Central Nervous System Pharmacology

Properties of benzodiazepines

Bind to gamma subunit of GABA(A) complex to increase frequecy of Cl

Benzodiazepine drugs

Alprazolam, diazepam, lorazepam, midazolam, temazepam, oxazepam

Uses of alprazolam

Anxiety, phobias, panic attacks

Uses of diazepam

Anxiety, preop sedation, muscle relaxation, withdrawal states

Uses of lorazepam

Anxiety, preop sedation, status epilepticus

Uses of midazolam

Preop sedation and anesthesia, anterograde amnesia

Uses of temazepam

Sleep disorders

Uses of oxazepam

Sleep disorder and anxiety

Pharmacokinetics of benzodiazepines

Liver metabolized to active compounds except oxazepam, temazepam, lorazepam; t1/2: diazepam \> lorazepam \> alprazolam \> temazepam \> oxazepam \> midazolam

Uses of barbiturates

Phenobarbital for seizures; thiopental for induction of anesthesia

Properties of barbiturates

Prolong GABA activity; increase duration of Cl

Pharmacokinetics of barbiturates

General inducers of P450; contraindicated in porphyrias

Withdrawal signs of benzodiazepines

Rebound insomnia, anxiety, seizures

Withdrawal signs of barbiturates and ethanol

Anxiety, agitation, life threatening seizures

Drug interactions of GABAa drugs

Life threatening respiratory depression if used with other CNS depressants (antihistaminics, opiates, beta blockers); Barbiturates induce metabolism of lipid

Flumazenil

Benzodiazepine receptor antagonist. Used as antidote for benzodiazepine overdose.

Zolpidem

BZ1 receptor agonist used in sleep disorders. No cognitive impairment (no BZ2 actions), overdose reversed by flumazenil, less tolerance and abuse liability

Buspirone

No effect on GABA, 5

Effects of alcohols

GABA mimetic activity causes CNS depression; metabolic acidosis; fetal alcohol syndrome

Metabolism of ethylene glycol

Ethylene glycol + alcohol DH

Effects of ethylene glycol

CNS depression, severe metabolic acidosis, nephrotoxicity

Metabolism of methanol

Methanol + alcohol DH

Effects of methanol

Respiratory failure, severe anion gap metabolic acidosis, ocular damage

Treatment of alcohol overdose

Fomepizole (alcohol DH inhibitor) and hemodialisis

Metabolism of ethanol

Ethanol + alcohol DH

Effects of ethanol

CNS depression, metabolic acidosis, acetaldehyde toxicity

Acetyldehyde toxicity

Nausea, vomit, headache, hypotension, inactivates folate, decreases availability of thiamine

Drugs that cause disulfram

like effects

Anticonvulsant drugs

Phenytoin, carbamazepine, benzodiazepines, barbiturates, lamotrigine, topiramate, felbamate, ethosuximide, valproic acid

Drugs used for partial seizures

Valproic acid, phenytoin, carbamazepine

Drugs used for general tonic

clonic seizures

Drugs used for general absence seizures

Ethosuximide

Drugs used for status epilepticus

Lorazepam, diazepam, phenytoin

Phenytoin MOA

Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation

Pharmacokinetics of phenytoin

Variable absorption, nonlinear kinetics at low doses, zero

Phenytoin side effects

CNS depression, gingival hyperplasia, hirsutism, osteomalacia (decreases vitamin D), megaloblastic anemia (decreases folate), aplastic anemia, teratogenic (cleft lip and palate).

Carbamazepine MOA

Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation

Pharmacokinetics of carbamazepine

Induces P450

Carbamazepine side effects

CNS depression, osteomalacia, megaloblastic anemia, aplastic anemia, exfoliative dermatitis, increases ADH secretion (dilutional hyponatremia), teratogenic (cleft lip and palate, spina bifida)

Valproic acid MOA

Inhibits fast Na channels in axons which decreases conduction and prevents seizure propagation; Inhibits GABA transaminase; Blocks presynaptic Ca+ channels

Uses of valproic acid

Seizures, bipolar mania, migraines

Pharmacokinetics of valproic acid

Inhibits P450

Valproic acid side effects

Hepatotoxic metabolite, thrombocytopenia, pancreatitis, alopecia, spina bifida

Ethosuxamide MOA

Blocks presynaptic T

Lamotrigine MOA

Blocks Na+ channels and glutamate receptors. Side effect: Steven

Inhaled anesthetic drugs

Nitrous oxide, halothane

Properties of halothane

High potency (0.8% MAC), high blood

Side effects of halothane

Malignant hyperthermia, hepatitis, cardiac arrhythmias

What is MAC?

Minimal alveolar concentration is the amount of anesthetic at which 50% of patients don't respond to surgical stimulus. Analogous to ED50, measures potency, the more lipid soluble the lower the MAC, lower in elderly

What is the blood

gas ratio?

Intravenous anesthetic drugs

Midazolam, thiopental, propofol, fentanyl, ketamine

General anesthesia protocol

Includes sedation and anterograde amnesia (midazolam), induction (propofol), analgesia (fentanyl), muscle relaxant for intubation (succinylcholine) and may or may not include atropine in case of CV depression due to propofol

Naloxone

Antidote for opiods

Neostigmine

AChE inhibitor reverses non

What are the ester local anesthetics?

Procaine, cocaine, benzocaine. Metabolized by plasma esterases. All have only one "i"

What are the amide local anesthetics?

Lidocaine, bupivacaine, mepivacaine. Metabolized by liver amidases. All have two "i".

MOA of local anesthetics

Nonionized form crosses axonal membrane

Side effects of local anesthetics

Neurotoxicity, cardiovascular toxicity, allergies. Use alpha

Skeletal muscle relaxants MOA

Nicotinic antagonists (competitive, nondepolarizing); Nicotinic agonists (noncompetitive, depolarizing)

Non

depolarizing muscle relaxant drugs

Non

depolarizing muscle relaxant properties

Properties of succinylcholine

Depolarizing muscle relaxant, nicotinic agonist; Phase I: depolarization, fasciculation, flaccid paralysis; Phase II: desensitization. Caution in atypical pseudocholinesterase, hyperkalemia, malignant hyperthermia

Malignant hyperthermia

Succinylcholine side effect in genetically susceptible people. Muscle rigidity, hyperthermia, hypertension, acidosis, hyperkalemia. Rx.: dantrolene

Opiod analgesic drugs

Morphine, meperidine, methadone, codeine, fetanyl, heroin

Contraindications of opiod analgesics

Head injuries, pulmonary dysfunction, hepatic or renal dysfunction, adrenal or thyroid deficiencies, pregnancy

Effects of morphine

Analgesia, sedation, respiratory depression (decreased response to PCO2), miosis, cough supression, nausea, vomiting

Pharmacokinetics of morphine

Phase 2 metabolism by glucoronidation. Caution in renal dysfunction as morphine

Opiod toxicity

Pinpoint pupils, repiratory depression and coma. Rx. Naloxone

Meperidine

Opiod without miosis or spasms. Metabolized via P450 to normeperidine which can cause seizures

Methadone

Used for opiate withdrawal in addicts

Codeine

Cough suppressant, analgesia, use in combination with NSAIDs

Symptoms of opiod withdrawal

Yawning, lacrimation, rhinorrea, salivation, anxiety, muscle spasms and CNS

Drugs used in Parkinson disease

Levodopa, tolcapone, selegiline, bromocriptine, benztropine, amantadine

Levodopa

Crosses CNS barrier. Converted to dopamine in CNS and periphery, so use tolcapone, carbidopa and selegiline

Tolcapone

Inhibits COMT which blocks levodopa conversion to methyldopa which has no pharm actions

Carbidopa

Inhibits conversion of levodopa to dopamine in peripheral tissues, increasing CNS availability

Selegiline

MAOb selective inhibitor, adjunt to levodopa to decrease dopamine metabolism in CNS

Bromocriptine

Dopamine receptor agonist used in hyperprolactinemia, acromegaly

Benztropine

Muscarinic blocker used to decrease Ach activity in Parkinson. Decreases tremor and rigidity but not bradykinesia

Atypical antipsychotics

Clozapine, olanzapine, risperidone, aripiprazole

Atypical antipsychotic MOA

Inhibition of dopamine and 5HT2 receptors

Side effects of antipsychotic drugs

Extrapyramidal symptoms, akathisia, tardive dyskinesia, dysphoria, endocrine dysfunction, weight gain, hypotension, muscarinic blockade tachychardia

Specific side effects of thioridazine

Torsades, retinal deposits

Typical antipsychotics

Chlorpromazine, thioridazine, fluphenazine, haloperidol

Specific side effects of haloperidol

Neuroleptic malignant syndrome, tardive diskynesia

Specific side effects of clozapine

Agranylocytosis, seizures, salivation

MAO inhibitor drugs

phenelzine, tranylcypromine

Drug interaction of MAO inhibitors

Tyramine, TCAs, alpha

Tricyclic antidepressant drugs

Amitriptyline, imipramine, clomipramine

TCAs MOA

Nonspecific blockade of 5HT and NE reuptake

Side effects of TCAs

Muscarinic blockade, alpha blockade, serotonin syndrome, hypertensive crisis

SSRI drugs

Fluoxetine, sertraline, paroxetine

Side effects of SSRI

Anxiety, agitation, bruxism, sexual dysfunction, weight loss

Serotonin syndrome

Sweating, rigidity, myoclonus, hyperthermia. Interaction between MAOi, TCAs, SSRIs, meperidine, dextromethorphan

Drug

induced hypertensive crisis

Venlafaxine

Selective reuptake inhibitor of NE and 5HT. Can cause hypertensive crisis and serotonin syndrome

Bupropion

Dopamine reuptake blocker. Used in smoking cessation

Lithium MOA

Prevents recycling of inositol (decreases PIP2), decreases cAMP

Lithium side effects

Narrow therapeutic index requires monitoring, tremor, hypothyroidism (decreases TSH effects and inhibits 5'

Methylphenidate

Reuptake inhibitor and releaser of DA and NE. Side effects: agitation, restlessness, insomnia, CV toxicity. Treats ADHD.