Pharmacology Review Sheets: Neuro Drugs, p.

1
Antidepressants
General comments: - All drugs involve phosphorylation in their mechanism of action (resulting in changes in release, cytoskeleton, gene expression) thus clinical improvement may take several weeks - All drugs have immediate pharmacological actions

Class
Tricyclic antidepressants (TCAs)

Drugs in that Class

Tertiary amines: - Imipramine - Amitryptiline Secondary amines: - Desimipramine - Nortryptiline

Mechs of Action/Effects
Block norepinephrine uptake Antimuscarinic (see side effects) Antihistaminergic (see side effects) -adrenergic blocker (see side-effects) Sedation (amitryptiline has the most) - Effect from antimusc. and antihist. Note: Do not elevate mood

Pharmacokinetics/Uses
Distribution: Large Vd (15-20L/kg) - Highly protein-bound Duration of action: Long t - Imipramine (3 amine): 12 hrs - Nortryptiline (2 amine): 31 hrs Metabolism: Many active metabolites, also w/long t Uses: - Depression - Panic disorder - Enuresis (bedwetting) - Chronic pain (mechanism unknown)

Adverse Effects/Toxicities/Drug Interactions

Adverse effects: Dry mouth, blurred vision, urinary retention, constipation Sedation Orthostatic hypotension Weight gain Excessive sweating Sexual dysfunction Acute toxicity: Can lead to death; give small prescriptions! Cardiac conduction defects: m/c cause of death from this Coma with shock, metabolic acidosis (can also cause death) Respiratory depression (can also cause death) Agitation/delirium Neuromuscular irritability/seizures Hyperpyrexia/hypothermia Bowel and bladder paralysizs Drug Interactions: Additive with alcohol and other sedatives Antagonizes guanethidine (uptake blockade) Reversal of methyldopa, clonidine activity Phenytoin, aspirin, etc. can displace TCAs from binding sites Antipsychotics, methylphenidate, steroids inhibit metabolism Adverse effects: Nausea, anorexia, imsomnia Sexual dysfunction Weight loss Seizures (fluoxetine only) due to seizure threshold Acute toxicity: < than TCAs or MAOIs Drug Interactions: MAOIs: Serotonin syndrome - tremor, hyperthermia, CV collapse. (Obviously) life-threatening - Wait 2 wks after MAOI use before starting SSRIs Fluoxetine inhibits cytP-450 (CYP2D6) Adverse effects: Seizures NO hypotension/cardiac toxicities (not antimuscarinic) Drug Interactions: Carbamazepine metabolism Adverse effects: sedation, mild orthostatic hypotension, impotence

Serotonin-selective Fluoxetine (Prozac) reuptake inhibitors Sertraline (SSRIs)

Selectively block reuptake of 5-HT - Results in 5-HT release, but 5-HT output overall

Atypical antidepressants

Bupropion (Welbutrin, Zyban)

Inhibits dopamine and norepinephrine reuptake (better at blocking dopamine) Reduces nicotine craving Not antimuscarinic or sedating Blocks serotonin reuptake (5HT2A and 5HT2C receptors) 2-adrenergic antagonist

Distribution: Vd >> that of the TCAs - Fluoxetine 35 L/kg; sertraline 76 L/kg - Highly protein bound - Fluoxetine 94%; sertraline 99% Duration of action: Long t - Fluoxetine 76 hrs; sertraline 23 hrs Uses: - Depression - Obsessive-compulsive disorder (OCD) - Panic disorder (more often than TCAs) - Bulemia - Not used for enuresis or pain Duration: t = 11-14 hrs

Nefazodone Mirtazapine

Duration: t= 20-40 hrs

Adverse effects: Sedation, mild orthostatic hypotension

Pharmacology Review Sheets: Neuro Drugs, p.2

Antidepressants, continued Class Drugs in that Class Mechs of Action/Effects/Uses Pharmacokinetics/Uses Adverse Effects/Toxicities/Drug Interactions
Adverse effects: Seen before benefits; severely limits use Tyramine hypersensitivity (aged cheese, Chianti wine, pickled herring, sardines) results in acute severe HTN, headache, agitation. Orthostatic hypotension Atropine-like effects (dry mouth, blurred vision, etc.) Tremors, insomnia, convulsions due to excess CNS stimulation (contraindicated in epileptics) Hepatotoxicity (hydrazine): 1:10,000 Drug Interactions: Serotonin syndrome with SSRIs Meperidine (Demerol) MAOIs potentiate depressant effects of all narcotics and may result in death! OTC nasal drugs too. Adverse effects: Nausea, vomiting, diarrhea Tremor (especially in hands) Renal: Polyuria from inhibition of ADH action; Na+ retention due to increased aldosterone secretion. Pt. feels bone dry Thyroid enlargement; intereference with iodination of tyrosine Edema Acute toxicity: Confusion, convulsions, arrhythmias Drug interactions: Diuretics plasma concentration Monoamine oxidase Hydrazines: Inhibits monoamine oxidase (MAO) (Not discussed) inhibitors (MAOIs) - Phenelzine - MAO-A has preference for serotonin - Iproniazid and is located peripherally Proparylamines: - MAO-B has perference of dopamine - Pargyline (suicide inhibitor) and is located in the CNS - Selegiline (MAO-B select.) - Result: in 5-HT, NE, DA in Cyclopropylamines: CNS and periphery - Tranylcypromine (suicide) Except for meclobemide and selegiline, Reversible inhibitors: MAOIs are irreversible and nonselective - Meclobemide (MAO-A sel.) for MAO-A and MAO-B Elevate mood

Lithium

Lithium

Interferes with monoaminergic transmitter release Decreases IP3 formation by blocking recycling of IP (inhibits myoinositol phosphatase). Important acute effect. Replaces Na+ in action potentials

Duration: t = 20 hrs Excretion: Renal Note: Narrow therapeutic window (0.5-1.25 mEq/L) Uses: Drug of choice for the manic phase of bipolar disorder

Alcohol
Blood alcohol concentration 10 mg% (0.010%) 50 mg% (0.050%) 100-150 mg% (0.1%-0.15%) 200 mg% (0.2%) 300 mg% (0.3%) 400 mg% (0.4%) 500 mg% (0.5%) Effects Subtle differences in visual acuity Motor/mental impairment Legal standard for prima facie intoxication (Breathalyzer) Mild/moderate intoxication Marked intoxication (> 300 mg% = medical and legal definition of drunk) Deaths can occur here (due to respiratory depression) Lethal dose for most individuals Fetal Alcohol Syndrome Miscarriage, stillbirth Low birth weight, slow postnatal growth Birth defects: Microcephaly, mental retardation, etc.

Pharamacodynamics of alcohol CNS: Depressant (slows EEG), slows heart rate, mild analgesic. Respiratory/vasomotor depression at > 400 mg% CV: Vasodilation GI: Gastric acid release Renal: Diuresis (due to ADH) Pharmacokinetics of alcohol Absorption/Distribution: Lipid soluble; absorbed through oral/GI mucosa and widely distributed

Metabolism Excretion Primary pathway: Alcohol dehydrogenase/aldehyde dehydrogenase (elimination by zero-order kinetics) Zero-order kinetics the average person eliminates 0.018%/hr Secondary pathway: Mixed ethanol oxidizing system (MEOS). Stimulatable! Widmarks equation (for calculating BAC) Note: MEOS is responsible for metabolizing other drugs. = (Amt EtOH ingested in oz /body weight in oz) (100/r), where r = 0.55 (female), 0.68 (male) on average - When a person has recently drank drugs metabolize more slowly - 10-12 hrs after drinking, drugs will metabolize faster

Pharmacology Review Sheets: Neuro Drugs, p.3

Psychomotor Stimulants
Biogenic amine actions in the CNS Dopamine: Involved with reward systems (frontal cortex, mesolimbic regions), motor systems, attention span (orbitofrontal cortex) Norepinephrine: Sympathetic activation in the hypothalamus, euphoria (frontal cortex) Serotonin: Sleep-wake cycles, appetite (hypothalamus), behavior, euphoria (frontal cortex)

Class

Drugs in that Class

Nicotine

Mechs of Action/Effects/Uses
Mechanism: Stimulates nicotinic ACh receptor Effects: Cortical activation: Arousal, euphoria, relaxation; improves attention Mechanism: Blocks adenosine receptors (phosphodiesterase, PDE, at higher doses) Mechanism: Blocks adenosine receptors (phosphodiesterase, PDE, at higher doses) Mechanism: Blocks adenosine receptors (phosphodiesterase, PDE, at higher doses) Mechanism: DA in synaptic cleft Competitively inhibits DA/NE transp. Ca2+-independent release of NE Competitive inhibition of MAO Mechanism: DA in synaptic cleft Competitively inhibits DA/NE transp. Ca2+-independent release of NE Competitive inhibition of MAO Uses: Ritalin/Cylert: ADHD Action: Blocks Na+-activated ATPase, and thus reuptake of NE into the adrenergic nerve terminal; NE stays around longer, causing sympathetic stimulation Effects: CNS: Stimulation; body temp. by effects on hypothalamus (pyrogenic) Local anesthetic: best available in terms of absorption through membranes and numbing effects. Not used clinically! Cardiovascular: Vasoconstriction

Pharmacokinetics
Absorption: Well-absorbed (oral mucosa, GI tract) Distribution: Lipid-soluble; gets in breast milk, lungs Metabolism: Liver, lung Excretion: Renal

Adverse Effects/Toxicities/Drug Interactions

Highly addictive Cigarette smoke adds health hazards Irritability, tremors Withdrawal anxiety, nervousness, lethargy, fatigue, etc.

Methylxanthines

Caffeine Theophylline

Absorption: Well absorbed Distribution: Tissues, crosses placenta Metabolism: Liver

Narrow therapeutic window CNS: Seizures, insomnia, motor impairment, tremors Cardiac arrhythmias

Theobromine Amphetamines Dextramphetamine

Methylphenidate (Ritalin) Pemoline (Cylert)

Admin/Absorption: Oral; well-absorbed in GI Metabolism: Liver Excretion: Renal Duration of action: t (Ritalin) < t (Cylert) Admin/Absorption: Oral; well-absorbed in GI Metabolism: Liver Excretion: Renal Duration of action: t (Ritalin) < t (Cylert)

Highly addictive/abused; amphetamine psychosis w/chronic use Tolerance with chronic use Drug interactions: MAO inhibitors, drugs affecting DA/NE appetite Insomnia GI upset Headaches Drug interactions: MAO inhibitors, drugs affecting DA/NE Potentiates adrenergic agonists Tonic-clonic seizures (high doses) Cardiac arrhythmias Respiratory depression (high doses) If taken with alcohol metabolites conjugate to form cocaethylene, a very toxic psychoactive compound with a long t .

Cocaine

Anorexiants

Sibutramine

Action: Blocks 5HT and NE reuptake Absorption: GI Use: Obesity (recently approved by FDA) Distribution: Placenta (but minimal) Metabolism: Liver Excretion: Renal

Increased blood pressure Headaches Insomnia Constipation Dry mouth Contraindicated with anorexia, MAO inhibitors, CV/renal disease, pregnancy, lactation

Dexfenfluramine

Action: Releases 5-HT & inhibits reuptake

Fenfluramine Phentermine

Action: Releases 5-HT & inhibits reuptake Action: Inhibits NE reuptake Inhibits 5-HT clearance in lung

Fen/Phen (now illegal) because of inhibition of 5-HT clearance in lung

Pharmacology Review Sheets: Neuro Drugs, p.4

Antipsychotic Drugs (Neuroleptics)
General Characteristics/Effects Reduces hallucinations, delusions, fear/panic, aggressive behavior Produces an indifference to surroundings w/out stupor or ataxia Takes time for drug to work (weeks); treatment is palliative, not curative Typical neuroleptics treat mainly positive symptoms (delusions, hallucinations); atypical neuroleptics can help with negative symptoms (emotional bluting, cognitive deficits) which affect the patients function Clinical Uses Schizophrenia Acute psychotic disorders Drug (amphetamine, LSD)-induced psychoses Tourettes syndrome (tics, curses) Anesthetic adjunct Antiemetic Antipruritic Intractable hiccups Initial Rx for bipolar disorder (remember, lithium is drug of choice!)

Pharmacokinetics Absorption/Distribution: Lipid soluble; well-absorbed in GI tract. Distributes to CNS; large volume of distribution Metabolism: Extensive 1st pass metabolism, to active metabolites!

Class

Drugs in that Class

Mechanism of action

Typical neuroleptics Chlorpromazine (Thorazine)

Low D2 blockade High 1, H1, M1 blockade

Drug-specific Adverse Effects

1-receptor blockade: postural hypotension, impotence, failure to ejaculate (> than haloperidol) Muscarinic receptor blockade: dry mouth, constipation, urinary retention, visual problems (> than haloperidol) Histaminic receptor blockade: Sedation, weight gain (> than haloperidol) DA prolactin gynecomastia, infertility, galactorrhea-amenorrhea syndrome Extrapyramidal side-effects (< than haloperidol) Cardiac arrhythmias Extrapyramidal side-effects (> than chlorpromazine) - Dystonias spastic reactions (1 week) - Akathesias (restlessness) (3 weeks) - Parkinson-like symptoms (tremors, rigidity, etc).(1-2 months) - Tardive dyskinesia (irreversible!) (12-16 months) Neuroleptic malignant syndrome: severe musuclar rigidity, body temp, impaired sweating. Seen more in patients experiencing Parkinsons symptoms. DA prolactin gynecomastia, infertility, galactorrhea-amenorrhea syndrome 1-receptor blockade: postural hypotension, impotence, failure to ejaculate (< than chlorpromazine) Muscarinic receptor blockade: dry mouth, constipation, urinary retention, visual problems (< than chlorpromazine) Histaminic receptor blockade: Sedation, weight gain (< than chlorpromazine) Extrapyramidal side-effects: < than typicals No increase in prolactin 1, histaminic, muscarinic blockade Agranulocytosis Seizures Extrapyramidal side-effects: < than typicals 1, histaminic, muscarinic blockade low to moderate side-effects

Haloperidol (Haldol)

High D2 blockade Low 1, H1, M1 blockade

Atypical neuroleptics Clozapine (Clozaril)

Very low D2 blockade High 1, H1, M1 blockade D1, D3, D4 blockade 5-HT2 blockade Very low D2 blockade Low 1, H1, M1 blockade 5-HT2 blockade

Risperidone (Risperidal)

Pharmacology Review Sheets: Neuro Drugs, p.5

Drugs affecting the Basal Ganglia (Drugs for Parkinson Disease) Drug
Atropine Levodopa

Mechs of Action/Effects
Anticholinergic (helps with tremor, but not bradykinesia) Crosses BBB, then converted to dopamine in the CNS

Drug-specific Uses

Pharmacokinetics
Metabolism: Extensively by: - Aromatic amino acid decarboxylase (AADC) - Catechol-O-methyltransferase (COMT) - Monoamine oxidase (MAO)

Adverse Effects
High levels of drug required lead to nausea, vomiting, postural hypotension, CV effects Effects as disease progresses (wearing-off phenomenon) (this takes about 3-5 years) Liver toxicity

Carbidopa Tolcapone

AADC inhibitor peripherally COMT inhibitor peripherally

Combo w/Levodopa (Sinemet) Can be combined w/Sinemet; useful in stopping wearingoff phenomenon

Bromocriptine Pergolide Pramipexole Ropinirole Selegiline (Eldepryl) Amantadine Baclofen

Non-specific D1, D2 agonist (ergot alk.) D2-specific agonist (ergot alkaloid) D2-specific agonist (non-ergot) D2-specific agonist (non-ergot) MAO-B selective inhibitor (CNS) Neuroprotective!! synthesis, release, re-uptake of DA Acts at GABA receptors in CNS Used in young patients to delay use of dopa (neuroprotective) Also an antiviral drug

Bromocriptine: D1-related side effects Ergot alkaloids: Autonomic side effects All dopamine agonists: Only effective for about 1 year of Rx

Restlesslessness, agitation; psychosis with high doses Orthostatic hypotension, urinary retention, dry mouth

Antianxiety drugs/Sleep drugs Class

Benzodiazepines

Mechanism of action/Effects

Drugs in that Class

Duration
Long-acting

Uses

Adverse Effects

Binds to benzodiazepine receptor adjacent Chlordiazepoxide (Librium) to the GABAA receptor, increasing the frequency of opening of the Cl channel Suppression of stage 4 sleep Diazepam (Valium) No effect on REM sleep/no rebound effect No induction of CYP-450 (cp. barbitur.) Lower potential for addiction, cp. barbiturates Flurazepam (Dalmane) Alprazolam (Xanax)

Long-acting

Long-acting Intermediate-acting

Temazepam (Restoril) Lorazepam (Ativan) Triazolam (Halcion)

Intermediate-acting Intermediate-acting Very short-acting

Anti-anxiety (but not OCD) Sedation Insomnia Muscular disorders Anti-anxiety (but not OCD) Sedation Insomnia, sleep terrors Anticonvulsant (drug of choice for status epilepticus) Muscular disorders Insomnia Sedation; metabolites are active; may cause falls as a result Anti-anxiety (but not OCD) Panic disorders Insomnia Insomnia Insomnia Insomnia Bizarre behavior (behavioral problems) Rebound insomnia (more trouble falling asleep afterwards) Anterograde amnesia (blocks process of recent learning)

Oxazepam Midazolam Flunitrazepam (Rohypnol) (Non-benzodiazepine) Binds to Benzodiazepine-1 receptor No effect on Stage 4/rebound insomnia Azapirones Blocks 5-HT1A receptor No muscle-relaxant properties Slow onset of action Zolpidem (Ambien) Buspirone (BuSpar)

Short-acting Short-acting Short-acting Short-acting

Insomnia Insomnia Insomnia Anti-anxiety (but not OCD or panic disorders)

Date-rape drug formulation now changes color w/EtOH

Minimal sedation

Benzodiazepine Antagonists

Flumazenil

Short (1 hr)

Rapid antagonism of benzodiazepine effects

Pharmacology Review Sheets: Neuro Drugs, p.6

Antianxiety drugs/Sleep drugs, continued Class
Barbiturates

Mechanism of action/Effects

Drugs in that Class

Duration
Longer-acting than pentobarbital Rapid onset/offset

Uses
Insomnia Insomnia Anticonvulsant Anesthetic (IV) Insomnia Sedation in pediatrics Mild/moderate insomnia Narcolepsy

Adverse Effects (in general)

Addiction potential Tolerance develops over time ( metabolism, cellular adaptation) - Induction of CYP-450! Rebound effect one must make up REM sleep after use Contraindicated in patients with porphyrias GI upset Synergism with alcohol (Mickey Finn)

Binds to GABAA receptor and increasing Pentobarbital duration of opening of the Cl channel Phenobarbital General depressants no antidote (only supportive care) Thiopental Suppression of REM sleep Reduced to trichloroethanol (active ingredient) (More later) Stimulates hypothalamus dopamine in synaptic cleft dopamine in synaptic cleft Eliminate REM sleep Chloral hydrate Diphenhydramine Modafinil (Provigil) Amphetamines Methylphenidate (Ritalin) Phenelzine Imipramine

Sedative-hypnotics Antihistamines CNS stimulants

MAO inhibitors

Narcolepsy Cataplexy assoc. w/narcolepsy

TCA antidepressants Block NE reuptake

Anticonvulsants Drug
Phenytoin

Mechs of Action/Effects

Inhibits voltage-gated Na+ channel

Uses

Focal seizures Tonic-clonic seizures

Pharmacokinetics
Admin/Absorption: Oral, variable absorption Distribution: > 90% protein-bound (displaceable) Metabolism: Not first order, but hydroxylated to inactive metabolite

Adverse Effects

CNS: Nystagmus, diplopia, ataxia, sedation/seizures (high dose) GI: Nausea, vomiting Endocrine: Increased metabolism of Vitamin D, interference of Ca2+ absorption (can lead to osteomalacia) Altered tissue growth: Hirsutism, thickened facial features, gingival hyperplasia Megaloblastic anemia (due to increase of folate metabolism) Skin allergy (possible Stevens-Johnson reaction) Teratogen (cleft palate) Inducer of CYP-450 CNS: Diplopia, ataxia, sedation (less serious than phenytoin) Aplastic anemia, other blood dyscrasias (rare) CNS: Drowsiness, lethargy at high doses GI: Nausea, vomiting, epigastric pain Hiccups

Carbamazepine Ethosuximide

Inhibits voltage-gated Na+ channel Inhibits T-type Ca2+ channel

Focal seizures Absence seizures (drug of choice) Absence seizures (Some tonic-clonic seizures)

Metabolism: Epoxide metabolite is active

Valproic acid

Blocks T-type Ca2+ channel GABA/ glutamate transmission Non-sedating

Metabolism: Hydroxylation (metabolite is active)

Hepatotoxicity (especially in kids) Teratogenic (associated with spina bifida) Affects clearance of phenytoin, carbamazepine, ethosuximide Narrow therapeutic window Sedation, ataxia

Phenobarbital

Binds to GABAA receptor and increasing Tonic-clonic seizures duration of opening of the Cl channel

 Inducer of CYP450 Contraindicated with porphyrias Diazepam Binds to benzodiazepine receptor adjacent to the GABAA receptor, increasing the frequency of opening of the Cl channel Binds to benzodiazepine receptor adjacent to the GABAA receptor, increasing the frequency of opening of the Cl channel Inhibits GABA transaminase ( GABA) Inhibits voltage-gated Na+ channel Enhances GABA transmission Antagonizes glutamate transmission Status epilepticus (drug of choice) Status epilepticus Tolerance can develop Narrow therapeutic window

Clonazepam

Vigabatrin Lomotrigine Felbamate

Absence seizures Partial & generalized seizures Generalized seizures in pts. with severe mental retardation (Lenox-Gestalt Syndrome)

Severe skin allergy (not used in kids less than 16) Hepatotoxicity Aplastic anemia

Pharmacology Review Sheets: Neuro Drugs, p.7

Antihistamines Type
1st generation Antihistamines (H1 blockade)

General mechs/General effects

Competitive, reversible inhibition of the H1 receptor Muscarinic cholinergic blockade -adrenergic blockade 5-HT receptor blockade Local anesthetic

Drugs
Diphenhydramine (Benadryl)

Duration

Uses
Anti-motion sickness Antitussive OTC sleep aid Anti-motion sickness Anti-motion sickness OTC cold remedy Anti-emetic Allergic rhinitis/urticaria Allergic rhinitis/urticaria Allergic rhinitis/urticaria

Adverse Effects (in general)

Sedation Antimuscarinic effects: dry mouth, blurry vision, constipation Convulsions (esp. in kids) Excitation (elderly) Sundown condition Postural hypotension (-blockade) Drug allergy (topical use)

Dimenhydrinate (Dramamine) Meclizine (Antivert) Long (12-24 h) Chlorpheniramine (ChlorTrimeton) Promethazine (Phenergan) Citeridine (Zyrtec) Loratidine (Claritin) Fexofenadine (Allegra) Cimetidine (Tagamet)

2nd generation Antihistamines (H1 blockade) H2 - specific Antagonists

More selective H1-receptor blockade No anesthetic effects Longer acting Block gastric acid secretion by blocking histamine, gastrin, vagal stimulation, Cholinomimetics

Minimal sedation No anticholinergic effects No antisertoninergic effects CV: QT prolongaion, arrhythmias

Ranitidine (Zantac)

Famotidine (Pepcid)

Nizatidine (Axid)

Peptic duodenal, gastric ulcers CNS: delirium, confusion (elderly); dizziness, headache Zollinger-Ellison syndrome, Anti-androgenic effects: gynecomastia, galactorrhea, impotence Erosive esophagitis Blood dyscrasias Inhibits CYP-450 GI: Hepatotoxicity, diarrhea Skin: Rash Peptic duodenal, gastric ulcers CNS: Diziness, headache Zollinger-Ellison syndrome GI: Hepatotoxicity, diarrhea Erosive esophagitis Skin: rash Peptic duodenal, gastric ulcers CNS: Diziness, headache Zollinger-Ellison syndrome GI: Hepatotoxicity, diarrhea Erosive esophagitis Skin: rash Peptic duodenal, gastric ulcers CNS: Diziness, headache Zollinger-Ellison syndrome GI: Hepatotoxicity, diarrhea Erosive esophagitis Skin: rash