* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Neurological Agents Chart
Pharmacokinetics wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Pharmaceutical industry wikipedia , lookup
Discovery and development of beta-blockers wikipedia , lookup
5-HT3 antagonist wikipedia , lookup
Discovery and development of antiandrogens wikipedia , lookup
Pharmacognosy wikipedia , lookup
Prescription costs wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
Nicotinic agonist wikipedia , lookup
Dextropropoxyphene wikipedia , lookup
Theralizumab wikipedia , lookup
Cannabinoid receptor antagonist wikipedia , lookup
Toxicodynamics wikipedia , lookup
Drug interaction wikipedia , lookup
NK1 receptor antagonist wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Neuropharmacology wikipedia , lookup
Psychopharmacology wikipedia , lookup
LOCAL ANESTHETICS: Drug General LA Potency Variable Onset (pKa) Between 7.8-9.0 -Closer the pKa is to physiological pH, the faster the onset (more nonionized form) -Can give bicarbonate to increase speed of onset Duration (Hydrophobicity) Variable -All LAs are hydrophobic due to presence of aromatic ring -Degree of hydrophobicity determines duration of action and potency -Use of EPI (vasoconstrict) to prolong effects Toxicity CNS: -Stimulation -Restlessness -Dizziness -Tremors -Confusion -Respiratory depression Formulations Many Uses Many CV: -Myocardial depression -Vasodilation (except cocaine) Smooth Muscle: -Depress GI contractions -Relax vascular and bronchial smooth muscle Hypersensitivity: esp. esters (PABA derivatives) -Allergic dermatitis -Asthma ESTERS Cocaine Low Medium (8.7) Medium (moderate hydrophobicity) Procaine Low Slow (8.9) 2-5 minutes Short (low hydrophobicity) Benzocaine Low Rapid (no amine group and therefore not protonated) Short (15-20 minutes) -Unique mechanism (small enough to fit in pore to stabilized CLOSED state) Tetracaine High* Faster (8.2) Long (high hydrophobicity due to butyl group) CNS: toxicity due to local anesthetic properties and blockade of catecholamine reuptake Topical: anesthesia of mucous membranes -Nose -Mouth/throat -Ear Adrenergic Effects: -HTN -Increased HR -Arrhythmia Hydrolyzed to PABA: -Hypersensitivity -Interaction with sulfa drugs Parenteral: infiltration and dental procedures; also spinal Cream Aerosol Ointment May be more pronounced: due to slower metabolism Topical: -Dermal -Oral (mucus membranes) -Insertion of medical devices Topical: larynx, trachea, esophagus anesthesia Parenteral: spinal Drug AMIDES Lidocaine Bupivacaine Ropivacaine Potency Onset (pKa) Duration (Hydrophobicity) Intermediate Rapid (7.8- lowest pKa of all) High Fast (8.1) Medium-long (moderate hydrophobicity) -Metabolites from metabolism in the liver also retain some anesthetic activity Very long (highly hydrophobic due to butyl piperidine group) High GENERAL ANESTHETICS (INTRAVENOUS): Drug Class Drugs in Class Barbiturates Sodium Thiopental Thiamylal Methohexital Benzodiazepines Diazepam Lorazepam Midazolam Opioids Morphine Fentanyl Phenols Propofol Imidazole Etomidate Dissociative Ketamine (PCP Analog) Fast (8.1) Not as long (not as hydrophobic) -Is itself a vasoconstrictor (do not need to add EPI) Toxicity Formulations Ointment Jelly Patch Aerosol Solution *Most widely used* Topical: dermal, laryngeal, oral Parenteral: epidural, infiltration, nerve block, spinal Parenteral: -Epidural* -Inflitration -Nerve block -Spinal Cardiotoxic properties Epidural for Labor: give dilute solution (will preferentially block sensory function, not motor) *Very similar to Bupivacaine* Parenteral: -Epidural -Infiltration -Nerve block Lower cardiotoxicity Use Ultra-short acting barbiturates capable of producing anesthesia within seconds Anxiolytic and anterograde amnesic properties (administered 15-60 minutes before induction to calm patient/erase memory of induction) Also used for intraoperative sedation Analgesia (poor amnesics) *Most popular IV anesthetic*- induction and maintenance Good choice for ambulatory surgery Good choice for prolonged sedation in critical care setting Primarily used in patients at risk for hypotension (no significant cardiac or respiratory depression) Induction and maintenance in combo with sedative Dissociative anesthesia (catatonia, amnesia, analgesia with no LOC) Use Other Duration of Action: 30-60 minutes after single bolus Fast onset: half-time to blood-brain equilibration 1-3 minutes Fast recovery: can ambulate earlier after general anesthesia Metabolism: rapidly in the liver Issues: high incidence of pain on injection and postoperative N/V Metabolism: extensive hepatic metabolism + in the plasma Rapid onset: with profound analgesia MOA: non-competitive antagonist of NMDA receptor Issues: only IV anesthetic to produce dose-related cardiostimulation; may cause hallucinations/irrational behavior Metabolism: liver GENERAL ANESTHETICS (INHALATION): Drug Onset/Recovery General Inhalation Determined by Blood:Gas partition Anesthetic coefficient/solubility -High B:G=High solubility=Slower equilibration -Low B:G=Low solubility=More rapid equilibration Other Factors ↑Speed of Onset: -High blood flow to tissue -Increased pulmonary ventilation -Decreased pulmonary blood flow Factors Affecting Speed of Recovery: -Faster in agents with low B:G solubility -Proportional to duration of anesthesia (longer duration= in muscle and adipose; %body fat can play a role) -Rate of recovery accelerated by increased ventilation INHALATION AGENTS Nitrous Oxide Potency Determined by Oil:Gas partition coefficient (lipid solubility)/MAC value -High lipid solubility=High O:G= Low MAC= High potency -Low lipid solubility=Low O:G= High MAC= Low potency Low potency (Low O:G, High MAC) More potent than N2O (Higher O:G; Lower MAC) Higher potency (High O:G, Low MAC) Halothane Medium induction/recovery (Higher B:G) Higher potency (High O:G, Low MAC) Desflurane Rapid induction/recovery (Low B:G) More potent than N2O (Higher O:G, Lower MAC) Isoflurane Systemic Effects CV: ↓BP Respiratory: ↓ ventilatory drive and airway patency -Exception: N2O Brain: ↑ cerebral BF= ↑ ICP MAC: alveolar concentration required to eliminate the response to standardized painful stimuli in 50% of patients Rapid induction/recovery (Low B:G) Rapid induction/recovery (Low B:G) Medium induction/recovery (Higher B:G) Sevoflurane Use Kidney: ↓ GFR and RBF; ↑ filtration fraction Liver: ↓ hepatic blood flow Not used alone: exception is dental procedures -Outpatient use -Use in children (sweet odor) *Most commonly used* -Induction/maintenance -Pungent odor -Induction in children (nonpungent) -Not used in adults (risk of hepatotoxicity- only one extensively metabolized in the liver) -Most widely used for outpatient surgery *Only agent that produces analgesia* -Risk of nephrotoxicity (metabolism to fluoride ions) -Rare risk of malignant hyperthermia -Respiratory tract irritation MORPHINE EFFECTS/USES (PROTOTYPE OPIOID): EFFECT USE Analgesia *Pain relief WITHOUT general sensory loss or LOC* -Pain still present but not longer bothers the patient -Better against dull continuous pain than sharp intermittent pain -Multiple sites of action (in brain and spinal cord) Mood/Cognitive Effects Miosis Cough Inhibition SIDE EFFECT Significant tolerance to this effect Paradoxical hyperalgesia: MOA unclear (possibly increased glutamate transmission in dorsal horn) Clinical Use: surgical anesthesia (in combination with other agents) Euphoria and tranquility -Site of action unclear (locus ceruleus, mesolimbic DA, nucleus accumbens?) -Prompt administration reduces risk for PTSD in combat injured soldiers -- Respiratory Depression MOA: depression of cough reflex mediated by medullary cough center (easily separated from respiratory depression) -- Increased ICP -- Nausea/Emesis -- CV Effects Use of IV morphine to relieve dyspnea in left ventricular heart failure due to pulmonary edema: decreases anxiety, venous tone and peripheral resistance GI Effects -- Other Effects OPIOD DRUGS: Drug Morphine MOA Mu receptor agonist Pharmacokinetics Absorption: well absorbed by multiple routes Metabolism: extensive first pass metabolism (35% bioavailability- limits oral use) Excretion: -Polar metabolites excreted in the urine (active/toxic) -Some in the bile Use See above Not pleasant in pain free individuals: dysphoria (depression/discontent), difficulty thinking, drowsiness, nausea Confusion/sedation possible: especially in the elderly MOA: excitation of PS innervation to the pupil (sign of intoxication/OD) Little/no tolerance to this effect with chronic us -MOA: dose-related depression mediated by brainstem centers (decreased response to CO2); especially concerning in those with COPD Synergistic with other CNS depressants MOA: decreased responsiveness to CO2 leads to increased pCO2 and cerebrovascular vasodilation; needs to be considered in patients with head trauma MOA: mediated by area postrema CTZ (more common in ambulatory patients, suggesting possible vestibular involvement) Tolerance to this effect develops rapidly Peripheral vasodilation and inhibition of baroreceptor reflex: orthostatic hypotension and fainting upon standing (not evident in supine patient) MOA: may be due to histamine release Decreased propulsive contractions ↑H2O reabsorption Constipation Little tolerance to this effect: issue with chronic use Ureters: increased sphincter tone (decreased urinary output); esp. elderly Uterus: prolongs labor and has effects on fetus Itching: due to effects on CNS and peripheral nerves (probably due to substance P or histamine release) Toxicity/SEs Renal Insufficiency: -Build-up of active metabolite (morphine-6-glucuronide) can lead to confusion/agitation -Build-up of proconvulsant metabolite (morphine-3-glucuronide) can lead to seizures Formulations Long-acting SR beads: do not chew Morphine + Naltrexone: prevent abuse DepoDur: single injection for post-surgical use (lasts 48 hours) Continual epidural or intrathecal infusion Heroin Oxycodone (Morphine backbone) Converted to morphine in vivo (deacetylation) Mu receptor agonist Fast acting and very potent Drug of abuse Absorption: more orally active than morphine Short-term relief of moderate pain (ie. cancer patients) Drug of Abuse: possibly lethal Efficacy: roughly equivalent to maximal efficacy of oral morphine Perodan: combo with aspirin Percocet: combo with acetaminophen Combunox: combo with ibuprofen Acurox: combo w/ niacin and ingredients that convert to gel upon extraction (abuse deterrent) Meperidine Codeine Fentanyl Propoxyphene Nalbuphine Butaphanol Pentazocine Tramadol Primarily a kappa receptor agonist Weak mu receptor agonist (deacetylation to morphine) Note: 10% of population lacks enzyme to do this Mu receptor agonist Mu partial agonist Kappa agonists with mu mixed agonist/antagonist effects Synthetic codeine derivative -Active metabolite is a weak mu agonist -Also blocks 5HT and NE uptake -GABA action? Onset/Duration: rapid onset with short duration of action Absorption: good oral absorption Metabolism: not much first pass metabolism (high oral:parenteral potency ratio) Potency: 100x more potent than morphine Duration of action: short (no active metabolites) Efficacy: very low Pain killer used in acute pain management only (ie. postsurgical) IM injection: irritating to tissue Toxicity: seizures, twitching, delirium, psychiatric changes -Due to accumulation of toxic metabolite -Painkiller (often given in combo formulation) -Antitussive effects (questionable) -IV use for surgical anesthesia (w/droperidol) -Acute post-op pain (PCA) Being pulled from the market due to toxicity Less analgesia Less respiratory depression Less tolerance Limited to chronic neuropathic pain: needs to be titrated Tylenol 3 Sustained release formulation Very potent: potentially dangerous Transdermal patch: -Be careful of heat exposure -Careful with CYP3A4 inh. Safety: very low TI Unique delivery routes: -Transdermal patch (change every 2-3 days) -Buccal tablet, film or lozenge (breakthrough pain) Combo with aspirin/caffeine Combo with acetaminophen Toxicity: due to buildup of toxic metabolite -Cardiotoxic -Convulsions -OD Less naloxone reversibility: for example, in OD More adverse behavioral symptoms: psychomimetic, Salvinorin-A like effects Increased frequency of seizures: esp. in those with seizure history OR on antidepressants DDIs: may lead to serotonin syndrome Extended release Combo with acetaminophen Tapentadol Methadone Tramadol-like compound -Weak mu agonist -NE reuptake inhibitor, but NOT 5HT Mu agonist Duration: long half-life (needs careful initial titration) Metabolism: hepatic (no active metabolites, so safe in renal failure) Potency: more potent than full agonist methadone Duration: long duration of action -Slow dissociation from R -Resistance to naloxone reversal Buprenorphine Partial agonist at mu Naloxone Opiate receptor antagonist (mu>kappa and delta) Naltrexone Opiate receptor antagonist (mu>kappa and delta) Methylnaltrexone Opiate receptor antagonist Does NOT cross BBB: does not affect analgesia Diphenoxylate Loperamide Dextromethophan Mu receptor agonist Mu receptor agonist D isomer of methylated levorphanol -NMDA receptor antagonist -Sigma receptor agonist Poor gut absorption Poor gut absorption Nalfurafine Kappa opioid receptor agonist Chronic pain: esp. in patients with renal failure Addict detoxification or maintenance: carefully dispensed Sublingual Combo with naloxone: prevent abuse Sustained release: once a month formulation being tested Opioid overdose -Blocks analgesic, antidiarrheal and antitussive effects Prevention of relapse to heavy drinking Opioid induced constipation in terminal patients under palliative care Exclusive use in diarrhea Exclusive use in diarrhea Antitussive: MOA unclear Relief of itching ER form: for use in opioid OD Oral Form: hepatotoxic in overdose Oral form: poor compliance Injectable ER form: once a month depot recently approved Naltrexone + Buprenorphine: obesity treatment Injectable Diphenoxylate+Atropine=Lomotil Potential for abuse Contraindications: -Young children -Combination products (ie. with antihistamines) Use of kappa agonist along should be unpleasant: psychomimetic effects Combination products discouraged SEDATIVE HYPNOTICS: Drug Class Drug General Benzodiazepines MOA Bind BZ receptor (part of GABA-A R) and prolong the effects of GABA -Increase FREQUENCY of GABA-mediated Cl channel opening Pharmacokinetics Highly Lipid Soluble: -Cross BBB rapidly -Cross placenta -Detected in breast milk Pharmacodynamics CNS effects highly dose dependent: depressant effects additive with other sedative hypnotics Metabolism: Phase I: most undergo hepatic oxidation by P450 (CYP3A4/2C19) Phase II: all conjugated to form glucuronides Safer than benzos: flatter dose-response curve Long Acting Agents: have active metabolites (can accumulate) Antagonist/Antidote: Flumazenil -Administer repeatedly (short half-life) -Be careful in patients with seizure history Use Anxiety: intermediate or long acting agents (short-term mgt.) -Panic/phobic disorders -GAD Insomnia: and other sleep disorders Anesthesia: anxiolytic Skeletal muscle relaxation: low doses Spasticity: diazepam Excretion: glucuronides excreted by kidney Seizures: clonazepam Withdrawal from EtOH or other S-H: long acting agents Adverse Effects DDIs: be careful of CYP3A4 interactions Adverse Events: -Impaired psychomotor functions -Behavioral disinhibition -Decreased REM sleep -Rebound increased REM sleep (discontinution) -Anterograde amnesia -Tolerance (chronic/high dose) -Dependence (physical, psychological) Withdrawal: more common with shorter acting drugs -Longer acting drugs selftaper OD: respiratory arrest, hypotension, CV collapse -Less common with benzos Oxazepam Lorazepam Short-acting: -Does not accumulate (no active metabolites) -Do not undergo hepatic microsomal oxidation (conjugated directly) Short-acting: same as above Alprazolam Triazolam Intermediate-acting Intermediate-acting Diazepam Long-Acting: -Active metabolites accumulate with continuous dosing High dose IV: used in treatment of status epilepticus Panic/Phobic disorders Primary insomnia and sleep disorders Highly lipophilic: makes use by IM injection unreliable High dose IV: used in treatment of status epilepticus Spasticity: effective at sedative doses Anxiety Anesthesia: anxiolytic Withdrawal effects common: one of the examples listed Daytime anxiety and amnesia: shorter acting Psychomotor dysfunction: more common with long acting benzos (long-lived metabolites) Prazepam Clorazepate Chlordiazepoxide Long-Acting Long-Acting Long-Acting Flurazepam Highly lipophilic: makes use by IM injection unreliable Long-Acting: -Active metabolites accumulate with continuous dosing Primary insomnia and sleep disorders Midazolam Clonazepam General Barbiturates Interact with other sites on GABA-A receptor (do not compete with BZ or GABA) -Prolong inhibitory effects of GABA -Increase DURATION of GABA mediated Cl channel opening Highly Lipid Soluble: -Cross BBB rapidly -Cross placenta -Detected in breast milk Management of withdrawal CNS effects highly dose dependent: depressant effects additive when 2 or more given together More dangerous than benzos: steeper doseresponse curve Production of anesthesia Low Dose: non-sedating dose used for treatment of seizures (selectivity) Panic/phobic disorders Anesthesia: induction by most barbiturates Seizures: phenobarbital Skeletal muscle relaxation: low doses Cannot use flumazenil as antagonist: in OD Psychomotor dysfunction: more common with long acting benzos SEs: -Impaired psychomotor functions -Behavioral disinhibition -Tolerance (chronic, high doses) -Dependence (physical, psychological) -Induction of formation of liver microsomal enzymes -Precipitation of acute intermittent porphyria Withdrawal: more common with shorter acting drugs OD: respiratory arrest, hypotension and CV collapse -More likely with barbiturates Thiopental Thiamylal Pentobarbital Methohexital Phenobarbital Ultra-short acting Most lipophilic agent: -Enters CNS rapidly Ultra-short acting Induction of anesthesia: due to high lipophilicity Anesthesia: induction Withdrawal: short acting agent given as example Ulltra-short acting Long-acting Duration of Action: over 30 hours Anesthesia: induction Low Dose: non-sedating dose used for treatment of seizures (selectivity) High dose IV: used in treatment of status epilepticus Carbamate Meprobromate Highly Lipid Soluble: -Cross BBB rapidly -Cross placenta -Detected in breast milk Muscle relaxant: shows selectivity for this effect OD: respiratory and CV depression more likely than with benzos Additive CNS depression Induction of the formation of liver microsomal enzymes: increase drug metabolism (same as barbiturates) Displacement of coumarins from plasma protein binding sites (increase anticoagulant effects) No use of flumazenil Alcohol Chloral Hydrate Highly Lipid Soluble: -Cross BBB rapidly -Cross placenta -Detected in breast milk Additive CNS depression No use of flumazenil Short duration of action: only a few hours Buspirone Partial 5HT1a agonist and agonist/antagonist at D2 receptor OD: respiratory and CV depression more likely than with benzos Additive CNS depression uncommon: no sedation or cognitive impairment No cross-tolerance: therefore, will not prevent benzo withdrawal BZ R Agonists Zolpidem Zaleplone Eszopiclone Modulate GABA-A R via interaction with BZ binding site Melatonin Agonist Ramelteon Melatonin R agonist Short duration of action: only a few hours Non-Prescription Hypnotics: Antihistamines: Diphenydyramine Doxylamine Serotonin Precursor: L-tryptophan Serotonin Biosynthetic Pathway Product: melatonin (secreted by pineal gland in circadian rhythm) Only anxiolytic effects: no hypnotic, euphoric, muscle relaxant or anticonvulsant effects Flumazenil can be used as antidote: b/c of MOA No risk of abuse: not a controlled substance Anxiety: esp. in patients with a past hx of substance abuse -Exact MOA unknown -Effects take ~week to develop (start on benzo and taper off) Sleep disorders and primary insomnia: -Less daytime sedation -Minimal effects on sleep patterns (no rebound increase in REM when stopped) Sleep onset: not sleep maintenance Dependence: less of an issue with these than others ↑ serum prolactin ↓ serum testosterone ANTIPSYCHOTICS: Drug General APD MOA MOA(s) not well understood Commonality of all APDs is D2 DA R blockade Pharmacokinetics Administration: oral and parenteral forms (compliance) Absorption: most readily but incompletely absorbed Metabolism: significant first pass metabolism by P450 Excretion: conjugated for urinary excretion Use Schizophrenia: primary indication Schizoaffective disorder: APD plus -Antidepressant -Lithium -Valproate Neuroleptoanesthesia: droperidol + fentanyl Pre-Surgical Use: older APDs with H1 block (anti-emetic effects, sedation and relief of itching) Other Uses: -Depression/BPD -Agitation in AD/Dementia (black box warning) -Autism (aggression/self-injurious behavior) -BPD in children over 10 FIRST GENERATION Chlorpromazine Haloperidol Other First Generation: -Perphenazine -Thioridazine -Mesoridazine -Trifluoroperazine -Fluphenazine Receptor Affinities: Alpha1>D2=H1>M Generic and inexpensive: may be a good choice for some patients Receptor Affinities: D2>Alpha1>>H1>>M Generic and inexpensive Depot preparation: compliance Side Effects Relatively Safe: high TI Muscarininc: -Dry mouth -Urinary retention -Constipation Alpha Adrenergic Block: -Orthostatic hypotension -Impotence CV Effects: varies based on agent; overall result is 2x increased risk of sudden cardiac death (dosedependent; both typical and atypicals) Endocrine: decreased action of DA -Amenorrhea -Galactorrhea -Infertility -Impotence Metabolic Effects: atypicals (H1/5HT block) -Weight gain -Diabetes Early EPS: -Acute dystonic reaction -Parkinsonism -Akathisia -Neuroleptic malignant syndrome Late EPS: -Tardive dyskinesia** (can be hard to reverse) Adverse autonomic effects: alpha1 and muscarinic block Risk of EPS/TD: action at D2 CV Effects: ↑HR, abnormal ECG Less autonomic effects: less block at alpha1 and M Higher risk for EPS/TD: stronger D2 block CV Effects: ↑HR, abnormal ECG (all phenothiazines) SECOND GENERATION Clozapine Receptor Affinities: 5HT2A>Alpha1=M>D2 Clearly most effective for refractory cases: but toxicity limits use Expensive: no generic Olanzapine Receptor Affinities: 5HT2A=M>D2>Alpha1 BPD: acute mania and mixed episodes -All atypicals approved for these More tolerable than other APDs May be somewhat more effective Expensive: no generic Risperidone Receptor Affinities: 5HT2A>D2=Alpha1>>M BPD: acute mania and mixed episodes Refractory Depression: combined with fluoxetine (mixed results) Autism: aggression/self-injurious behavior in kids over 5 May be more tolerable than other APDs Generic and inexpensive Depot preparation: compliance Seizures: 1-4% of patients Agranulocytosis: potentially fatal (requires weekly blood counts) Less risk for EPS/TD: less D2 block Weight gain/diabetes: more action at 5HT2A Less Risk of EPS/TD: less D2 block Metabolic Effects: more action at 5HT2A (most prominent) -Weight gain -Diabetes Borderline typical/atypical: -Less 5HT-related weight gain -More DA-related SEs (↑PRL, EPS) Risperidone + Li: approved for refractory BPD Quetiapine Arpiprazole Ziprasidone BPD: acute mania and mixed episodes BPD: acute mania and mixed episodes BPD in Children: over the age of 10 BPD: acute mania and mixed episodes BPD in Children: over the age of 10 BPD: acute mania and mixed episodes CV Effects: risk of QT prolongation (possible with several atypical APDs, but most prominent with ziprasidone) ANTISEIZURE DRUGS: Drug Phenytoin (First Generation) Carbamazepine (First Generation) Valproic Acid (First Generation) MOA Blockade of Na channels (prolong inactivation) is primary effect, but not only effect Pharmacokinetics Absorption: depends on formulation -Fosphenytoin: soluble prodrug that can be given IM or IV Blockade of Na channels (prolong inactivation) is the primary effect Elimination: via the liver -Dose-dependent elimination, so need to titrate slowly at first Metabolism: significant microsomal induction of P450s (induces its own metabolism) -May need to adjust dose of this and/or other drugs Broad spectrum of action probably due to multiple MOAs -Blockade of Na channels -GABA effects -Histone deacetylation inhibition to increase gene expression -Effects on Ca++ channels (works for absence seizures) Phenobarbital (First Generation) Potentiate GABA effects (barbiturate) Lamotrigine (Second Generation) Blockade of Na channels (may have addition MAOs due to broad spectrum of activity) Levetiracetam (Second Generation) Binds SV2A to interfere with release of NT Different Formulations: -Divalproex Na ER (complex partial seizures, absence seizures, migraine) Use Partial seizures (simple/complex) Generalized tonic-clonic seizures Although considered 2nd line by some, still one of the most widely used drugs in the world Fosphenytoin: status epilepticus Partial seizures (simple/complex) Generalized tonic-clonic seizures Other Uses: -BPD -Trigeminal neuralgia -Possibly for drug abuse Partial seizures (simple/complex) Generalized tonic-clonic seizures Absence seizures Myotonic seizures Atonic seizures Combination seizures Other Uses: -BPD -Migraine (Divalproex sodium ER) Alternative for: Partial seizures (simple/complex) Generalized tonic-clonic seizures Status epilepticus (IV) Factors that can make it a DOC: rapid effects, safety profile (prevents seizures in low dose), and cost Alternative for: Partial seizures (simple/complex) Generalized tonic-clonic seizures Shown to be as effective as DOCs: may now be considered one Alternative for: Partial seizures (simple/complex) Generalized tonic-clonic seizures Good for refractory seizures: in adults and kids; possible DOC Adverse Effects Early: nystagmus Dose-Limiting: diplopia and ataxia Chronic Use: gingival hyperplasia and hirsutism Teratogenicity: fetal hydantaoin syndrome (possibly) Exacerbation of myoclonic and absence seizures: do not use! Dose-Related: diplopia and ataxia Elderly: idiosyncratic blood dyscrasia Rare: SJS (serious skin reaction) -Genetically determined (HLA test) -More common in Asians ER Formulation: may decrease SEs Serious effects are rare: but may not be first line because of them -Risk of severe idiosyncratic hepatotoxicity -Need to monitor liver function Teratogenicity: risk of spina bifida and IQ effects Sedative effects: can be limiting Rare Event: life threatening dermatitis in infants Well tolerated Gabapentin and Pregabalin (Second Generation) Binds voltage gated Ca channel subunit (NOT related to GABA) Topiramate (Second Generation) Broad spectrum, probably with multiple MOAs Ethosuximide Blocks T-type Ca++ channel Clonazepam Benzodiazepine (increases frequency of GABA channel opening) Diazepam/Lorazepam Benzodiazepines Alternative for: Partial seizures (simple/complex) Generalized tonic-clonic seizures Other Uses: -Neuropathic pain -Migraine -Anxiety -Surgical analgesia Alternative for: Partial seizures (simple/complex) Generalized tonic-clonic seizures Absorption: good Metabolism: complete ONLY for use in absence seizures Absence seizures: less effective than VA or ethosuximide Myoclonic seizures Atonic seizures Infantile spasms IV treatment of status epilepticus (followed by IV treatment with Phenobarbital or fosphenytoin) NON-PHARMACOLOGICAL INTERVENTIONS: Ketogenic Diet: low calories and high fat (simulates fasting) MOA: unclear Use: refractory seizures in children (ie. Lennox-Gastaut Syndrome) Surgery: Anterior temporal lobectomy: effective for refractory and harmful cases of most common partial seizures of adults Corpus callostomy: Lennox-Gastaut Syndrome Hemispherectomy: Ramussen Syndrome (autoimmune) and Sturge-Weber Syndrome Vagal Nerve Stimulation: Use: poor surgical candidates with refractory complex partial and generalized seizures MOA: unclear but effective Well tolerated: -Dose-related gastric distress -Rare cases of rashes/psychosis Typical benzo SEs: limit use -Sedation -Development of tolerance -Withdrawal syndrome ANTIPARKINSON’S DRUGS: Drug Levodopa (L-dopa) MOA Precursor to DA (replenish DA) Use Early Use: very effective (more for bradykinesia than tremor) Over time: decreased efficacy (wearing off after 2-5 years) Side Effects Major Issues: -On/Off phenomenon -Dyskinesias (up to 80% of patients; dopa-PD interaction) Other Effects: -Early: anorexia, nausea, hypotension -Chronic use: hallucinations, delusions, agitations, insomnia, gambling and hypersexuality Formulations Sinemet/Atamet: levodopa + carbidopa (3-6 times/day) -Carbidopa: amino acid decarboxylase inhibitor; allows more levodopa to reach the brain -SR formulation now available Parcopa: immediate release levodopa/carbidopa taken w/o water (management of acute events) Lodosyn: carbidopa alone (if needed to be added to regimen) Bromocriptine (Ergot) DA receptor agonist Pergolide (Ergot) DA receptor agonist Pramipexole (Non-Ergot) DA receptor agonist (D3>D2) Not typically used for PD anymore Current Use: neuroleptic malignant syndrome (due to APDs) Not typically used for PD anymore Current Use: low doses for hyperprolactinemia First line monotherapy in PD: probably not as effective as L-dopa (originally just an adjunt), but better SE profile Other Use: Restless Leg Syndrome Ropinirole (Non-Ergot) Apomorphine DA receptor agonist (D2) DA receptor agonist (some D2 preference) Same as pramipexole PD: treatment of off episodes (injectable formulation for rescue) Rotigone Selegiline DA receptor agonist MAO-B inhibitor (inhibition of DA metabolism) -Increased DA -Metabolism to amphetamine -Antidepressant effects Similar to pramipexole PD: in combination with dopa or as initial monotherapy (modest benefits) Use limited due to side effects Use limited due to side effects: incidence of cardiac valve regurgitation SEs: -Nausea -Edema -Hypotension -Pathologic gambling/other compulsions -Somnolence (drowsiness) Treatment of SEs: -Daytime sleep attacks (modafinil) -Peripheral DA effects (trimethobenzamide, domperidone) Same as pramipexole Same as pramipexole, PLUS -Yawning -Hypersexuality Treatment of SEs: -Emesis/nausea (trimethobenzamide) Contraindications: ondansetron is contraindicated for treatment of nausea due to risk of severe hypotension Similar to pramipexole MAO-B specific: less peripheral MAO inhibition (less cheese effect) Transdermal Patch: convenience Rasagiline MAO-B inhibitor (inhibitor of DA metabolism) -Increased DA -Metabolism to amphetamine -Antidepressant effects -Neuroprotective (?) COMT inhibitor (given with L-dopa to increase its levels by blunting metabolism in periphery and brain) PD: clearly effective in treatment of early PD (monotherapy) or as adjunct in advanced PD Amantadine (Antiviral) Relevant MOA may be NMDA antagonism Antimuscarinics: Benztropine Trihexyphenidyl Procyclidine Biperiden Decreases action of ACh to offset neurochemical imbalance in striatum created by loss of DA PD: modest and transient benefits (may only last a few weeks); better for TREMOR PD: only useful for the following (NOT bradykinesia) -Early onset tremor -Rigidity -Drooling Entacapone PD: adjunt to Sinemet to reduce fluctuations and off time TREATMENT OF COMORBIDITIES: Depression: SSRIs Psychosis: clozapine or other atypicals Dementia: cholinesterase inhibitors SURGICAL INTERVENTIONS: DA cell replacement Ablations: not done anymore (irreversible) Deep Brain Stimulation: effective (esp. subthalamic nucleus) Use: o Patients refractory to medication o Patients with significant dyskinesia o Patients with significant clinical fluctuation o Patients with intact cognition Neurorestoration: local injections of trans-genes currently in trials ESSENTIAL TREMOR: Description: action/kinetic tremor (similar to cerebellar intention tremor) with uncertain pathology Treatment: Beta blockers Anti-Seizure drugs: primadone, topiramate DBS: refractory patients MAO-B specific: less peripheral MAO inhibition (less cheese effect) Other Effects: -Nausea -Orthostatic hypotension May increase risk of dyskinesia (increases action of L-dopa) No hepatotoxicity (unlike early COMT inhibitor tolcapone) Livedo reticularis: lace-like purple discoloration of skin Psyhosis: rare Prominent side effects: may limit use -CNS: impaired memory, drowsiness, confusion and delusions -PNS: dry mouth, blurred vision, urinary retention, tachycardia ALZHEIMER’S DRUGS Drug Donepezil MOA Reversible ChE inhibitor Pharmacokinetics Long Half-Life: once-daily dosing (convenient) Metabolism: hepatic (CYP2D6/3A4)- DDIs Use AD: mild, moderate, severe Mild cognitive impairment PD with dementia Lewy body dementia Vascular dementia Rivastigmine Reversible, non-competitive ChE inhibitor Galantamine Reversible, competitive ChE inhibitor -Also binds allosterically to nACh R AD: mild to moderate PD with dementia Lewy body dementia AD: mild to moderate Vascular dementia Memantine Uncompetitive NMDA receptor antagonist -Binds R once it has bound Glu -Blockade of the most active NMDA R that pass Ca++, possibly leading to excitotoxicity Shorter Half-Life: BID dosing Metabolism: ChE hydrolysis (no DDIs) Transdermal patch available: good absorption Shorter Half-Life: BID dosing -Now an ER formulation as well Metabolism: hepatic (CYP2D6/3A4)- DDIs Excretion: some also secreted unchanged Shorter Half-Life: BID dosing Excretion: unchanged in the urine AD: moderate to severe Vascular dementia Aggression/agitation: try before use of APDs (black box warning) Side Effects Occur esp. during dose escalation; decrease over time: -N/V/D -Muscle cramps -Bradycardia -Urinary incontinence Same as donepezil Same as donepezil Well tolerated: -Headaches -Dizziness -Confusion Efficacy: similar to ChE inhibitors NEW THERAPIES: Anti-Amyloid Therapy: has decrease plaque formation but so far, no effect on disease process Increasing Aβ Clearance: active or passive immunization Decreasing Aβ Generation: o Inhibition of BACE1 o Inhibition of γ-Secretase Semagegecestat (did not slow disease progression; increased risk of skin cancer) Targeting GSAP (new hope for therapeutics directed toward this target) Disruption of Amyloid Aggregation: o Arenflurbril and Tramiprosate o PTB2 (modulator of copper and zinc) Anti-Tau/Tangles Therapy: not targeted as often as amyloid AL-108 (NAP): derived from neuroprotective protein (reduces tangles and plaques in animal models) Methylthioninium Chloride (Methylene Blue): disrupts tau-tau binding (tau mediated tangle formation); showed some benefit in cognition in trials Lithium and Valproic Acid: both inhibit GSK03 (may be involved in tau hyperphosphorylation) ANTIDEPRESSANTS: Drug Class TCAs: Imipramine (5HT and NE) Desipramine (NE) Chlorimipramine (5HT) SSRIs: Fluoxetine Sertraline Paroxetine Citalopram Vilazodone (SSRI + 5HT1A agonist activity) SNRIs: Venlafaxine Desvenlafaxine Duloxetine Milnacipran MAOIs: Phenelzine Tranylcypromine Selegiline (MAO-B) Moclobemide (MAO-A) MOA Regulated serotonergic and noadrenergic neurotransmission by inhibiting re-uptake of these monoamines Selective inhibition of 5HT reuptake Inhibition of both 5HT and NE reuptake Inhibition of the enzyme monoamine oxidase (MAO-A and/or MAO-B) leading to an increase in monoamine packaging and release (5HT, NE, DA) Therapeutic Considerations Delayed therapeutic effects: 2-4 weeks (although increase in monoamines is immediate) -Suggests need to develop secondary adaptive responses to Tx -Reflects persistence of memory Response varies: not everyone will respond to a given TCA Pharmacokinetics Absorption: generally well absorbed orally Distribution: bind to plasma proteins (DDIs) and accumulate in tissue (lipophilic) Metabolism: hepatic (CYPs- DDIs) -Some production of active metabolites Most widely used antidepressants Delayed therapeutic effects: 2-4 weeks (although increase in monoamines is immediate) -Suggests need to develop secondary adaptive responses to Tx -Reflects persistence of memory Response varies: not everyone will respond to a given SSRI Augment w/ Atypical APD: may modestly augment efficacy, but also increases adverse effects Same as SSRIs Absorption: generally well absorbed orally Distribution: variable plasma protein binding and half-lives (hours-days) Metabolism: multiple hepatic enzymes -Some active metabolites (ie. norfluoxetine) Non-Specific MAOIs: irreversibly inhibit both MAO-A and MAO-B MAO-A: found in 5HT, NE and DA neurons MAO-B: found mostly in 5HT neurons MAO-B Specific: Selegiline (irreversible inhibitor for use in PD) DDIs: potential DDIs with uptake inhibitors MAO-A Specific: Moclobemide (reversible inhibitor- not in US) Other: Burpropion Mirtazapine Nefazodone Trazodone Precise MOA as it is related to depression is unknown Use: based upon relief of specific side effects -Example: Trazodone given to help with insomnia (sedative properties) Low Safety: ODs potentially life threatening due to cardiac toxicity -Conduction delays -Arrhythmias Same as SSRIs Side Effects Limit use: -Antimuscarinic: dry mouth, constipation, blurred vision -Anti-alpha1: orthostatic hypotension Other: -Weight gain -Sedation -Sexual dysfunction -Induction of mania in patients with undiagnosed BPD Much less prominent than with TCAs: -Jitteriness -Insomnia -N/V/D -Headache -Dizziness -Fatigue -Sexual dysfunction Use in pregnancy: relatively low risk Same as SSRIs Non-Specific: loss of ability to metabolize tyramine, possibly leading to hypertensive crisis MAO-B Specific: less in the periphery and therefore cheese effect less likely MAO-A: cheese effect less likely due to reversibility -Increase in NE results in outcompeting for MAO-A (levels never get too high) MOOD STABILIZERS: Drug Lithium Proposed MOA Inhibition of phosphoinositol signaling: prevents recycling of inositol phospholipids, preventing formation of PIP2 Inhibition of GSK-3: inhibition of WNT signaling Pharmacokinetics Safety: low TI (monitor plasma levels) Absorption: well absorbed orally Elimination: by the kidney -[Li] affected by changes in Na clearance (ie. diuretics) Use Acute mania: in combo with antipsychotic or benzodiazepine Maintenance: monotherapy is effective, but often combine with valproic acid or carbamazepine *Protective against suicide* Better choice for use in pregnancy Anticonvulsants: Valproic Acid Carbamazepine Lamotrigine (Topiramate, Gabapentin) Inhibition of inositol signaling: VA inhibits an enzyme involved in metabolism of inositol phospholipids Inhibition of GSK-3: VA inhibits WNT signaling VA/Carbamazepine: -Neither approved for maintenance treatment, but extensively used -Not protective against suicide Side Effects At Therapeutic Doses: -N/V/D -Daytime drowsiness -Polyuria/polydipsia -Weight gain -Fine tremor -Acne Toxicity: only Tx is supportive -N/V/D -Mental confusion -Tremor and ataxia -Convulsions -Coma VA/Carbamazepine: use during pregnancy is discouraged (Li preferred agent) Lamotrigine: only approved for maintenance Atypical Antipsychotics: Quetiapine Olanzapine Risperidone Aripiprazole Ziprasidone PANIC DISORDER: SSRIs: Fluoxetine Sertraline Paroxetine Fluvoxamine SNRIs: Velafaxine TCAs/MAOIs: second line Benzodiazepines: provide rapid relief, but not for long-term management OCD: TCA: chlorimipramine (slightly superior to SSRIs) SSRIs/SNRIs: same as panic disorder MAOIs Note: NE uptake inhibitors NOT effective in OCD treatment Topiramate/Gabapentin: have not yet been proven effective Use: effective for management of acute episodes AND possibly maintenance Side effects limit use DRUGS FOR MIGRAINE: Non-Severe (no N/V): NSAIDs Severe (N/V): Triptans: mainstay of Tx (very effective); best when given early (prevent inflammatory process from starting) and in combo with NSAID o Sumatriptan o Frovatriptan (longer acting) Dihydroergotamine: more SEs and less efficacy Prevention: Beta blockers Antiepileptic drugs: o Valproate o Topiramate TCAs: amitriptiline Non-Drug Therapy: behavioral therapy (relaxation, EMG biofeedback, cognitive therapy) Future: CGRP Receptor Antagonist: block vasodilation/extravasation