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88 Cards in this Set

  • Front
  • Back
Goals for local anesthetic use
Minimize local irritation
Minimize systemic toxicity
Rapid onset: high conc needed (0.5-4%)
Sufficient duration
types of linkages for local anesthetics?
Amide-metabolized by liver via n-alkylation

Ester-hydrolyzed by plasma esterases to form PABA
Local anesthetic mechanism of action
Block Na channels from the cytoplasmic mouth

Stabilize inactivated state of channel
lidocaine and carbomazapene
Quaternary lidocaine and carbomazapene are ineffective from outside the neuron
Factors that influence effectiveness of local anesthetics
firing rate-fast
blood flow-epinephrine
drug size-smaller
pH-basic to be uncharged
What is the effect of inflammation on local anesthetics?
At more acidic pH (inflammation), more drug is charged and therefore less drug crosses nerve membranes, and therefore less nerve block.
Toxicity of local anesthetics: CNS
initially drowsiness and excitation (up to seizures), Followed by general depression, coma.
Toxicity of local anesthetics: Cardiac
especially bupivacaine)
depressed pacemaker activity
decreased conduction
potentiated by hyperkalemia.
Amides synergize with anti-arrhythmic drugs to induce arrhythmias
Toxicity of local anesthetics: Peripheral blood vessels
vasodilation leading to hypotension (except cocaine – hypertension caused by block of NE reuptake)
Toxicity of local anesthetics: Allergies
esters: PABA derivatives
amides: preservatives
Routes of administration
Topical (mucous membranes)
Infiltration (local)
Regional block
nerve block
The most widely used local anesthetic
Intermediate duration amide (~2 hr spinal anesthesia, 30-60 min for topical )
Higher systemic toxicity than ester-linked drugs
Metabolized by liver
Uses – spinal, epidural, local, topical anesthesia
careful: concurrent use with amiodarone
Short acting ester (40 sec plasma ½ life)
Low toxicity
Main use – infiltration and regional anesthesia
Interaction: PABA blocks sulfonamide action
Intermediate duration of action ester (slowly hydrolyzed; ~2 hr spinal anesthesia, 30-60 min for topical )
Higher systemic toxicity than other esters
Tends to cause mucous membrane irritation, urticaria, burning.
Main uses – spinal, & topical anesthesia of nose and throat for diagnostic procedures.
Widely used amide local anesthetic
Long duration amide (3-9 hr regional anesthesia, plasma ½ life 3.5 hr adult, >8 hr neonate)
Concurrent epidural use with opiates in labor can reduce the amount of opiate needed for analgesia
More cardiac and CNS effects than lidocaine due to slower dissociation from cardiac Na channels
Synergistic with anti-arrhythmics on heart- can induce arrythmias!
Desired duration of block
short (20-45 min):
medium (1-2 hr):
medium to long (3-9 hr):
procaine, benzocaine
tetracaine, BUPIVACAINE
Desired area of block
benzocaine, proparacaine
LIDOCAINE, procaine
tetracaine, BUPIVACAINE
What is a seizure?
A seizure results from uncontrolled, synchronous firing of large populations of cortical neurons
Incidence of epilepsy
high at 1st year of life and later in life
Risk Factors
penetrating head wounds
severe head trauma and stroke
not neonatal hypoxia
a significant genetic contribution
70% - currently available anticonvulsants
20% - surgery
10% - intractable
What causes partial seizures?
often caused by focal trauma or cortical malformation(acquired epilepsies)
What causes general seizures?
complex genetic disorder
Principles of pharmacotherapy for epilepsy
Be sure of the diagnosis
-Two unprovoked seizures
-One unprovoked seizure plus clear EEG
Drug treatment is symptomatic
Most anticonvulsants have low therapeutic index
Pharmacokinetics are important
Molecular targets of anticonvulsant drugs
Na channels-Carbamazepine
Ca2+ channels-Ethosuximide
GABAA receptors-Lorazepam
GABA transporters
GABA transaminase
P450 inducer (1/2 life shortens from 36 hr to 12 hr with chronic treatment)
common adverse reactions: diplopia, drowsiness, ataxia
Tegratol-XR sustained release form
used also for neuropathic pain, bipolar disorder
highly bound to plasma proteins
limited capacity for metabolism
1+2 cause “saturation kinetics”
Adverse effects:
gingival hyperplasia
coarsening of facial features
Drug of choice for absence epilepsy
t-type Ca channels not involved in transmitter release
no plasma protein binding
½ life 40-60 hrs with renal excretion
divalproex-Na is a sustained release form
adverse effects: reduced clotting, pancreatitis, weight gain, polycystic ovaries, hepatotoxicity (esp in children <2yr)
mixed mechanism: also blocks Na channels
also used for bipolar disorder, migraine
Status epilepticus
long-lasting (>20 min) seizure, or seizure cluster
cerebral injury; 15-20% mortality
some causes: non-compliance, withdrawal from EtOH or barbiturates
Treatment of Status epilepticus
initial treatment – i.v. lorazepam or diazepam
if not stopped, fosphenytoin
if not stopped, phenobarbital
if not stopped, midazolam or propafol
GABApentin (Neurontin):
levetiracetam (Keppra):
lamotrigine (Lamictal):
topiramate (Topomax):
oxcarbazepine (Trileptal):
tiagabine (Gabatril):
pregabalin (Lyrica):
Ca channel blocker
mech. unknown
Na channel blocker
Na channel block + GABA potenti.
Na channel blocker
GABA uptake blocker
son of Gabapentin
Antiepileptic Drug Interactions
Drugs that induce metabolism of other drugs: carbamazepine, phenytoin, phenobarbital

Drugs that inhibit metabolism of other drugs: valproate, felbamate

Drugs that are highly protein bound: valproate, phenytoin
defective alleles high in AA but 0 in asians
causes decrease clearance and increased toxicity
Pregnancy and Epilepsy
Most pregnancies in epileptic mothers produce normal children but higher rate of fetal abnormalities. Give folate to minimize NTD esp with valproate and carbamazepine. Swith to monotherapy if possible.
Vagal Nerve Stimulator
Intermittent programmed electrical stimulation of left vagus nerve (e.g., 30 sec. on, 5 min. off)
Option of patient-triggered stimulation (auras)
Adverse effects are local, related to stimulus (hoarseness, throat discomfort, dyspnea)
Mechanism unknown
Ketogenic diet
starvation reduces seizures--mainly used in peds. Possible due to anticonvulsant ketone or improved energy metabolism.
Block Na channels
carbamazepine, phenytoin
block Ca channels
potentiate GABAergic inhibition
tiagabine, lorazepam
topiramate, zonisamide
partial complex
carbamazepine, phenytoin, gabapentin, vigabatrin, topiramate, tiagabine
generalized tonic-clonic
phenytoin, valproate
ethosuximide, valproate (if t-c also present)
Theories of Depression
Lack of Amine Neurotransmitter
Serotonin, norepinephrine and dopamine.

Lack of Receptor Function.

Disturbed HPA Axis.
Classes of Drugs
Mechanisms of SSRIs
Blockade of SERT causes:
Stimulation of Receptors
Activation of Signaling Pathways
Altering Gene Expression (BDNF?)
Available FDA approved drugs for alzheimers
• Tacrine (Cognex)
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Reminyl, renamed Razadyne)
• Memantine (Nemenda)
Two major mechanisms of AD drugs
Cholinesterase inhibition and NMDA inhibition- with antagonist of moderate affinity
Two major drugs
Donepezil (aricept) and memantine (nemenda)
Evidence for Cholinergic hypothesis
The brain of AD patients have reduced cholinergic systems (low choline acetyltransferase in brains of AD pts)
What is the beta amyloid 42 aa precursor?
What is tau protein and what is its normal function?
Hyperphosphorylated tau proteins which form tangles causing cell death and brain shrinkage. Normally tau is a component of microtubules.
Side effects of anticholinesterase drugs?
Mainly GI- nausea, vomiting, diarrhea, anorexia
Why aricept instead of tacrine?
A healthy regimen for old age is:
A lot of light
Proper nutrition
Using the brain
Behavioral treatments are important
Dose-related progression of effects of anti-anxiety drugs
Behavioral disinhibition
Ataxia / nystagmus
Sleep (hypnosis)
Coma, respiratory depression,
cardiovascular depression
What is the difference in the dose response curves between barbs and benzos?
Barb-linear and can be used for anesthesia

Benzo-nonlinear and plateau at sleep
Benzodiazepine Mechanism of action
potentiate the action of the inhibitory neurotransmitter -aminobutyric acid (GABA) at the GABA-A receptor
bind to the benzodiazepine receptor and competitively block the effects of benzodiazepine agonists on GABA-mediated Cl- conductance and neuronal inhibition
Inverse agonists (e.g., beta-carboline carboxyethyl ester):
bind to the benzodiazepine receptor and reduce GABA-mediated Cl- conductance and neuronal inhibition, resulting in anxiety, muscle spasms, and a proconvulsant state
Two general classes of benzos
1. Short Acting-Tx sleep disorders in absence of anxiety; rapid onset and elimination
2. Long-acting-steady state in CNS to provide constant effects
Tolerance and Physical Dependence of benzos?
Pharmacodynamic tolerance to the anti-anxiety and hypnotic effects develops with chronic use.

Chronic use of benzodiazepines leads to physical dependence

Abrupt withdrawal of short-acting benzo lead to severe withdrawal

Severe withdrawal syndrome can be precipitated in dependent individuals by administration of flumazenil in long acting benzo
Non-benzodiazepine benzodiazepine receptor agonists (NBRAs):
Zolipidem (Ambien)
Eszopiclone (Lunesta)
Non-benzodiazepine benzodiazepine receptor agonists (NBRAs)-Mechanism of Action:
bind to subtypes of benzodiazepine receptor and facilitate GABA-mediated Cl- conductance and neuronal inhibition. The effects of zolpidem and eszopiclone are antagonized by flumazenil.
relatively selective for the type 1 benzodiazepine receptor.

It is rapidly absorbed and eliminated.

Useful for the acute treatment of sleep disorders; no morning hangover.
First sedative-hypnotic indicated for chronic treatment of insomnia.

It also has a rapid onset of action, but a longer half-life (~6h) than zolpidem.

Appears to bind to all three benzodiazepine receptor types; mechanism for selectivity unclear.

No evidence of diminished efficacy in a six month clinical trial.
Therapeutic uses of benzodiazepines and NBRAs
anxiety, panic attacks, PTSD, muscle spasms, spasticity, convulsive disorders, sedative-hypnotic withdrawal, relaxation for scope, re-entrainment of circadian rhythm
Therapeutic uses of flumazenil
treatment of benzodiazepine overdose

hasten recovery from anesthesia when a benzodiazepine is used as an adjunctive agent
Drug interactions
Benzodiazepines and non-benzodiazepine receptor agonists potentiate the CNS depressant effects of all sedative-hypnotic drugs.

Cross tolerance is observed between benzodiazepines and other sedative-hypnotic drugs.
Anxioselective drugs (prototype: buspirone)
anti-anxiety properties comparable to diazepam
must be taken for several days or weeks
useful for treatment of chronic anxiety disorder
not a sedative-hypnotic drug
Mechanism of action
bind to a site on the GABA-A receptor that is distinct from the GABA and benzodiazepine binding sites
Low-enhance GABA-mediated neuronal inhibition by increasing Cl- channel open time
High-open the Cl- channel independently of GABA binding leading to inhibition of excitatory trans and nonselective inhibition of action potential conductance
Classes of barbiturates
- ultra-short acting (thiopental)

- short acting(secobarbital)
- long acting(phenobarbital)
Barbs and induction of liver enzymes
potent inducers of the liver microsomal oxidases

induce gamma-aminolevulinic acid synthase--why they are contraindicated for intermittent porphoryia
Barbs-- Tolerance and Physical Dependence
pharmacokinetic tolerance due to induction of the liver microsomal oxidases which is much greater to the sedative-hypnotic effects than to the toxic effects of the drugs

physical dependence
Therapeutic uses of Barbiturates
Ultra-short acting: short-term anesthesia
Short-acting: induction of sleep, preoperative sedation, rapid seizure control
Long-acting: treatment of anxiety, prophylactic treatment of epilepsy (phenyl-substituted barbiturates), daytime sedation, treatment of sedative-hypnotic withdrawal
BARBS-drug interactions
synergistically potentiate the CNS depression caused by other sedative-hypnotic drugs
potentiate CNS depression is potentiated by ritalin and MAOI
Chronic use will enhance the metabolism and reduce the therapeutic effects of a wide variety of drugs, including digitalis, oral contraceptives, and other drugs and hormones metabolized by the hepatic microsomal oxidases
result in the development of cross-tolerance to all sedative-hypnotic drugs
dose-related progression of CNS depression, similar to that observed with other sedative-hypnotic drugs

most sensitive CNS structures are the polysynaptic reticular activating system and the cerebral cortex (blood ethanol 40-150 mg%); depression of these areas results in euphoria, disorganized thought, and dulling of performance that depends on training and previous experience
Ethanol dose responses
180-400 mg%
350-600 mg%
depression of cerebellum, loss of motor control

depression of midbrain function, spinal reflexes, depression of medullary respiratory control
Ethanol-mechanisms of action
dissolves in the lipid bilayer of plasma membranes, reducing membrane viscosity and disrupting protein function

increases GABA-mediated Cl- conductance through the GABA-A receptor

decreases glutamate-mediated cation conductance through subtypes of NMDA receptors

increases serotonin-mediated cation conductance through 5HT3 receptors located on inhibitory interneurons
Ethanol-Tolerance and Dependence

pharmacokinetic tolerance(variable)
inc. alcohol dehydrogenase, synthesis of NAD+ (cofactor for alcohol dehydrogenase), MEOS activity
Ethanol-Tolerance and Dependence

pharmacodynamic tolerance
dec. sensitivity to the membrane fluidizing effects of ethanol, GABA-A receptors

inc. NMDA receptors
Neurological consequences of chronic ethanol ingestion
peripheral neuropathy
CNS deficits-dementia, ventriculomegaly, dec white matter (CC), neuronal loss (ERC, Hypothal., cerebellum), shrinkage of nuclei
Ethanol neurotoxicity
Hepatic encephalopathy
Consequences of chronic ethanol ingestion
skeletal and cardiomyopathies
acute and chronic pancreatitis
induction of liver microsomal oxidases
increased fat in liver; cirrhosis of the liver
increased risk of various cancers
Ethanol Drug Interactions
-potentiates CNS depressant and respiratory depressant effects of other sedative-hypnotic drugs
-GI bleeding-aspirin, anti-clotting
-liver damage-acetaminophen
-reduces effectiveness of some ABxs
Pharmacological treatment of alcoholism
disulfiram (Antabuse) – inhibitor of aldehyde dehydrogenase

naltrexone – decreases the rewarding effects of alcohol

acamprosate (Campral) – reduces glutamate neurotransmission – reduces relapse in de-toxified patients
substitute for ethanol or accidental poisoning
metabolized to formaldehyde and formic acid
metabolic acidosis, blindness, seizures, coma, death
Tx with ethanol, fomeizole(inhibits OHDH), correct acidosis