and mood

• Thought content, thought form, and concentration

Items included in the MSE

• Orientation

• Memory

• General intellectual level

• Insight and judgment

Mental Status Exam

I. Questions (Total of 30 points)

A. Orientation (10 points)

1. Year, Season, Date, Day of week, and Month

2. State, County, Town or City

3. Hospital or clinic, Floor

B. Registration (3 points)

1. Name three objects: Apple, Table, Penny

2. Each one spoken distinctly and with brief pause

3. Patient repeats all three (one point for each)

4. Repeat process until all three objects learned

5. Record number of trials needed to learn all 3 objects

C. Attention and Calculation (5 points)

1. Spell WORLD backwards: DLROW

2. Points given up to first misplaced letter

3. Example: DLORW scored as 2 points only

D. Recall (3 points)

1. Recite the 3 objects memorized in Registration above

E. Language (9 points) 1. Patient names two objects when

they are displayed Example: Pencil and Watch (1 point each)

2. Repeat a sentence: 'No ifs ands or buts'

3. Follow three stage command a. Take a paper in your right hand b. Fold it in half c. Put it on the floor

E. Language (9 points)

1. Read and obey the following

Close your eyes

2. Write a sentence

3. Copy the design (picture of 2 overlapped pentagons)

Interpretation of Mini-mental State Score (Maximum: 30)

• Normal score: 24 or higher

Educational and Age Norms

• Fourth Grade Education– Ages 18 to 69: Median MMSE Score 22-25– Ages 70 to 79: Median MMSE Score 21-22– Age over 79: Median MMSE Score 19-20

Interpretation of MSE

• Eighth Grade Education– Ages 18 to 69: Median MMSE Score 26-27– Ages 70 to 79: Median MMSE Score 25– Age over 79: Median MMSE Score 23-25

• High School Education– Ages 18 to 69: Median MMSE Score 28-29– Ages 70 to 79: Median MMSE Score 27– Age over 79: Median MMSE Score 25-26

Interpretation of Mini-mental State Score (Maximum: 30)

• College Education– Ages 18 to 69: Median MMSE Score 29– Ages 70 to 79: Median MMSE Score 28– Age over 79: Median MMSE Score 27