Sedatives / Hypnotics Benzodiazepines *Diazepam (Valium®) *Lorazepam (Ativan®) *Alprazolam (Xanax®) *Temazepam (Restoril®) Oxazepam (Serax®) Midazolam (Versed® Clorazepate (Tranzene®) Flurazepam (Dalmane®) Clonazepam (Klonopin®) Chlordiazepoxide (Librium®) Quazepam (Doral®) Triazolam (Halcion®) Mechanism of Action • Enhances the actions & binding of gamma-aminobutyric acid (GABA) to its CNS binding sites. • GABA is an inhibitory CNS neurotransmitter that inhibits neuronal activity. Therapeutic Uses • Anxiolytic – Reduces anxiety. • Insomnia, sedative/hypnotic (sleeping pill) – Do not use benzodiazepines with long halflives, especially in the elderly. Use sleeping pills for short term treatment of insomnia only. • Seizure disorders – (diazepam, lorazepam) – Quick onset. Drugs of choice for status epilepticus. • Alcohol withdrawal – (oxazepam, chlordiazepoxide) – Lessen de-toxification symptoms. • Muscle spasm – (diazepam) – Relax the skeletal muscle spasticity by actions on the spinal cord. Adverse Effects • CNS depression: drowsiness, confusion, hangover feeling with agents with long half-lives. • Respiratory depression: especially if combined with other drugs that cause respiratory depression such as alcohol, opioids, and barbiturates. • Anterograde amnesia (forgetfulness): especially midazolam & triazolam. • Sleep-walking: Engaging in activities while not fully awake with no memory of the event (e.g. walking, eating, driving, etc.). This can obviously be very dangerous. • Abuse: Schedule IV controlled substance; some addiction potential exists. • Physical dependence / Withdrawal symptoms: Withdrawal symptoms include anxiety, insomnia, panic, sweating, tremors, agitation, HTN, muscle twitching, & fatal SEIZURES. Antidote for benzodiazepine overdose: *flumazenil (Romazicon) Benzodiazepine-like Drugs: The “Z” drugs *Zolpidem (Ambien®, Ambien Cr®) Eszopiclone (Lunesta®) • • Zaleplon (Sonata®) Same mechanism of action as the benzos; structurally unrelated to benzos. Very short half-lives Most widely used hypnotics. Not indicated for anxiety. Similar adverse effects to benzos. Other Sleep Aids Ramelteon (Rozerem) • Melatonin receptor agonist; melatonin is a hormone involved in circadian rhythm sleep cycle. • Minimal adverse effects; no abuse potential. *Diphenhydramine (Benadryl, Unisom, Tylenol PM) (dyefenHYEdrameen) • Sedating antihistamine; tolerance develops with routine use; strong anticholinergic side effects. Barbiturates (bahrbiTEWRates or bahrBITCHoorates) No longer commonly used as sleep aids and therefore will not be discussed here; see your text for a description of these medications. 54 Treatment of Transient Insomnia At one time or another, nearly everyone suffers from situation insomnia: worry about exams, job-related stress, life-related pressures, and unfamiliar surroundings while traveling, etc. Sleep Phases Stage I: 5%; light sleep Stage II: 50 – 60%; relatively light sleep Stage III & IV: 10 – 20%; deeper sleep REM sleep: 20 – 25%; rapid eye movement Cause-specific therapy • Try to identify and treat the cause first. • Many medications can cause insomnia including caffeine, Parkinson’s drugs, theophylline, nicotine, corticosteroids, SSRIs, and others. • Non-drug treatment is preferred. • Follow good sleep hygiene / sleep fitness rules; this may take several weeks to become effective. • Hypnotics should only be used when non-drug treatment has failed and should be considered a temporary measure. Chronic use of sleep aids is not recommended. Limit use to 2 – 3 times per week if possible. Sleep Hygiene / Sleep Fitness • Establish a routine sleep schedule to help reset your circadian rhythm (biological clock). • Avoid daytime naps. • Avoid CNS stimulants, heavy meals, alcohol, laxatives, and diuretics near bedtime; although alcohol may help you fall asleep, the sleep is fragmented. • Increase daytime physical activity; but exercise no later than 7pm. • Increase daytime sunlight; this helps reset your biological circadian rhythm. • Make bedroom comfortable, quiet, & dark. • Reserve the bedroom for sleeping (and sex); don’t eat, read or watch TV in bed. • Wind down before bedtime with soothing music, a warm bedtime drink, back rub, relaxing reading, eating a light snack. • If you don’t fall asleep within 20 minutes or so, get up and do something relaxing and then return to bed; avoid lying in bed worrying about the fact that you can’t get to sleep. Treatment of Anxiety • • • Anxiety is an unpleasant state of tension, apprehension, or uneasiness – a fear that seems to arise from an unknown source. Anxiety disorders are the most common mental disorders. Anxiety requires medical treatment if it is severe, chronic, or debilitating to the individual. Anxiety and clinical depression can occur together Types of anxiety disorders include generalized anxiety disorder (GAD), posttraumatic stress disorder (PTSD), panic disorders, obsessive-compulsive disorders (OCD), acute stress disorders and phobic disorders Medications to Treat Anxiety Disorders • SSRIs, SNRIs, and buspirone (Buspar), can all be used to treat anxiety disorders. They have a delayed initial response, 1 – 3 weeks. • If rapid relief is needed, only a benzodiazepine will work quickly. Such situations may include anxiety prior to surgery, chemotherapy, or acute anxiety. • When depression & anxiety occur together, an antidepressant would be the drug of choice *Buspirone (Buspar • • • ) Mechanism of action is unclear but probably affects serotonin. Initial response in 1 – 3 weeks Advantages: no sedation, no abuse potential, no potentiation of other CNS agents Disadvantage: anxiolytic effects take many weeks to many months to develop fully 55 Schizophrenia and Antipsychotics Etiology of Schizophrenia • Exact etiology is unknown. It involves excessive dopamine and possibly serotonin in the brain. • 1% incidence in the U.S. Emerges in adolescence and early adulthood. • Has a genetic / biological component. • Psychosis may occur in schizophrenia, schizoaffective disorder, bipolar disorder, major depression, and the dementias. Clinical Features During an acute schizophrenic episode, delusions and hallucinations are common. Delusions are typically religious, grandiose, or persecutory. Auditory hallucinations may consist of voices arguing or commenting on one’s behavior. The patient may feel controlled by external influences. Disordered thinking may make rational conversation impossible. After an acute episode, less vivid residual symptoms may remain. These symptoms may include suspiciousness, anxiety, and diminished judgement. These patients may find it difficult to maintain close relationships and employment. Symptoms are classified as positive, negative, or cognitive. • Positive symptoms: Hallucinations (auditory >> visual), delusions, agitation, tension, paranoia, hostility, excitement, grandiosity • Negative symptoms: Lack of motivation, uncooperativeness, blunted affect, poor self-care, social withdrawal, little speech, poor abstract thinking • Cognitive symptoms: impaired attention, impaired short-term memory, impaired executive function, impaired verbal fluency 1st Generation Antipsychotics (also called typical or conventional) *Haloperidol (Haldol) Fluphenazine (Prolixin) Loxapine (Loxitane)    Chlorpromazine (Thorazine) (clor PROE ma zeen) Thioridazine (Mellaril) Perphenazine (Trilafon) Triflupromazine (Vesprin)   Thiothixene (Navane) Pimozide (Orap)   ) Molindone (Moban) Trifluoperazine(Stelazine)   • • All of these agents are considered to be equally effective in the treatment of psychosis. (considered 70 – 86% effective at relieving positive symptoms) For unknown reasons, some patients may respond better to one agent than another. Mechanism of Action: Block dopamine receptors (mainly D2) in certain areas of the brain. Therapeutic Uses • Very effective at suppressing “positive” symptoms during acute psychotic episodes. • Chronic therapy will reduce the risk of relapses. • Control the manic phase of bipolar disorder (manic/depressive disorder). • Suppression of severe Tourette’s symptoms. • Suppression of psychosis & hallucinations caused by Parkinson’s medications. • Antiemetic: chlorpromazine, blocks dopamine receptors in the chemoreceptor trigger zone. • Control aggressive behavior in dementia and delusion disorders. Although orders for “haloperidol prn” agitation are common, it should be a last choice in treatment of such behaviors. 56 Common Adverse Effects (non-selective) • Sedation: due to histamine blockade, lessens after a few weeks • Sexual dysfunction • Orthostatic hypotension: due to α1-blockade • Anticholinergic side effects: due to muscarinic blockade, lessens after a few weeks • QT prolongation: Torsades de pointes, a life-threatening arrhythmia • Hyperprolactinemia: reversible, due to dopamine blockade, may lead to galactorrhea & amenorrhea Extrapyramidal Side Effects (EPSE) (due to blockade of dopamine, D2-receptors) 1) Acute dystonia: May develop within the first days of therapy. Includes severe spasms of muscles of tongue, face, neck, or back. Considered a medical emergency. Treat with anticholinergic drugs. 2) Parkinsonism-like movement disorders: Usually occurs within the first few months of therapy. Bradykinesia, drooling, tremor, rigidity, shuffling gait, cogwheeling, stooped posture. Best treated with anticholinergic drugs. Anti-Parkinson drugs like levodopa or bromocriptine will counteract the extrapyramidal side effects, but may worsen the schizophrenia. 3) Akathisia: Usually occurs within the first few months of therapy. Includes pacing, squirming, and the need to constantly be in motion. May also respond to anticholinergic drugs. 4) Tardive Dyskinesia: Develops in 15 – 20 % of patients receiving long-term therapy. Mechanism unclear. Involuntary movement of tongue or face. Include lip-smacking, tongue twisting, tongue flicking out of mouth. Can interfere with chewing, swallowing, and speech. May progress to the limbs. May be irreversible in some patients. Reduce dose or switch to a 2nd generation antipsychotic if tardive dyskinesia develops. Anticholinergic & antiParkinson drugs will not be effective to reverse these symptoms. 2nd Generation Antipsychotics *Risperidone (Risperdal)  *Quetiapine (Seroquel)  *Clozapine (Clozaril)  (also called atypical) Olanzepine (Zyprexa) Ziprasidone (Geodon)  ( Aripiprazole (Abilify) Asenapine (Saphris®)  (a SEN a peen) Paloperidone (Invega) Iloperidone (Fanapt®)  (eye loe PER i done) Mechanism of Action • Block serotonin & dopamine receptors. • The main differences between the 1st and 2nd generation antipsychotics are: 2nd generation agents generally block serotonin receptors and D1-receptors more than D2receptors, thus they have a much lower risk of causing extrapyramidal side effects. Some 2nd generation agents may relieve negative symptoms of psychosis better than 1st generation agents. 57 Common Adverse Effects • Sedation: due to histamine blockade • Sexual dysfunction • Orthostatic hypotension: due to α1-blockade • Anticholinergic side effects (much milder than with 1st generation antipsychotics) • QT prolongation: Torsades de pointes, a life-threatening arrhythmia • Hyperprolactinemia (much milder than with 1st generation antipsychotics) • Much lower risk of extrapyramidal side effects than with the 1st gen antipsychotics • Metabolic effects: new-onset diabetes, hyperlipidemia, weight gain. All increase chance of cardiovascular event. Special information regarding clozapine • May cause life threatening adverse effect of agranulocytosis (1-2%). Because of this, weekly monitoring of CBC is required. If WBC falls too much, the drug should be stopped. • Warn patients of signs of infections like fever, sore throat, and fatigue. General Principles for Rx treatment of Schizophrenia • • • • 1st and 2nd generation agents are equally effective; select agent based on individual patient profile financial considerations may come into play (Some 2nd generation are 10 times more expensive than 1st generation—some available generically) Symptoms should begin to resolve within 1 to 2 days. Significant improvement will be seen in 1 to 2 weeks. Full response to therapy may not be seen for several months. Withdrawal of medication in chronic schizophrenia is highly associated with relapse. Always use the minimal effective dose to prevent adverse effects. General Principles of Patient Education • • • Continuously discuss importance of compliance with patient & family members Discuss management of orthostatic hypotension, anticholinergic side effects, sedation, etc. Report adverse effects to prescriber. 58 Overview of Parkinson’s disease • • • • Parkinsonism is a progressive neurological disorder of muscle movement, characterized by tremors, muscle rigidity (increase in resistance to passive movement), bradykinesia (slowness in initiating and carrying out voluntary movements & reductions in passive movements such as swinging the arms while walking), and postural instability (increased risk of falls). Tremor is most obvious at rest. Often one side of the body may be affected more than the other Nonmotor symptoms include: micrographia (small handwriting), sleep disturbance (70%), speech problems (reduced voice volume, slurring, monotone, stammering), loss of smell, dysphagia, visual problems, orthostatic hypotension, urinary incontinence, etc Correlated to a decrease of inhibitory dopaminergic neurons in the substantia nigra. Dopamine is normally inhibitory in the substantia nigra while acetylcholine is excitatory. The imbalance dopamine / acetylcholine imbalance is responsible for the symptoms of Parkinson’s The Unified Parkinson’s Disease Rating Scale (UPDRS) is used to define the degree of disability. Strategy of Treatment • To treat the symptoms of Parkinson’s, we try to balance the inhibitory effects of dopamine & the excitatory effects of acetylcholine. • Therapy is aimed at restoring the effects or increasing levels of dopamine in these brain centers. • Therapy may also include antagonizing or blocking the effects of acetylcholine in these centers. • There is not idea treatment: current treatments can temporarily relive symptoms of the disease, but they do not affect the degeneration of dopaminergic neurons or reverse the disease. Levodopa dopa decarboxylase COMT Dopamine MAO-B Inactivated dopamine 3-O-methyldopa (not what we need) Drug Therapy to Treat Parkinson’s *levodopa / carbidopa (Sinemet , Sinemet CR, Parcopa) oral (leevoeDOEpa / karbiDOEpa) • Levodopa is a metabolic precursor of dopamine. • Dopaminergic neurons convert levodopa to dopamine in the CNS. A certain level of active neurons must still be present to adequately convert the drug to active form. • Over time, the effectiveness of this drug will decline due to ever diminishing numbers of dopaminergic neurons. Why don’t we just administer dopamine itself? Dopamine cannot cross the blood brain barrier. A large amount of levodopa is converted to dopamine before it is able to cross the blood brain barrier. Carbidopa is a drug given with levodopa to prevent or block this conversion. It inhibits the enzyme, dopa decarboxylase. Carbidopa itself does not cross the blood brain barrier & therefore does not inhibit the conversion of levodpa to dopamine in the CNS. • Levodopa/carbidopa decreases the rigidity, tremors, and other symptoms of Parkinsonism. Adverse Effects (Dopaminergic) • Peripheral dopaminergic adverse effects: Nausea, vomiting, constipation, & orthostatic hypotension, dizziness • Central dopaminergic adverse effects: Psychiatric disturbances (hallucinations and delusions), insomnia. 59 Drug Interactions • Antispychotics: many antipsychotics act by blocking dopamine receptors & can by themselves produce Parkinsonian symptoms. • Antiemetics: several antiemetics (Medications to treat nausea and vomiting) act by blocking dopamine receptors and can cause Parkinson’s symptoms. Dopamine Receptor Agonists oral *pramipexole (Mirapex) ropinirole (Requip) rotigotine (Neupro®) (pramiPEKSole) (roePINirole) Mechanism of Action: Act directly on the CNS dopamine receptors. • Can be used as first-line agents. • They can be used with levodopa/carbidopa for synergy. Adverse effects: • Same peripheral & central dopaminergic adverse effects as levodopa/carbidopa. • Other adverse effects: sleep attacks, impulse control disorders (compulsive gambling, shopping, binge eating, and hypersexuality) Catechol OMethylTransferase Inhibitors (COMT-inhibitors) oral *entacapone (Comtan) (enTAkapone) levodopa, carbidopa, entacapone (Stalevo) Mechanism of Action: Inhibits breakdown of levodopa by COMT • Only about 5-10% of orally administered levodopa reaches the brain despite coadministration with carbidopa. • COMT-inhibitors target another metabolizer of levodopa, the enzyme COMT. • Used in conjunction with levodopa/carbidopa. • Adverse effects: Most common adverse effects include diarrhea (10-18%) & hallucinations (5-10%) Monoamine Oxidase-B Inhibitor oral *rasagiline (Azilect) selegiline (Eldepryl, rapid dissolving Zelapar) (raSAJileen) (seLEjileen) Mechanism of Action: Selectively inhibits the enzyme that breaks down dopamine: MAO-B. • This drug does not inhibit MAO-A which breaks down norepinephrine, serotonin, & tyramine. • At normal doses, this drug does not have the food & drug interactions that the MAO-Inhibitor antidepressants have. Remember, at higher doses, it may lose its selectivity. • This drug enhances the actions of levodopa & can allow smaller doses of levodopa to be given. • May be used as first line therapy for mild Parkinson’s symptoms Adverse effects: Most common adverse effect is insomnia. Minimize this by not giving any doses after noon. • Avoid use with dextromethorphan, pseudoephedrine, tramadol, & meperidine Amantadine (Symmetrel ) • • (aMANtadeen) oral Enhance the synthesis, release, or re-uptake of dopamine from the surviving neurons. Less efficacious than levodopa & tolerance rapidly develops. Discovered as an additional benefit during studies of this drug as an antiviral agent. 60 Anticholinergic Agents *benztropine (Cogentin) trihexyphenidyl (Artane) oral (BENZtroepeen) (tryehekseeFENidil) Pharmacologically similar to atropine: These agents preferentially antagonize acetylcholine in the damaged motor control centers. • Much less effective than levodopa. • Usually not used alone to treat Parkinson’s. Usually used in conjunction with levodopa/carbidopa. • Also used in the treatment of antipsychotic induced extrapyramidal side effects. • Adverse Effects: 61 • • • • • • Anti-Epilepsy Drugs (AEDs) 2.3 million patients have epilepsy; 140,000 new cases each year. Approx 2/3 are treatment responsive…kept seizure free with medications. Since these patients will remain on that initial or second therapy for several years, the burden is on the treating prescriber to select the AED that is most tolerable, lowest potential for harm, and least negative impact on quality of life. Before 1990 only six AEDs were available on the market. Some causes of seizures include: Congenital abnormalities, Hypoxia (lack of O2) at birth, Alcohol or Benzodiazepine withdrawal, Uremia, Hypo/Hyperglycemia, Head trauma, Cancer / brain tumors, Vascular disease, stroke, Alzheimer’s disease, Infectious diseases (Meningitis, Herpes encephalitis, etc), Febrile seizures in children A single seizure does not constitute a diagnosis of epilepsy. If the underlying cause of the seizure is permanent epilepsy may result; some epilepsy is idiopathic. Classification of Seizures Partial Seizures (affect only part of the brain) 1. Simple partial seizures (focal): specific symptoms depend on function of affected brain tissue. Focal motor symptoms (compulsive jerking) or somatosensory symptoms (paresthesias or tingling) that spread to other areas of the body. Some seizures will involve certain senses (light flashes, buzzing). 2. Complex partial seizures (temporal lobe or psychomotor): Impaired consciousness may be preceded, accompanied, or followed by symptoms mentioned above. Generalized Seizures (involving the whole brain & loss of consciousness) 1. Tonic-clonic (grand mal) seizures: Sudden loss of consciousness, patient becomes rigid & falls to the ground, and respiration is arrested. This phase lasts < 1 min. The clonic phase consists of jerking of the body musculature. May last 2 – 3 min, and is then followed by flaccid coma. 2. Absence (petit mal) seizures: Impairment of consciousness for a brief time (10-30 sec) sometimes with mild clonic, tonic, or atonic components (i.e. loss of postural tone), autonomic components (enuresis), or accompanying automatisms. Onset & termination are abrupt. Patients may not even be aware of the seizure. 3. Myoclonic seizures: single or multiple myoclonic jerks Mechanisms of Action of Antiseizure Drugs • Suppress discharge of overactive neurons & to suppress propagation to other areas. (1) Suppression of Na+ influx. (2) Suppression of Ca++ influx. (3) Promotion of K+ efflux. (4) Potentiation of GABA (5) Antagonism of glutamate Suppression of Sodium Influx • Neuronal action potentials are propagated by sodium influx. Some drugs bind to these sodium channels and prolong their inactivation phase. • Phenytoin, Carbamazepine, Oxcarbazepine, Valproic Acid, & Lamotrigine. Suppression of Calcium Influx • Influx of calcium through calcium channels promotes transmitter release across the synapse and propagating the action potential from one neuron to another. Blocking the calcium channels suppress the transmission of the action potential. • Valproic Acid and ethosuximide Promotion of Potassium efflux • During an action potential, the influx of sodium causes the neuron to depolarize, and the efflux of potassium causes the neuron to repolarize. Increased potassium efflux is believed to slow down neuronal firing. • Ezogabine 62 Potentiation of GABA (gamma-aminobuytric acid) • GABA is an inhibitory neurotransmitter widely found throughout the brain. Benzodiazepines & barbiturates enhance the effects & binding of endogenous GABA. • Gabapentin & pregabalin promote GABA release from CNS neurons. Tiagabine is possibly a GABA reuptake inhibitor. Antagonism of Glutamate • Glutamate is the primary excitatory neurotransmitter in the CNS. By blocking the receptors of glutamate (NMDA and AMPA), neuronal excitation is suppressed. • Felbamate and topiramate Therapeutic Goals for Management of Epilepsy • • • • Decrease seizure frequency to an acceptable level of function for the patient Balance the benefits of the medications with their potential toxicities and adverse effects Non-compliance is an issue & may account for up to 50% of therapy failures Quality of life goes beyond balancing seizures & ADRs. One must consider other patient concerns about driving, their future, forming relationships, safety, social isolation, stigma, etc Drug Selection: • Drug selection is based on seizure type Seizure Type Partial seizures Generalized seizures Absence First-Line Drugs Lamotrigine, Carbamazepine, Levetiracetam, Oxcarbazepine, Alternative Drugs Topiramate, Valproic acid, Gabapentin,Phenytoin, Felbamate, Phenobarbital, Primidone, Tiagabine, Zonisamide, Valproic acid, Ethosuximide, Lamotrigine Myoclonic Valproic acid, Clonazepam Tonic-clonic Valproic acid, Lamotrigine, Levetiracetam Topiramate, Phenobarbital, Primidone, Oxcarbazepine, Phenytoin, AEDs in Children There is little information about efficacy and safety of the newer AEDs in children; lamotrigine can be included in the options for children with newly diagnosed absence seizures. Here are the most common reasons listed for children to stop therapy. • Phenytoin: gingival hyperplasia • Carbamazepine: CNS effects • Valproate: weight gain & gastrointestinal adverse effects • Phenobarbital: hyperactivity & behavior problems Discontinuing Therapy • There are no concrete guidelines here. • If there are no structural abnormalities causing the seizure & the patient is seizure free for > 3 years, you may consider discontinuing therapy. Weigh this decision carefully! • Taper slowly. Reduce dose by 25% every 2 – 4 weeks. • If the patient is on more than one antiseizure medication, stop them one at a time. • Seizure recurrence rate is about 25% in patients without risk factors and about 50% in patients with risk factors. • About 80% of recurrent seizures occur within 4 months of drug taper, 90% within the 1st year. 63