Pharmacology of CNS Disorders PDF

Pharmacology of the Central Nervous System 1. Serotonergic Neurotransmission 2. Treatment of Depression, Psychosis and Mania Panayiota Christodoulou, PhD 5-Hydroxytryptamine = 5-HT = Serotonin CNS – Neurotransmitter Receptors and Effectors Serotonergic Neurotransmission Serotonergic neuronal cel...

Pharmacology of the Central Nervous System 1. Serotonergic Neurotransmission 2. Treatment of Depression, Psychosis and Mania Panayiota Christodoulou, PhD 5-Hydroxytryptamine = 5-HT = Serotonin CNS – Neurotransmitter Receptors and Effectors Serotonergic Neurotransmission Serotonergic neuronal cell bodies – in raphe neuclei or midline regions of pons + upper brain stem Descending pathways – innervate spinal cord – modulate pain perception Ascending pathways – innervate cortex, cerebellum, substantia nigra, limbic system – promote sleep, determine mood, involved in mental illness The receptors: • All (5-HT1 - 5-HT7 + subtypes) except 5-HT3 – metabotropic • 5-HT3 = ligand-gated ion channel • 5-HT1A share same K+ channel as GABAB receptors Actions: • Inhibition or excitation of CNS neurons depending on the receptor subtype present • Both inhibition + excitation of same neuron if appropriate receptors are present Serotonerigic Actions are Complex Why? Many receptor subtypes with sometimes opposing roles  Blood vessels  Vasoconstriction via 5-HT2  Vasodilation - activation of 5-HT2B → Vasorelaxant mediators release from the vascular endothelium  GI  GI motility via 5-HT4  Vasodilation via vasorelaxant mediators released from the vascular endothelium due to activation of 5-HT2B Serotonerigic Actions are Complex CNS – again many effects  Serotonin agonists→ migraine treatment  Serotonin agonists → recreational use as psychedelics  Selective reuptake inhibitors→ antidepressants  Antagonists of 5-HT3 → antiemetics (for emesis induced by cytotoxic drugs) Serotonin Synthesis What amino acid are the monoamines dopamine, epinephrine and norepinephrine synthesized from? Tryptophan Tyrosine Rate limiting step – catalyzed by tryptophan hydroxylase Aromatic L-amino acid decarboxylase 5-Hydroxytryptamine i.e., Serotonin Cytosolic enzymes – present in soma + processes of serotonergic neurons Presynaptic Regulation of Serotonin Neurotransmission Tryptophan taken up by presynaptic neuron Serotonin is synthesized Serotonin is packaged into vesicles by VMAT Ca2+-dependent vesicular release Serotonin is in the synaptic cleft Presynaptic Regulation of Serotonin Neurotransmission Serotonin is in the synaptic cleft Recycled serotonin Activates presynaptic 5HT receptors (5HT1B) Recycled via: Feedback inhibition Selective serotonin transporters (SERT) Nonselective Transporters VMAT – repackaged in vesicles Ca2+-dependent vesicular release Serotonin is in the synaptic cleft Serotonin is inside the presynaptic neuron Similarities between Monoamines D2 Serotonin Norepinephrine Dopamine Similarities between Serotonin and Norepinephrine Gi pathway Gq pathway Gs pathway Are all serotonin receptors G-protein coupled? No Are any of these presynaptic? α2 adrenergic + 5-HT1B Drugs acting in CNS Depression • It is the most common of the affective disorders (defined as disorders of mood) → May range from a very mild condition, bordering on normality, to severe (psychotic) depression accompanied by hallucinations and delusions • It is a mood disorder that causes a persistent feeling of sadness and loss of interestis often associated with other psychiatric conditions, including anxiety, eating disorders and drug addiction • It is a serious medical illness that negatively affects how you feel, the way you think and how you act Depression Emotional symptoms include: • Low mood • Excessive rumination of negative thought • Misery • Apathy • Pessimism • Low self-esteem: feelings of guilt and inadequacy • Indecisiveness • Loss of motivation • Anhedonia • Loss of reward Biological symptoms include: • Retardation of thought and action • Loss of libido • Sleep disturbance • Loss of appetite The Amine Hypothesis 1940s + 1950s - Reserpine induced depression - Imipramine and Iproniazid - uplifted mood = Reduction of serotonin and norepinephrine signaling → development of major depression Treatment  serotonin and/or norepinephrine Balance is restored And depression can be reduced or even reversed Does Reserpine affect serotonin?  Indirectly Serotonin release → can lead to depressive mood Pharmacological evidence supporting the monoamine hypothesis BUT The Monoamine Hypothesis is Insufficient to Explain Depression Monoamine hypothesis = depression is due to deficiency in NE and 5-HT at key sites of the brain • Depression is the opposite of mania + mania is due to overproduction of NE + 5-HT BUT • Treatment with drugs that increase NE and 5-HT levels in the synapse – takes WEEKS to provide relief → low NE + 5-HT may be just the result and not the CAUSE Current view – depression may be due to neurodegeneration and reduced neurogenesis in the hippocampus Depressive syndrome There are two distinct types of depressive syndrome: Unipolar depression - The mood changes are always in the same direction Bipolar disorder - Depression alternates with mania Mania • Excessive exuberance • Enthusiasm and self-confidence • Accompanied by impulsive actions • Rapid thought and speech patterns • Impatience • Aggression As with depression, the mood and actions are inappropriate to the circumstances Mechanism of action Antidepressant drugs potentiate directly or indirectly, the actions of norepinephrine and/or serotonin (5-HT) in the brain • Depression is due to a deficiency of monoamines (norepinephrine and serotonin) • Mania is caused by an overproduction of these neurotransmitters • The theory of depression and mania is overly simplistic • Therapeutic response, usually occurs over several weeks compared to the immediate pharmacodynamic effects of the agents, which are usually immediate • The decreased reuptake of neurotransmitters is only an initial effect of the drugs, which may not be directly responsible for the antidepressant effects Types of Antidepressant drugs Antidepressant drugs Monoamine Receptor Antagonists 1. Atypical Antidepressants 2. Selective Serotonin Reuptake Inhibitors (SSRIs) 3. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Monoamine Oxidase Inhibitors (MAOIs) → inhibit the catabolism of NE and 5-HT Tricyclic antidepressants Amitriptyline, Nortriptyline, Imipramine, Desipramine  Structurally related to phenothiazines (antipsychotic drugs)  but have different pharmacological effects Mechanism of action  Block the reuptake of the biogenic monoamines norepinephrine and serotonin into the presynaptic neuron Also interact with many other receptor types e.g. muscarinic (M1) histamine (H1) adrenergic (α1) - Unclear if this leads to therapeutic benefit BUT - Clear that it leads to side effects Tricyclic antidepressants Amitriptyline, Nortriptyline, Imipramine, Desipramine Mechanism of action 1. Inhibition of neurotransmitter reuptake • TCAs are potent inhibitors of the neuronal reuptake of norepinephrine and serotonin into presynaptic nerve terminals • Maprotiline and Desipramine are relatively selective inhibitors of norepinephrine reuptake 2. Blocking of receptors • TCAs block serotonergic, α-adrenergic, histaminic, and muscarinic receptors • TCAs have many adverse effects. • Amoxapine blocks 5-HT2 and dopamine D2 receptors. ✓ The onset of the mood elevation is slow, requiring 2 weeks or longer! ✓ Tapering of these agents is recommended → discontinuation syndromes and cholinergic rebound effects Tricyclic antidepressants Amitriptyline, Nortriptyline, Imipramine, Desipramine Amitriptyline -blocks both norepinephrine and serotonin reuptake equally Desipramine -most potent inhibitor of norepinephrine reuptake - 1000x less potent on serotonin reuptake Uses: Depression Typical Metabolism of TCAs CYP2D6 – Subject to polymorphisms → individual variability in TCA action Inhibition of NE and Serotonin reuptake by TCA and their metabolites Effects of Tricyclic Antidepressants NO TCAs → 5HT release controlled by inhibition of 5HT1A receptors on dendrites Acute reuptake inhibition → 5HT extracellularly BUT inhibition of 5HT1A receptors on dendrites also increased → synaptic levels of 5HT do not rise as much as expected Chronic reuptake inhibition → 5HT extracellularly BUT dendritic 5HT1A receptors eventually are desensitized → synaptic levels of 5HT Tricyclic antidepressants Amitriptyline, Nortriptyline, Imipramine, Desipramine Adverse effects • Due to anticholinergic action: dry mouth, blurred vision, urinary retention, and constipation • Due to antiadrenergic action: postural (orthostatic) hypotension and delayed cardiac conduction • Due to antihistaminergic action: sedation • Weight gain • Sexual dysfunction • Manic behavior – patients with bipolar disorder • Narrow therapeutic index Drug Interactions of Tricyclic Antidepressants Amitriptyline, Nortriptyline, Imipramine, Desipramine + Alcohol → additive sedation + anticholinergics → additive action: dry mouth, blurred vision, urinary retention, and constipation + adrenergic drugs + MAOIs → severe CNS toxicity – RARE Accidental or deliberate overdose of tricyclic antidepressants - frequent - a serious medical emergency - may result in death Signs may include excitement, seizures, coma with depressed respiration, hypoxia, hypothermia, and hypotension No antagonists are available → NO antidote Treatment = supportive measures in an intensive care unit Summary of Effects Amitriptyline, Nortriptyline, Imipramine, Desipramine Acutely • Drowsiness • Decreased blood pressure Sustained use: • Eventually will lead to elevation of mood Also: • Suppression of rapid eye movement (REM) sleep • Sleep promotion Monoamine Oxidase Inhibitors (MAOIs) e.g., Tranylcypromine, Phenelzine, and Isocarboxazid Mechanism of action: • MAOIs inhibit both monoamine oxidase A and B (MAO-A and MAO-B • Their use is limited due to the complicated dietary restrictions Phenelzine and Isocarboxazid - “suicide” inhibitors of the enzyme i.e. irreversible →To restore MAO activity → new enzyme needs to be synthesized Tranylcypromine – reversible • Increased stores of norepinephrine, serotonin, and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space ✓ MAO is fully inhibited after several days of treatment, the antidepressant action of the MAOIs, is delayed several weeks! Monoamine Oxidase Inhibitors (MAOIs) e.g., Tranylcypromine, Phenelzine, and Isocarboxazid  MAOIs interfere with hepatic metabolism of many drugs + are not selective for MAO-A or MAO-B → incidence of drug-drug interactions  MAOIs interfere with hepatic metabolism of tyramine (potentially toxic – present in a number of food e.g. red wine, aged cheese, air-dried meats, soy sauce, sauerkraut → incidence of drug-food interactions → to avoid these – diet needs to be carefully monitored → use-limiting Specificity of Monoamine Oxidase Inhibitors (MAOIs) **Phenelzine is a non-selective and irreversible inhibitor of the enzyme MAO **Selegiline is available in a transdermal patch Monoamine Oxidase Inhibitors (MAOIs) e.g., Tranylcypromine, Phenelzine, and Isocarboxazid Effects: May take 2 to 3 weeks to become apparent Uses:  Depression when TCAs + other antidepressants are ineffective  Rasagiline, Selegiline (MAOB-specific) – also used in Parkinson’s disease Effects (additional) → Cardiovascular system: postural (orthostatic) hypotension → Suppression of REM sleep Side effects  Hepatotoxicity and CNS stimulation → SSRIs should not be co-administered with MAOIs (Serotonin Syndrome) → Both SSRIs and MAOIs require a washout period of at least 2 weeks (exception of fluoxetine) ➢ Serotonin Syndrome: too much Serotonin. Severe serotonin syndrome can cause death if not treated!  Acute poisoning → causes agitation, hallucinations, hyperreflexia, and convulsions →Treatment - maintaining vital functions in a hospital setting until effects wear off Tyramine-MAOI Interactions May Participate Hypertensive Crisis • Drug–food and drug–drug interactions → cheeses and meats, liver, pickled or smoked fish, and red wines • Unable to degrade tyramine obtained from the diet • Hypertensive crisis → occipital headache, stiff neck, tachycardia, nausea, hypertension, cardiac arrhythmias, seizures, and, possibly, stroke) Selective Serotonin Reuptake Inhibitors (SSRIs) ➢ May be safer than tricyclics and MAOIs in overdose situations BUT selective serotonin reuptake inhibitors (SSRIs) are not as effective in treating severe depression as TCAs • Specifically inhibit serotonin reuptake, having greater selectivity for the serotonin transporter, as compared to the norepinephrine transporter. • Little blocking activity at muscarinic, α-adrenergic, and histaminic H1 receptors ++++ = very strong affinity; +++ = strong affinity; ++ = moderate affinity; + = weak affinity; 0 = little or no affinity Mechanism of Action of SSRIs Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, and Escitalopram Mechanism of Action: • Block the reuptake of serotonin, leading to increased concentrations of the neurotransmitter in the synaptic cleft Pharmacokinetics • Completely absorbed from the gastrointestinal (GI) tract • Extensively metabolized in the liver • Eliminated in the urine and feces • The therapeutic effect takes 10 to 14 days to develop • Long half-life (days) Onset of Therapeutic Effects of Antidepressants is SLOW Therapeutic uses of SSRIs Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, and Escitalopram Uses: • The primary indication for SSRIs is depression • Obsessive–compulsive disorder (e.g., fluvoxamine and fluoxetine) • Panic disorder • Generalized anxiety disorder • Posttraumatic stress disorder • Social anxiety disorder • Premenstrual dysphoric disorder • Bulimia nervosa (only fluoxetine is approved for bulimia) Side Effects of SSRIs Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, and Escitalopram Fewer anticholinergic and sedative effects than with tricyclics (do not interfere with cardiac conduction or cause orthostatic hypotension) Side effects: - Headache, tremor, insomnia, diarrhea, and nausea. Diarrhea and nausea diminish or resolve over time - Stimulate the CNS → agitation - Psychotic reactions may be exacerbated in depressed schizophrenics - Sexual dysfunction and anorgasmia - both men and women - Less weight gain than seen with other TCAs and with MAOI - Altered sleep - Akathisia (a movement disorder characterized by motor restlessness) Adverse effects of SSRIs Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, and Escitalopram 1. Sleep disturbances • Paroxetine and Fluvoxamine are more sedating than activating. • Fluoxetine or Sertraline for fatigued or excessive somnolence 2. Sexual dysfunction Sexual dysfunction (loss of libido, delayed ejaculation, and anorgasmia) 3. Use in children and teenagers • Reports of suicidal ideation • Fluoxetine, Sertraline, and Fluvoxamine (obsessive– compulsive disorder) • Fluoxetine and Escitalopram (childhood depression) Adverse effects of SSRIs Fluoxetine, Paroxetine, Sertraline, Fluvoxamine, Citalopram, and Escitalopram 4. Overdose • Citalopram, may cause QT prolongation • Seizures (lower the seizure threshold) • Serotonin syndrome (MAOI or other highly serotonergic drug), hyperthermia, muscle rigidity, sweating, myoclonus (clonic muscle twitching), and changes in mental status 5. Discontinuation syndrome • Abrupt withdrawal (shorter half-lives) • Fluoxetine no risk of causing an SSRI discontinuation syndrome (long half-life) • Headache, malaise and flu-like symptoms, agitation and irritability, nervousness, and changes in sleep pattern Serotonin Syndrome Due to drug interaction between SSRIs antidepressants and MAOIs The symptoms: -Hyperthermia -Rigidity -Myoclonus (quick, involuntary muscle jerks) -Confusion -Delirium -Coma 20%-40% of Patients do NOT Respond to Any of the Above Drugs ➔Atypical antipsychotics (i.e., serotonin and dopamine antagonists) e.g., Aripiprazole, Brexpiprazole, Quetiapine or combination of Fluoxetine and Olanzapine Added as an adjunct therapy for these patients Per os Death These are the most commonly prescribed group of anti-depressants Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Venlafaxine, Desvenlafaxine, Levomilnacipran and Duloxetine • Inhibit the reuptake of both serotonin and norepinephrine • Chronic pain can be modulated by serotonin and norepinephrine pathways in the central nervous system • Treatment of pain syndromes, such as diabetic peripheral neuropathy, postherpetic neuralgia • Little activity at α-adrenergic, muscarinic, or histamine receptors (fewer adverse effects) • Precipitate a discontinuation syndrome if treatment is abruptly stopped Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) Highly metabolized in the liver Atypical Antidepressants Bupropion, Mirtazapine, Nefazodone, trazodone, Vilazodone and Vortioxetine Bupropion • Weak dopamine and norepinephrine reuptake inhibitor • Decreasing cravings and attenuating withdrawal symptoms of nicotine • Dry mouth, sweating, tremor, and a dose dependent increased risk for seizures • Avoided in patients at risk for seizures or bulimia Mirtazapine • Enhances serotonin and Nor neurotransmission (antagonist α2 and 5-HT2 receptors) • Antihistaminic activity→ Sedation (increased appetite, weight gain) • Not interfere with sexual function Atypical Antidepressants Bupropion, Mirtazapine, Nefazodone, trazodone, Vilazodone and Vortioxetine Nefazodone • Weak inhibitors of 5-HT reuptake and antagonists at 5-HT2a receptor • Sedative →Block H1 receptor • Associated with a risk for hepatotoxicity Trazodone • Off-label for the management of insomnia • Associated with priapism Vilazodone • Serotonin reuptake inhibitor and a 5-HT1a receptor partial agonist • Discontinuation syndrome Vortioxetine • Serotonin reuptake inhibition, 5-HT1a agonism, and 5-HT3 and 5-HT7 antagonism • Nausea, constipation, and sexual dysfunction Antidepressants - Summary 1st generation MAOIs TCAs 2nd generation SNRIs 3rd generation SSRIs Adverse effects of Antidepressants Pharmacology of Mania and a Word About Bipolar Disorder Mania – symptoms  Abnormally elevated mood Increased activity Feelings of grandiosity Increased agitation Decreased need for sleep Impaired judgement Increased talkativeness Disorganized, racing thoughts Mania – etiology  Unclear Theory – Monoamine theory – BUT now hypothesis is that serotonin and norepinephrine are increased Theory – insufficient to explain the disease  Some antimania drugs are being used to treat manic episodes  Care needs to be taken with antidepressants as they may trigger manic episodes Treatment of Mania and Bipolar Disorder A. Lithium • Lithium salts are used acutely and prophylactically for managing bipolar patients Used to treat • Mania (70-80% patients with acute mania – improve) • Manic-depressive illness • Unipolar depression Healthy individuals - no effects UNLESS toxic levels are reached Mechanism of action – unknown BUT it can inhibit many enzymatic functions Pharmacokinetics - Absorption – Complete - Distribution – Crosses BBB - Excretion – Urine NARROW THERAPEUTIC INDEX – Serum and Urine levels need to be monitored to prevent toxicity Treatment of Mania and Bipolar Disorder Side effects • Neurologic effects • mild - tremor to muscle twitches, ataxia, and confusion • Severe - seizures, hallucinations, and delirium  Cardiac • Severe - arrhythmias and sudden death  Due to inhibition of antidiuretic hormone (ADH) • Polydipsia and polyuria (if late in treatment – may indicate reduced renal function  Thyroid enlargement Acute intoxication (or overdose) - symptoms: Nausea, Vomiting, Profuse Diarrhea, Tremor, Convulsions and Coma → Treatment - supportive Treatment of Mania and Bipolar Disorder B. Other drugs • Antiepileptic drugs (Carbamazepine, Valproic acid, and Lamotrigine) can be stabilizers for bipolar disorder • Older (Chlorpromazine and Haloperidol) and newer antipsychotics • The atypical antipsychotics (Risperidone, Olanzapine, Ziprasidone, Aripiprazole, Asenapine, Cariprazine, and Quetiapine) • Quetiapine, Lurasidone, and the combination of Olanzapine and Fluoxetine have been approved for bipolar depression Clinical uses of drugs in depression Question A 55-year-old teacher was diagnosed with depression. After 6 weeks of therapy with fluoxetine, his symptoms improved, but he complains of sexual dysfunction. Which of the following drugs might be useful for management of depression in this patient? A. Sertraline B. Citalopram C. Mirtazapine D. Lithium Question A 25-year-old woman has a long history of depressive symptoms accompanied by body aches and pain secondary to a car accident. Which of the following drugs might be useful in this patient? A. Fluoxetine B. Sertraline C. Phenelzine D. Duloxetine Question Which mood-stabilizing agent is most likely to decrease the thyroid function? A. Carbamazepine B. Lithium C. Valproic acid D. Chlorpromazine Question A 51-year-old woman with symptoms of major depression also has angle-closure glaucoma. Which antidepressant should be avoided in this patient? A. Amitriptyline B. Bupropion C. Mirtazapine D. Fluvoxamine Question A 36-year-old man presents with symptoms of compulsive behavior. He realizes that his behavior is interfering with his ability to accomplish his daily tasks but cannot seem to stop himself. Which drug would be most helpful to this patient? A. Desipramine B. Paroxetine C. Amitriptyline D. Selegiline Drugs acting in CNS Antipsychotic Drugs (neuroleptics) - Ameliorate the symptoms of psychosis in disorders such as: → Schizophrenia → Acute mania → Schizoaffective disorders → Borderline personality disorders - other uses: → antiemetics in Huntington’s disease, chronic multiple tics disorder, neurogenic pain, infantile autism, intractable hiccups Antipsychotic Medications Older Typical Antipsychotics Newer Typical Antipsychotics **Differ in the receptors, the symptoms of schizophrenia, and their side effects Psychosis is a Defining Feature in:  Schizophrenia  Substance-induced (i.e., drug-induced) psychotic disorders  Schizophreniform disorder  Schizoaffective disorder  Delusional disorder  Brief psychotic disorder  Psychotic disorder due to a general medical condition is an Associated Feature in:  Mania  Depression Cognitive disorders Alzheimer’s dementia Schizophrenia Hypothesis – Symptom Types can be Matched to Unique Brain Regions and Malfunctioning Circuits • Mental disorder characterized by significant alterations in perception, thoughts, mood, and behaviour • Type of chronic characterized by psychosis delusions, hallucinations • The onset of illness is during late puberty or early adulthood. • Has a strong genetic component → dysfunction of some dopaminergic neuronal pathways Schizophrenia ➢ Positive symptoms • Delusions (often paranoid in nature) • Hallucinations (often in the form of voices, which may be exhortatory in their message) • Thought disorder (comprising wild trains of thought, delusions of grandeur, garbled sentences and irrational conclusions) • Abnormal, disorganized behavior (such as stereotyped movements, disorientation, occasionally aggressive behaviors) ➢ • • • • Negative symptoms (apathy or diminished expression) Withdrawal from social contacts (asociality) Flattening of emotional responses Anhedonia (an inability to experience pleasure) Reluctance to perform everyday tasks ➢ Cognition • Deficits in cognitive function (e.g., attention, memory), 70% of patients Clinical efficacy of Antipsychotic drugs Clinical efficacy • Primarily used in schizophrenia treatment (useful in other psychotic and maniac states) • Not curative, do not eliminate chronic disorders • Antipsychotic drugs enabled schizophrenic patients to lead more normal lives • The inpatient population (mainly chronic schizophrenics) of mental hospitals declined sharply in the 1950s and 1960s • While they control the positive symptoms (thought disorder, hallucinations, delusions, etc) effectively, most are ineffective in relieving the negative symptoms (second-generation agents can improve them) Antipsychotic drugs Schizophrenia – a Disease of Many Hypotheses Dopamine Hypothesis  Chlorpromazine  Competitive inhibitor of D2 receptors ➔Almost all antipsychotic drugs inhibit D2 receptors BUT therapeutic success is mostly limited to the positive symptoms Extended hypothesis Negative symptoms and cognitive impairment may actually be due to decreased dopaminergic activity in the hippocampus Schizophrenia – a Disease of Many Hypotheses Serotonin Hypothesis  LSD and Mescaline = hallucinogens → Must be caused by transmission serotonergic  Stimulation of 5-HT2A (and maybe 5-HT2C) → hallucinogenic  Stimulation of 5-HT2A → release of Dopamine, Glutamate, GABA, Acetylcholine, NE in striatum and cortex Activation of 5-HT2A receptors leads to:  Hallucinations  GI - constriction  Dopamine activity in the brain can contribute to the positive symptoms of schizophrenia 1st Generation Antipsychotics, Typical or traditional Antipsychotics = competitive inhibitors of D2 receptors (but not only) -Further subdivided into: a) Low potency antipsychotics – e.g. chlorpromazine b) High potency antipsychotics – e.g. haloperidol Potency – reflects the affinity of a drug for a receptor Efficacy – i.e., what is the maximal therapeutic effect of the drug - depends on the ability of a drug to alter the function of a receptor BUT also, on the contribution of the receptor to the overall response There is NO clinical evidence that haloperidol is more potent than chlorpromazine for the treatment of schizophrenia 2nd Generation Antipsychotics, Atypical Antipsychotics = competitive inhibitors of D2 receptors, but also serotonin receptors (5-HT2A) Also block M1 muscarinic, H1 histamine, and α1-adrenergic receptors to varying degrees, which accounts for some of their side effects. Aripiprazole – UNIQUE - partial agonist at the D2 receptor • Binding primarily to autoreceptors as an agonist and • Secondarily, as an antagonist on postsynaptic receptors Extrapyramidal symptoms (EPS) **Second-generation agents have better efficacy against negative symptoms Antipsychotics Drugs 1. Dopamine antagonism • Block D2 dopamine receptors in the brain and the periphery 2. Serotonin receptor–blocking activity • Inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors 1st Generation 2nd Generation All of the first generation and most of the second-generation antipsychotic agents block D2 dopamine receptors in the brain and the periphery! Some Antipsychotic Dopamine Receptor Antagonists Bind D1 as well as D2 Receptors, e.g., Clozapine Antipsychotic drugs Serotonin receptor–blocking activity ➢ Risperidone blocks 5-HT2A receptors >D2 receptors, as does Olanzapine ➢ Aripiprazole, Brexpiprazole and Cariprazine are partial agonists at D2 and 5-HT1A receptors, as well as antagonists of 5-HT2A receptors ➢ Quetiapine is relatively weak at blockade of D2 and 5-HT2A receptors (low risk for EPS) ➢ Pimavanserin is an inverse agonist and antagonist at the 5-HT2A receptor and the 5-HT2C receptor (no affinity for D2) ➢ Pimavanserin is indicated for psychosis associated with Parkinson disease. **5-HT1A receptors are implicated in the control of mood, cognition and memory **5-HT2A receptor → Role in memory and learning Actions of Antipsychotic drugs ✓ Antipsychotic drugs block dopaminergic and serotonergic receptors as well as adrenergic, cholinergic, and histamine-binding receptors! Antipsychotic Drugs Compete with Receptors IN ADDITION TO D2 Actions of Antipsychotic drugs Antipsychotic effects • Can reduce hallucinations and delusions (“positive” symptoms) → blocking D2 receptors in the mesolimbic system of the brain • The “negative” symptoms (blunted affect, apathy, impaired attention and cognitive impairment) are not as responsive to therapy • Second-generation agents (Clozapine) can reduce the negative symptoms Actions of Antipsychotic drugs Extrapyramidal effects • Dystonia, Parkinson-like symptoms, akathisia (motor restlessness), and tardive dyskinesia (involuntary movements, usually of the tongue, lips, neck, trunk, and limbs) • Blockade of dopamine receptors cause unwanted movement symptoms • The second-generation antipsychotics show a lower incidence of EPS Anticholinergic effects • Thioridazine, Chlorpromazine, Clozapine, and Olanzapine, produce anticholinergic effects • Blurred vision, dry mouth (exception is Clozapine), confusion, and inhibition of gastrointestinal and urinary tract smooth muscle • The anticholinergic effects assist in reducing the risk of EPS Some Antipsychotics are Used as Antiemetics Activation of D2 receptors in the CTZ (chemoreceptor trigger zone in the medulla) ➔ Dizziness and emesis ➔ Blockade of D2 receptors in the CTZ can be therapeutically beneficial ➔ Antiemetic effects Effects of Receptor Blockade by Antipsychotic Agents Pharmacokinetic aspects of Antipsychotic Drugs • Most antipsychotic drugs can be given p.o. or in urgent situations i.m. • Pass the BBB • The relationship between the plasma concentration and the clinical effect of antipsychotic drugs is highly variable → The dosage has to be adjusted on a trial-and-error basis • →This is made even more difficult by the fact that at least 40% of schizophrenic patients fail to take drugs as prescribed • Elimination half-life ranges from 20 to 40 hours →Clearance is entirely by hepatic transformation via a combination of oxidative and conjugative reactions • Wide variations in plasma levels occur among individuals • Very high therapeutic index Side Effects of Antipsychotic drugs They induce a range of side effects that include: • Extrapyramidal Motor • Anosognosia • Endocrine • Sedative Effects • Cardiac Effects Side Effects of Antipsychotic Drugs – Part I Due to Blockade of D2 Receptors in the Extrapyramidal System (EPS): • Parkinsonism with bradykinesias, rigidity, and tremor (within 1 week to 1 month of treatment initiation) - Treated with anticholinergics (e.g., Benztropine) or with Amantadine • Acute dystonia = sustained, often painful muscular spasms in which the patient adopts a twisted posture. - Rare - Treated with anticholinergic antiparkinsonian agents (e.g., Benztropine). • Tardive dyskinesia • Akathisia = strong subjective feeling of distress or discomfort (within the first 2 weeks therapy) - Treated with dose adjustment - Dose- and age dependent motor disorder - Irreversible and persists after discontinuation of therapy (facial jaw, ‘’fly catching’’) Side Effects of Antipsychotic Drugs – Part II Autonomic nervous system: - Anticholinergic effects: dry mouth, urinary retention, constipation, blurred vision - Block adrenergic receptors: Orthostatic (postural) hypotension, impotence, and failure to ejaculate Endocrine: - Hyperprolactinemia =increased blood prolactin → Can result in: Amenorrhea = absence of a menstrual period - Galactorrhea = spontaneous flow of milk from the breast - Infertility - Impotence Other: – – – – – Sedation Weight gain Agranulocytosis (acute low white blood cell count) Pigmentary degeneration of the retina (rare) Neuroleptic malignant syndrome Side Effects of Antipsychotic Drugs – Part III Tolerance, dependence, and withdrawal – Tolerance develops to sedative effects – Some signs of dependence may occur – Withdrawal may include muscular discomfort and difficulty sleeping Drug interactions – May potentiate the sedative effects of central depressants and opioid analgesics – Antiparkinsonian agents should NOT BE used in combination with antipsychotics → They potentiate extrapyramidal side effects of antipsychotics Atypical Drugs may Limit Relapses in Schizophrenia Patients  Relapse – symptoms returning after a period of remission  Vast majority of patients experience relapses  Warning signs of relapse  Insomnia  Loss of interest  Increasing paranoia  Difficulty concentrating  Irritability  Hallucinations NOTE: Atypical drugs may decrease relapses but will not stop them from occurring EPS, extrapyramidal side effects; Hypo, hypotension; Sed, sedation. Neutropenia **Neutropenia is an abnormally low concentration of neutrophils in the blood → the condition may become life-threatening **Agranulocytosis is an acute condition involving a severe and dangerous lowered white blood cell count neutrophils Clinical Use Question An adolescent male is newly diagnosed with schizophrenia. Which antipsychotic agent may have the best chance to improve his apathy and blunted affect? A. Chlorpromazine B. Fluphenazine C. Haloperidol D. Risperidone Question Which of the following antipsychotic agents is considered to be the most potent and thus have the highest risk of extrapyramidal symptoms? A. Olanzapine B. Haloperidol C. Quetiapine D. Clozapine Question Which of the following antipsychotics is a partial agonist at the dopamine D2 receptor? A. Brexpiprazole B. Clozapine C. Haloperidol D. Risperidone Question Which antipsychotic agent is most associated with the possibility of a hematological dyscrasia such as agranulocytosis in a patient being treated for schizophrenia? A. Chlorpromazine B. Quetiapine C. Haloperidol D. Clozapine