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Antipsychotics

Typical Atypical Chlorpromazine Clozapine Haloperidol Olanzapine

Thioridazine Apiprazole Fluphenazine Risperidone

Antipsychotics can all be thought of as “anti‐schizophrenia drugs.” as a general model. Remember that schizophrenia has positive symptoms (things that are there that shouldn’t, stimulation) such as hallucinations or voices, as well as negative symptoms (things that should be there but aren’t, depression) such as affective blunting or anhedonia. This causes a major problem for pharmacological management. Essentially, schizophrenia and other psychotic‐like symptoms are caused by excess dopamine in the mesolimbic‐mesocortical region of the CNS. Thusly, the administration of dopamine antagonists limits the symptoms of schizophrenia. However, treating the positive symptoms of psychosis can exacerbate the negative symptoms.

Remember for a bit how we treated Parkinson’s disease. There was a lack of dopamine in the nigro‐ striatal pathway that caused Parkinsonian symptoms. If we now block dopamine in the brain, we block dopamine everywhere. That means these drugs can lead to parkinsonian symptoms. More importantly, dopamine antagonism treats only positive symptoms of schizophrenia. Since schizophrenia was discovered, new insight has lead to the activity of serotonin receptors. As the drugs become newer, they do a better job of treating both the positive and negative symptoms and limiting their depressive side effects. Therefore, these drugs are separated by their ability to target positive and negative symptoms, on their side effects, and on which receptors they either antagonize or agonize.

Major side effects of antipsychotics are extrapyramidal symptoms. In the acute phase they cause pseudoparkinsonism, dystonia, or akathisia. In this case, the patients don’t move much. In the chronic phase they suffer from tardive dyskinesia that presents like a chorea or Huntington’s presentation caused by a hypersensitivity to dopamine stimulation. The only way to fix these symptoms is to withdraw the drug (which can push the patient back into psychosis) or switch to an atypical antipsychotic. Another major side effect is seen particularly in strong Dopamine Antagonists is neuroleptic malignant syndrome (NMS) characterized by temperature dysregulation, muscle rigidity, and potential for renal failure. In addition another major side effect is that of muscarinic and alpha blockade leading to orthostatic hypotension (α), dry mouth (M), constipation(M), and urinary retention(M). ALL antipsychotics can produce a prolonging of the QT interval

The typical antipsychotics are the older drugs that target dopamine and are prone to tardive dyskinesia. The atypical antipsychotics block dopamine and serotonin and are devoid of tardive dyskinesias. We should mention that all of these drugs inhibit multiple receptors to some degree, but for a second year medical student, you can safely learn “dopamine” or “dopamine and serotonin” and forget about most of the minutia.

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TYPICALS – Block Dopamine

Chlorpromazine, Thioridazine, Fluphenazine. These are the phenothiazines. They contain sulfur, so you must be cautious for sensitivity reactions. These are the oldest and the cheapest of the antipsychotics and are used as the prototype for others. They block dopamine receptors without much specificity, and therefore effect the entire brain. These have the largest alpha and muscarinic blockade and suffer from side effects involving sedation, orthostatic hypotension, dry mouth, constipation, and other anti‐ACh side effects. These really aren’t great drugs, but they are first choice since they are cheap, and not everyone suffers from the side effects. These are taken PO daily, and are for chronic management of psychosis.

Haloperidol. This is a high potency dopamine antagonist usually used either within the hospital setting or for controlled injected dosages. You don’t start someone off on haloperidol, but this is usually is what is in the syringe in movies where a psych patient is “freaking out” and has to be sedated by men in white suits. It is a very potent dopamine antagonist. It causes significant sedation. Unfortunately it has two major side effects in addition to those shared with all antipsychotics. It has the capacity to lower the seizure threshold and highest risk for NMS. It is used in the non‐emergent setting in noncompliant patients who can receive an injection that lasts for weeks. This way, even if they don’t take their meds, they have some dosage of antipsychotics to limit their symptoms.

ATYPICALS – Block Dopamine and Serotonin, Now Considered FIRST LINE DRUGS

Clozapine. Clozapine is the prototype for atypical antipsychotics. It is atypical for two reasons. Firstly, it has extremely reduced extrapyramidal symptoms. Secondly, it also blocks 5HT receptors. Inhibition of

5HT2 Receptors then treats the negative symptoms of schizophrenia. How is not really important, but just to let you know, inhibition of the presynaptic, inhibitor 5HT2 receptor causes an increase in the release of serotonin which treats the negative symptoms. Clozapine is able to limit its extrapyramidal symptoms because of its selectivity for D2c receptors, found primarily in the mesolimbic‐mesocortical pathway, unlike the D2A receptors found in the nigro‐striatal pathway. Unfortunately, it has also been known to cause agranulocytosis with a significant compromise of WBC and the immune system, requiring weekly blood tests (which also suffer from noncompliance). Also causes weight gain.

Olanzapine. Since Clozapine had the trouble with agranulocytosis, drug companies had to look elsewhere. An analogue of Clozapine, Olanzapine has lower selectivity for D2C receptors than Clozapine, but strongly antagonizes 5HT2 receptors. Most importantly, it does not suffer from agranulocytosis. Therefore, Olanzapine is not as good as treating psychosis as Clozapine, but does not have that major complication. It still suffers from orthostatic hypotension, muscarinic blockade, and causes weight gain.

Risperidone. This is a different class of drug than the “‐apines” but is still considered atypical because of its stronger antagonism of 5HT2. This drug, while although it is an atypical, has an increased risk for tardive dyskinesias.

Apiprazole. You will see commercials for this drug on TV. It was mentioned in our class, which means it is going to get more play in future years. It’s an atypical that is also a partial dopamine agonist.

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ANTIPSYCHOTICS Drug Unique Feature Unique Side Effect Typicals Chlorpromazine Prototype for antipsychotics, large side effects, but cheap Extrapyramidal Side Effects to use Haloperidol Super Strong Dopamine Antagonist Greatest Risk for NMS Atypicals

Clozapine Selective for D2C Receptors without EPS symptoms Agranulocytosis Equipotent antagonist for 5HT2 receptors Olanzapine Weak selectivity for D2C receptors, increased affinity for No Agranulocytosis 5HT2 receptors Risperidone 5HT2 Receptor Increased risk for Tardive Dyskinesia Apiprazole Dopamine Agonist None Known Yet

ANTIPSYCHOTIC SIDE EFFECTS Symptom Character Receptor that Causes It Extrapyramidal Found in the acute phase of dopamine antagonism. Dopamine Antagonism Symptoms – Parkinsonian symptoms caused by inhibition of Dyskinesia dopamine outside the psychosis center Extrapyramidal Found in the chronic phase of dopamine antagonism. Dopamine Antagonism Symptoms – Huntington’s symptoms caused by remodeling and Tardive Dyskinesia hypersensitivity to dopamine Orthostatic Get dizzy when you stand up Alpha Blockade Hypotension Neuroleptic Thermal dysregulation (patient gets hot) Severe Dopamine Antagonism Malignant Muscle Rigidity, ↑Heart Rate, ↓BP Syndrome Renal Failure Antimuscarinic Dry mouth, constipation, urinary retention Acetyl Choline Antagonism Symptoms Sedation Sedation Histamine Blockade Prolonged QT All antipsychotics carry this potential Alpha and Muscarinic Blockade

ANTIPSYCHOTIC SIDE EFFECTS BY DRUG AND RECEPTOR

Drug D2 α M H1 EPS symptoms Chlorpromazine ++ ++++ +++ +++ ++ Haloperidol ++++ + + + ++++ Clozapine ++ +++ ++ + ‐ Olanzapine + ++ + + ‐ Risperidone ‐ ++ ‐ ++ + Apiprazole + ? ? ? ? Effectiveness Orthostatic Dry Mouth, Sedation and EPS Hypotension Constipation, symptoms Urine Retention

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Antidepressants

SSRIs MAO‐Is TCAs Atypicals Lithium

Phenylzine Amitriptyline Bupropion Li Fluoxitine Tranylcypromine Imipramine Venlafaxine Citalopram Selegiline Trazodone Sertraline Mocolbemide Paroxetine

Depression can be explained by the monoamine hypothesis. Essentially, there is not enough Norepi, serotonin, and/or dopamine in the brain. Whatever the underlying cause (insufficient production, release, activation, or response), by increasing neurotransmitter concentration we can eliminate depressive symptoms. Well that is all well and good, but it turns out that despite the increase in local levels of neurotransmitters immediately, it takes 2‐3 weeks for depressive symptoms to decline. This indicates that there is some neuronal plasticity in effect, requiring remodeling of synapses before therapeutic effect can be seen. Likewise, it takes 2‐3 weeks once a drug has been removed for the effects to wear off. It is important to ensure this length of time before switching to a different antidepressant to ensure there are no drug interactions.

Much like the neurology CNS block, this block is very class‐heavy. Knowing the names of the drugs simply to identify the class is sufficient. Once you know the class and how it works, it becomes a drug name recognition game.

SSRIs = Selective Serotonin Reuptake Inhibitors

Fluoxitine, Paroxetine, Sertraline. These drugs are the first line therapy for depression. However, they have also been used to treat bulimia, OCD, anxiety, and even PMDD (the new PMS). They have benign side effects relative to the other antidepressants, and what side effects they do have are mild or are useful to expand their indication list. As the name implies, these selectively inhibit the reuptake of serotonin, essentially eliminating the side effects associated with norepinephrine found in MAO‐Is and in TCAs. The side effects involve ↓ libido, which at first glance might be a big problem. However, since they do lower libido, high doses can be used to control mentally retarded patients from masturbating in public, or to control a pedophile’s urges. Another side effect is weight gain, which can be used to treat anorexia or bulimia. A major problem with SSRIs, however, is that they may not always work. When they don’t work, our instinct is to change to another drug type. Switching from an SSRI to a TCA or MAO can have significant drug interactions, including serotonin syndrome (orthostatic hypotension, excessive heat, muscle rigidity). Even though the drug itself is rapidly metabolized, the active metabolite hangs around for 8 days. Thusly, it is important to wait 2‐3 weeks after stopping an SSRI before starting something else. As with all antidepressants, you must also wait 2‐3 weeks from initiation before therapeutic effects can be seen. SSRIs also carry a black box warning, especially for children. Depression is mood, motivation, and suicide. When you start an SSRI the first thing to come back is motivation. However, the mood is still poor, suicide is still considered, and now with increased motivation, the patient actually tries something. There is an increased risk of suicide upon initiation of SSRIs.

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MAO‐Is = Monoamine Oxidase Inhibitors

Phenylzine, Tranylcypromine, Selegiline, Mocolbemide. MAO is monoamine oxidase, responsible for the degradation of various neurotransmitters. MAO‐A is present in the brain and intestinal tract. MAO‐B is primarily the Brain MAO. These guys break down the neurotransmitter after it has been reuptaken. This is of relevance because, in the US, most MAO‐Is are nonselective to avoid potential serious side effects. MAO‐Is are not first line and are used for atypical depression that does not respond to reuptake inhibition. There mechanism is to increase the concentration of neurotransmitter by preventing its destruction. This means that Dopamine, Serotonin, and Norepinephrine are all increased. This works great to treat the depression, but produces some potential side effects. A hypertensive crisis may result from an elevation of norepinephrine. This occurs in particular with the coadministration of drugs that enhance the release of (tyramine), prevent the reuptake of (SSRIs, or TCAs) or mimic (α1 agonists) neurotransmitters. For this reason you usually prescribe only one antidepressant at a time, and avoid foods that contain tyramine (cheese). A serotonin syndrome may result from an elevation of serotonin. This is characterized by orthostatic hypotension, muscle rigidity, and excessive heat/sweating. It is important to know that MAO‐Is are irreversible inhibitors of MAO. That means the neurons must synthesize more MAO to combat the effect of the drug. If MAO‐Is were not working for some reason, or a patient suffered a hypertensive crisis, it is not enough to simply remove the drug and try something else. You must wait 2‐3 weeks after stopping an MAO‐I before trying another drug. If you do not, you are likely to induce one of the potentially lethal side effects we just talked about. Of specific differences between drugs, you should remember the factoids that Selegiline is a MAO‐B specific inhibitor and mocolbemide is a short acting reversible inhibitor of MAO‐A.

TCAs

Amitriptyline and Imipramine. The TCAs are now an out‐of‐date drug class. While still used, SSRIs and MAO‐Is are used much more readily than the TCAs. Nevertheless, there are two broad classes of TCAs represented as the “‐triptylines” and the “‐pramines.” There mechanism of action is blockage of reuptake pumps that is nonselective for both serotonin and norepinephrine. This, like MAO inhibition, increases the effective concentration of neurotransmitters in the synaptic cleft. Common to all TCAs is muscarinic and α blockade leading to the three “C”s of medicine: coma, convulsions and cardiotoxicity. Because they are so potentially toxic and posses a narrow therapeutic window, their use has been very limited. In addition, there have been some pretty nasty side effects when it comes to other antidepressant medications as well as prevention of action of some antihypertensives (Guanethidine).

Atypicals

Trazodone. Antidepressant that does not increase serotonin, but rather it interferes with the metabolism of serotonin. It creates a serotonin receptor agonist. It is associated with cardiac arrhythmias and priapism.

Venlafaxine. Nonselective reuptake blocker. It does not have a tricyclic structure and it is devoid of ANS side effects. That means it is a “TCA without side effects.”

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Bupropion. This is a dopamine reuptake blocker. It was first marketed as an antidepressant for depression that might not be responding well to the typical Norepi and Serotonin drugs. It didn’t really work as an antidepressant because it causes problems with dopamine overload – psychosis, hallucinations, and dyskinesia. However it works great for smoking cessation. It maintains dopamine levels on a low, long‐term scale, supplementing the dopamine in the reward center that generates cravings for the drug of abuse. It is contraindicated in patients with seizure disorder (or bulimia/anorexia), and has less sexual dysfunction than others antidepressants.

LITHIUM

Lithium. Say we had someone suffering a major depressive episode. We put them on an SSRI, which is well tolerated. Two months later they suffer from psychosis and mania. Now let’s say that person is 20. What do you think we have? Right, Bipolar Disorder. The SSRI was capable of treating the depressive symptoms of Bipolar, but will do little, if not exacerbate, the manic stage of Bipolar disorder. Remember, these mood swings come in the periods of weeks to months, so we have to do something for this patient during her manic episode. Lithium is the drug we are looking for. Lithium is the only drug and therefore the drug of choice for bipolar. We don’t know why it works; only that it does. It is usually given in conjunction with antidepressant (if in the depressive phase) or with an antipsychotic (if in the manic phase). We think it has something to do with second messenger systems. It is a monovalent ion, much like sodium. We think that is prevents recycling of inositol (PIP2) which ultimately means there will be reduced calcium for second messenger signaling. Since it affects the entire body, and it affects calcium, you can imagine it has a very narrow therapeutic index. Lithium has two side effects. (1) It looks like sodium, and is about the same size as sodium. Therefore, it causes tremors and seizures as if you had too much Na. (2) Endocrine dysfunction in that it causes hypothyroidism (prevents iodination of T3) and Nephrogenic diabetes Insipidus (preventing secretion of ADH). It is also highly teratogenic. When a bipolar female gets pregnant, we struggle, since Li is the only treatment for bipolar. Instead, we try to use benzos or Gabapentin to get them through the pregnancy.

ANTIDEPRESSANTS Drug Class Mechanism and Indications Side Effect SSRIs Specific Inhibition of Serotonin Reuptake Weight Gain, ↓Libido, Agitation, First line therapy for depression, bipolar, OCD, anorexia, Anxiety, Bruxism, Serotonin Syndrome, and bulimia Increased Suicide in Children MAOIs Nonselective Inhibition of Monoamine Oxidase Hypertensive Crisis (Tyramine, TCA) Second line therapy for depression Serotonin Syndrome (SSRI) TCAs Nonselective Reuptake Inhibitor Coma, Convulsions, Cardiotoxicity Historical Drugs not usually prescribed anymore Hypertensive Crisis (MAO‐I) Bupropion Dopamine Reuptake Inhibitor Dyskinesia, seizure, Smoking Cessation Venlafaxine Same As TCA, or an “Uber TCA” No ANS Side Effects Used in Atypical Depression Trazodone Alters metabolism of serotonin to generate a serotonin Cardiac Arrhythmias and Priapism receptor agonist. Used in Atypical Depression ‐ All antidepressants require 2‐3 weeks at a minimum before clinical effects can be seen (indicates plastic changes) ‐ Switching between antidepressants can have potentially fatal interactions; a waiting period is often required ‐ Bipolar disorder can be hidden; once depressive symptoms are alleviated manic episode is interpreted as SE

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Anxiolytics

Barbiturates Benzos Benzo‐Like Sleep Aids Others

Phenobarbital “‐pam” and “‐lam” Zaleplon (Sonata) Buspirone

Diazepam Zolpidem (Ambien) Ramelteon Lorazepam Eszopiclone (Lunesta)

Chlorodiazepoxide

BARBITURATES

Phenobarbital. We covered this in the last CNS block. It binds to GABAA receptors and enhances the GABA signal in the brain without directly agonizing the channels. This increases the general inhibitory signal in the brain, acting as a CNS depressant. Barbiturates have no antidote and run the risk of medullary depression or coma with overdose. They are particularly useful for short‐term surgeries as they are slowly cleared from the body but may distribute into fat reservoirs. They do generate some anterograde amnesia (so the patient won’t remember the surgery), and, if abused, the patient will also suffer from tolerance and dependence.

BENZOS

Diazepam, Lorazepam, Midozalam, and Chlorodiazepoxide. Another class covered in the CNS block, they also bind to GABAA receptors at a site different from the barbiturates but basically do the same thing: enhance the inhibitor GABA signal. There is an antidote (Flumazenil) despite the fact that there is a low risk of overdose. There is most often a combination of sedatives (like alcohol) to produce toxic effects of coma or death. These also suffer from tolerance and dependence, and will generate anterograde amnesia. These are only useful for the acute treatment of wide variety of diseases, all of which require CNS depression to be successful. They are very useful as an adjunct or calming agent prior to surgery, alleviate an acute anxiety attack, and can be used to prophylactically treat alcohol withdrawal seizures. Unfortunately, they are also a drug of abuse and may even be used in date rape.

BENZO‐LIKE SLEEP AIDS

Zaleplon, Zolpidem, Eszopiclone. These drugs claim to activate only the sedative effects of benzos without also inducing amnesia and psychomotor impairment associated with benzos. They bind selectively to the GABAA α‐1 receptor (a specific subtype of benzo receptor on the GABA channel). They also claim to limit the tolerance and dependence. You have probably seen commercials for Lunesta on TV (the butterfly that drops sleepy‐dust on the woman in bed). So far they are pretty legit, though amnesia (sleep walking) has been reported, and they do offer the warning of ensuring a complete recovery time (“dedicate a minimum of 8 hours to sleep”) as you might be impaired upon waking. Still, these have gained national approval and appeal.

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OTHERS

Buspirone is a selective serotonin agonist, binding to the 5HT1A subtype. I know that seems like a minutia, but Clarkson put it in red on his slides. This is an anxiolytic that induces no drug dependence. It must be used chronically as relief from anxiety does not set on until about 1 week (or more) from initiation of therapy. Because it has no dependence, it can safely be given to patients with long standing anxiety who also have a history of drug abuse. Benzos, even TCAs or SSRIs, may be habit forming, especially for those with drug dependence. Buspirone gets around this complication.

Ramelteon had an amusing commercial, where the guy is walking through his kitchen where he encounters an Astronaut, Abe Lincoln, and a talking beaver playing poker. They are his dreams, wondering where he went. This drug is a melatonin agonist used to correct your circadian rhythm. It is not a widely used drug because if there is no deficiency in your circadian rhythm, this drug will do very little for you. It is most useful for people who travel a lot, and end up “jet lagged.” We didn’t really talk a lot about it, and my guess is, if there is going to be a question, “melatonin agonist” is going to go a long way.

ANXIOLYTICS / SEDATIVE / HYPNOTICS Drug / Class Character Benzos Enhanced GABA signal without being a GABA agonist, binds to Alpha and Gamma Subunits Binding blocked by Flumazenil (benzo antidote) Lorazepam, Diazepam, Usually cannot overdose, limited toxicity unless mixing drugs (like alcohol) Midozalam, Temazepam, Induces an anterograde amnesia so the patient won’t remember the procedure Alprazolam, Flurazepam, Chlordiazepoxide Psychomotor Impairment and Behavioral Inhibition Physical Tolerance, dependence and withdrawal Useful for seizures, acute attacks of anxiety or phobia, alcohol withdrawal (no long term use) Barbiturates Enhanced GABA signal without being a GABA agonist at a different site Cannot be blocked by Flumazenil (no antidote for barbiturates) Phenobarbital, others from Are capable of reaching toxicity = medullary depression, complete CNS depressant last block Induces an anterograde amnesia so the patient won’t remember the procedure Psychomotor Impairment and Behavioral Inhibition Physical Tolerance, dependence and withdrawal Induce Cytochrome P450

Benzo‐Like Binds to a subset of GABAA receptor with α‐1 subunits Sleep Aids Produce pure sedation without anxiolytic or muscle relaxation (sleep only) Less daytime impairment and almost no amnesic effects (is this really true? We shall see…) Zolpidem (Ambien), Reduced tolerance and dependence Zaleplon (Sonata), They cost a lot and may cause sleepwalking Eszopiclone (Lunesta) Used for Insomnia

Buspirone (Buspar) Partial 5‐HT1A antagonist Anxiolytic, not sedating, with No drug dependence Slow Onset (one week or more) Used for chronic anxiety or for patients with a history of drug abuse Ramelteon (Rozerem) Melatonin Agonist Affects the circadian rhythm or sleep cycle; if you have no disturbance there, it probably won’t work (but it does for people who travel to India and back and get “jet lagged.”

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PSYCHOSTIMULANTS / DRUGS OF ABUSE Drugs Notes Cocaine 5‐10% of EM Visits are due to cardiac complications related to cocaine abuse Most powerful stimulant or natural origin Cocaine is metabolized to cocaethylene when you drink alcohol at the same time; it has a similar potency and longer half‐life of the original drug Intensity is the same at its height, but speed of onset is IV > Smoked > Snorted > Eat it Blocks Reuptake of Norepi, Dopamine, and Serotonin while also blocking K and Na channels Increased dopamine in the reward center leads to high, the addiction, the tolerance and withdrawal Toxicity is broken into stages: (early = mydriasis, “bugs under the skin,” ↑Hr & ↑BP, ↑Elevated) Toxicity is broken into stages: (late = MO, Seizure, Hyperthermia, Violent Behavior, Paranoia) Treat toxicity with controlling body temperature, benzos for seizures, and bicarb for acidosis Amphetamines Multiple mechanisms of action: it can be taken up by the Dopamine Transporter, is a weak inhibitor of MAO, can be taken up by VMAT and kick out Dopamine from vesicle, Dopamine is released directly Dextroamphetamine (Aderal) and finally, it can actually trade with dopamine through the dopamine transporter Methamphetamine, Methylphenidate (Ritalin) Used to treat ADHD (Ritalin and Adderall), the most common mental disorder in pediatrics, as well as short term weight loss and even narcolepsy. These have qualitatively similar toxicities to cocaine (mydriasis, ↑HR, ↑BP, ↑Temp, but are usually less arrhythmogenic MDMA (Ecstasy) Amphetamine like effects with a higher affinity for serotonin Acutely leads to an elevation of 5‐HT levels, but chronically leads to depletion Side effects are hyperthermia and dehydration Hallucinogens These are either serotonin antagonism or serotonin agonism, and are considered partial agonists LSD, Mescaline, Psilocybin, It enhances sensations from all receptor inputs producing visual and auditory hallucinations PCP To treat patients, talk down the patient, which is usually labor intensive Phencyclidine (PCP) Most dangerous hallucinogen that is a psychomimetic and induces dissociative anesthesia The physiologic effects are hyprereflexia, hypersalivation, nystagmus, catatonia, seizures Dissociative effects = loss of reality, inability to communicate, aggression, insensitivity to pain PCP is an NMDA antagonist Treating this patient is done with antipsychotics (haldol) or benzodiazepines, there is no antidote Cannabinoids (THC) Acute Early Effects = laughter, increased appetite (“munchies”), altered sense of time Acute Late Effects = Difficulty concentrating, decreased memory, driving impairment THC is a CB1 and CB2 Receptor Agonists (cannabinoids) which have the endogenous Anandamide ligand Used for Cancer Nausea & Vomiting, Appetite Stimulant in Wasting Syndrome, Chronic Pain

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