Pharm J6 2

Front 1

Goals for local anesthetic use

Back 1

Minimize local irritation
Minimize systemic toxicity
Rapid onset: high conc needed (0.5-4%)
Sufficient duration

Front 2

types of linkages for local anesthetics?

Back 2

Amide-metabolized by liver via n-alkylation

Ester-hydrolyzed by plasma esterases to form PABA

Front 3

Local anesthetic mechanism of action

Back 3

Block Na channels from the cytoplasmic mouth

Stabilize inactivated state of channel

Front 4

lidocaine and carbomazapene

Back 4

Quaternary lidocaine and carbomazapene are ineffective from outside the neuron

Front 5

Factors that influence effectiveness of local anesthetics

Back 5

diameter-small
firing rate-fast
position-proximal
blood flow-epinephrine
drug size-smaller
hydrophobicity-more
pH-basic to be uncharged

Front 6

What is the effect of inflammation on local anesthetics?

Back 6

At more acidic pH (inflammation), more drug is charged and therefore less drug crosses nerve membranes, and therefore less nerve block.

Front 7

Toxicity of local anesthetics: CNS

Back 7

initially drowsiness and excitation (up to seizures), Followed by general depression, coma.

Front 8

Toxicity of local anesthetics: Cardiac

Back 8

especially bupivacaine)
depressed pacemaker activity
decreased conduction
arrhythmias
potentiated by hyperkalemia.
Amides synergize with anti-arrhythmic drugs to induce arrhythmias

Front 9

Toxicity of local anesthetics: Peripheral blood vessels

Back 9

vasodilation leading to hypotension (except cocaine – hypertension caused by block of NE reuptake)

Front 10

Toxicity of local anesthetics: Allergies

Back 10

esters: PABA derivatives
amides: preservatives

Front 11

Routes of administration

Back 11

Topical (mucous membranes)
Infiltration (local)
Regional block
nerve block
spinal
epidural

Front 12

Lidocaine

Back 12

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

Front 13

Procaine

Back 13

Short acting ester (40 sec plasma ½ life)
Low toxicity
Main use – infiltration and regional anesthesia
Interaction: PABA blocks sulfonamide action

Front 14

Tetracaine

Back 14

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.

Front 15

Bupivacaine

Back 15

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!

Front 16

Desired duration of block
short (20-45 min):
medium (1-2 hr):
medium to long (3-9 hr):

Back 16

procaine, benzocaine
LIDOCAINE
tetracaine, BUPIVACAINE

Front 17

Desired area of block
topical:
local:
regional:

Back 17

benzocaine, proparacaine
LIDOCAINE, procaine
tetracaine, BUPIVACAINE

Front 18

What is a seizure?

Back 18

A seizure results from uncontrolled, synchronous firing of large populations of cortical neurons

Front 19

Incidence of epilepsy

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high at 1st year of life and later in life

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Risk Factors

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penetrating head wounds
severe head trauma and stroke
not neonatal hypoxia
a significant genetic contribution

Front 21

Management:

Back 21

70% - currently available anticonvulsants
20% - surgery
10% - intractable

Front 22

What causes partial seizures?

Back 22

often caused by focal trauma or cortical malformation(acquired epilepsies)

Front 23

What causes general seizures?

Back 23

complex genetic disorder

Front 24

Principles of pharmacotherapy for epilepsy

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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

Front 25

Molecular targets of anticonvulsant drugs

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Na channels-Carbamazepine
Ca2+ channels-Ethosuximide
Mixed-Valproate
GABAA receptors-Lorazepam
GABA transporters
GABA transaminase

Front 26

carbamazepine

Back 26

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

Front 27

phenytoin

Back 27

highly bound to plasma proteins
limited capacity for metabolism
1+2 cause “saturation kinetics”
Adverse effects:
gingival hyperplasia
Hirsutism
coarsening of facial features

Front 28

ethosuximide

Back 28

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

Front 29

valproate

Back 29

broad-spectrum
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

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Status epilepticus

Back 30

long-lasting (>20 min) seizure, or seizure cluster
cerebral injury; 15-20% mortality
some causes: non-compliance, withdrawal from EtOH or barbiturates

Front 31

Treatment of Status epilepticus

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initial treatment – i.v. lorazepam or diazepam
if not stopped, fosphenytoin
if not stopped, phenobarbital
if not stopped, midazolam or propafol

Front 32

GABApentin (Neurontin):
levetiracetam (Keppra):
lamotrigine (Lamictal):
topiramate (Topomax):
oxcarbazepine (Trileptal):
tiagabine (Gabatril):
pregabalin (Lyrica):

Back 32

Ca channel blocker
mech. unknown
Na channel blocker
Na channel block + GABA potenti.
Na channel blocker
GABA uptake blocker
son of Gabapentin

Front 33

Antiepileptic Drug Interactions

Back 33

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

Front 34

3A4*1B

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defective alleles high in AA but 0 in asians
causes decrease clearance and increased toxicity

Front 35

Pregnancy and Epilepsy

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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.

Front 36

Vagal Nerve Stimulator

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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

Front 37

Ketogenic diet

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starvation reduces seizures--mainly used in peds. Possible due to anticonvulsant ketone or improved energy metabolism.

Front 38

Block Na channels

Back 38

carbamazepine, phenytoin

Front 39

block Ca channels

Back 39

ethosuximide

Front 40

potentiate GABAergic inhibition

Back 40

tiagabine, lorazepam

Front 41

mixed

Back 41

topiramate, zonisamide

Front 42

partial complex

Back 42

carbamazepine, phenytoin, gabapentin, vigabatrin, topiramate, tiagabine

Front 43

generalized tonic-clonic

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phenytoin, valproate

Front 44

absence

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ethosuximide, valproate (if t-c also present)

Front 45

myoclonic

Back 45

valproate

Front 46

Theories of Depression

Back 46

Lack of Amine Neurotransmitter
Serotonin, norepinephrine and dopamine.

Lack of Receptor Function.

Disturbed HPA Axis.

Front 47

Classes of Drugs

Back 47

SSRI
TCA
MAOI

Front 48

Mechanisms of SSRIs

Back 48

Blockade of SERT causes:
Stimulation of Receptors
Activation of Signaling Pathways
Altering Gene Expression (BDNF?)

Front 49

Available FDA approved drugs for alzheimers

Back 49

• Tacrine (Cognex)
• Donepezil (Aricept)
• Rivastigmine (Exelon)
• Galantamine (Reminyl, renamed Razadyne)
• Memantine (Nemenda)

Front 50

Two major mechanisms of AD drugs

Back 50

Cholinesterase inhibition and NMDA inhibition- with antagonist of moderate affinity

Front 51

Two major drugs

Back 51

Donepezil (aricept) and memantine (nemenda)

Front 52

Evidence for Cholinergic hypothesis

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The brain of AD patients have reduced cholinergic systems (low choline acetyltransferase in brains of AD pts)

Front 53

What is the beta amyloid 42 aa precursor?

Back 53

APP

Front 54

What is tau protein and what is its normal function?

Back 54

Hyperphosphorylated tau proteins which form tangles causing cell death and brain shrinkage. Normally tau is a component of microtubules.

Front 55

Side effects of anticholinesterase drugs?

Back 55

Mainly GI- nausea, vomiting, diarrhea, anorexia

Front 56

Why aricept instead of tacrine?

Back 56

Hepatotoxicity

Front 57

A healthy regimen for old age is:

Back 57

A lot of light
Proper nutrition
Crosswords
Using the brain
Behavioral treatments are important

Front 58

Dose-related progression of effects of anti-anxiety drugs

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Sedation
Behavioral disinhibition
Ataxia / nystagmus
Sleep (hypnosis)
Anesthesia
Coma, respiratory depression,
cardiovascular depression

Front 59

What is the difference in the dose response curves between barbs and benzos?

Back 59

Barb-linear and can be used for anesthesia

Benzo-nonlinear and plateau at sleep

Front 60

Benzodiazepine Mechanism of action

Back 60

potentiate the action of the inhibitory neurotransmitter -aminobutyric acid (GABA) at the GABA-A receptor

Front 61

bind to the benzodiazepine receptor and competitively block the effects of benzodiazepine agonists on GABA-mediated Cl- conductance and neuronal inhibition

Back 61

flumazenil

Front 62

Inverse agonists (e.g., beta-carboline carboxyethyl ester):

Back 62

bind to the benzodiazepine receptor and reduce GABA-mediated Cl- conductance and neuronal inhibition, resulting in anxiety, muscle spasms, and a proconvulsant state

Front 63

Two general classes of benzos

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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

Front 64

Tolerance and Physical Dependence of benzos?

Back 64

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

Front 65

Non-benzodiazepine benzodiazepine receptor agonists (NBRAs):

Back 65

Zolipidem (Ambien)
Eszopiclone (Lunesta)

Front 66

Non-benzodiazepine benzodiazepine receptor agonists (NBRAs)-Mechanism of Action:

Back 66

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.

Front 67

Zolpidem

Back 67

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.

Front 68

Eszopiclone

Back 68

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.

Front 69

Therapeutic uses of benzodiazepines and NBRAs

Back 69

anxiety, panic attacks, PTSD, muscle spasms, spasticity, convulsive disorders, sedative-hypnotic withdrawal, relaxation for scope, re-entrainment of circadian rhythm

Front 70

Therapeutic uses of flumazenil

Back 70

treatment of benzodiazepine overdose

hasten recovery from anesthesia when a benzodiazepine is used as an adjunctive agent

Front 71

Drug interactions

Back 71

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.

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Anxioselective drugs (prototype: buspirone)

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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

Front 73

Barbiturates
Mechanism of action

Back 73

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

Front 74

Classes of barbiturates

Back 74

Thiobarbiturates
- ultra-short acting (thiopental)


Oxybarbiturates
- short acting(secobarbital)
- long acting(phenobarbital)

Front 75

Barbs and induction of liver enzymes

Back 75

potent inducers of the liver microsomal oxidases

induce gamma-aminolevulinic acid synthase--why they are contraindicated for intermittent porphoryia

Front 76

Barbs-- Tolerance and Physical Dependence

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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

Front 77

Therapeutic uses of Barbiturates

Back 77

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

Front 78

BARBS-drug interactions

Back 78

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

Front 79

Ethanol

Back 79

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

Front 80

Ethanol dose responses
180-400 mg%
350-600 mg%

Back 80

depression of cerebellum, loss of motor control

depression of midbrain function, spinal reflexes, depression of medullary respiratory control

Front 81

Ethanol-mechanisms of action

Back 81

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

Front 82

Ethanol-Tolerance and Dependence

pharmacokinetic tolerance(variable)

Back 82

inc. alcohol dehydrogenase, synthesis of NAD+ (cofactor for alcohol dehydrogenase), MEOS activity

Front 83

Ethanol-Tolerance and Dependence

pharmacodynamic tolerance

Back 83

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

inc. NMDA receptors

Front 84

Neurological consequences of chronic ethanol ingestion

Back 84

peripheral neuropathy
CNS deficits-dementia, ventriculomegaly, dec white matter (CC), neuronal loss (ERC, Hypothal., cerebellum), shrinkage of nuclei
Ethanol neurotoxicity
Wernicke-Korsakoff
Hepatic encephalopathy

Front 85

Consequences of chronic ethanol ingestion

Back 85

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
FAS

Front 86

Ethanol Drug Interactions

Back 86

-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
-

Front 87

Pharmacological treatment of alcoholism

Back 87

disulfiram (Antabuse) – inhibitor of aldehyde dehydrogenase

naltrexone – decreases the rewarding effects of alcohol

acamprosate (Campral) – reduces glutamate neurotransmission – reduces relapse in de-toxified patients

Front 88

Methanol

Back 88

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