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Pharmacology
Pharmacology
Drugs
Drugs That
That Affect
Affect The:
The:
Nervous
Nervous System
System
Topics
Topics
••
••
••
••
••
••
••
Analgesics
Analgesics and
and antagonists
antagonists
Anesthetics
Anesthetics
Anti-anxiety
Anti-anxiety and
and sedative-hypnotics
sedative-hypnotics
Anti-seizure
Anti-seizure // anti-convulsants
anti-convulsants
CNS
CNS stimulators
stimulators
Psychotherapeutics
Psychotherapeutics
ANS/PNS/SNS
ANS/PNS/SNS agents
agents
But
But first...
first...
A
A colorful
colorful review
review of
of
neurophysiology!
neurophysiology!
Nervous
Nervous System
System
CNS
CNS
PNS
PNS
Autonomic
Autonomic
Sympathetic
Sympathetic
Parasympathetic
Parasympathetic
Somatic
Somatic
Analgesics
Analgesics
••
••
Decrease
Decrease in
in sensation
sensation of
of pain.
pain.
Classes:
Classes:
–– Opioid.
Opioid.
•• Agonist.
Agonist.
•• Antagonist.
Antagonist.
•• Agonist-antagonist.
Agonist-antagonist.
–– Non-opioids.
Non-opioids.
•• Salicylates.
Salicylates.
•• NSAIDs.
NSAIDs.
•• Adjuncts.
Adjuncts.
Opioids
Opioids
•• Generic
Genericreference
referenceto
to
morphine-like
morphine-like
drugs/actions
drugs/actions
–– Opiate:
Opiate:derivative
derivativeof
ofopium
opium
•• Prototype:
Prototype:morphine
morphine
–– Morpheus:
Morpheus:god
godof
ofdreams
dreams
•• Act
Acton
onendorphin
endorphin
receptors:
receptors:
––
––
Mu
Mu(most
(mostimportant)
important)
Kappa
Kappa
Actions
Actions of
of Opioid
Opioid Receptors
Receptors
Response
Mu
Kappa
Analgesia
;
;
Respiratory
Depression
Sedation
;
Euphoria
;
Physical Dependence
;
⇓ GI motility
;
;
;
;
Actions
Actions at
at Opioid
Opioid Receptors
Receptors
Drugs
Mu
Kappa
Pure Agonists
Agonist
Agonist
-morphine, codeine, meperidine (Demerol®),
fentanyl (Sublimaze®), remifentanil (Ultiva®),
propoxyphene (Darvon®), hydrocodone (Vicodin®),
oxycodone (Percocet®)
Agonist-Antagonist
-nalbuphine (Nubaine®), butorphanol (Stadol®)
Pure Antagonist
-naloxone (Narcan®)
Antagonist Agonist
Antagonist Antagonist
General
General Actions
Actions of
of Opioids
Opioids
••
••
••
••
••
••
••
Analgesia
Analgesia
Respiratory
Respiratory depression
depression
Constipation
Constipation
Urinary
Urinary retention
retention
Cough
Cough suppression
suppression
Emesis
Emesis
Increased
Increased ICP
ICP
–– Indirect
Indirectthrough
throughCO
CO22
retention
retention
••
••
••
Euphoria/Dysphoria
Euphoria/Dysphoria
Sedation
Sedation
Miosis
Miosis
–– Pupil
Pupilconstriction
constriction
•• ⇓⇓ Preload
Preload &
& afterload
afterload
–– Watch
Watchfor
for
hypotension!
hypotension!
Non
-opioid Analgesics
Non-opioid
Analgesics
•• Salicylates
Salicylates
–– Aspirin
Aspirin (Bayer
(Bayer®® )) ** (prototype
(prototype for
for class)
class)
•• Non-Steroidal
Non-Steroidal Anti-Inflammatory
Anti-Inflammatory Drugs
Drugs
®
•• Ibuprofen
Ibuprofen(Motrin®,
(Motrin®,Advil
Advil®))
–– Propionic
PropionicAcid
Acidderivative
derivative
®
•• Naproxen
Naproxen(Naprosyn
(Naprosyn®))
®
•• Naproxen
Naproxensodium
sodium(Aleve
(Aleve®))
•• All
Allcompete
competewith
withaspirin
aspirinfor
forprotein
proteinbinding
bindingsites
sites
–– Ketorolac
Ketorolac (Toradol
(Toradol®®))
NSAID
NSAID Properties
Properties
Drug
Fever
Inflammation Pain
Aspirin
;
;
;
Ibuprofen
;
;
;
Acetaminophen
;
;
Aspirin
Aspirin Mechanism
Mechanism of
of Action
Action
•• Inhibit
Inhibit synthesis
synthesis of
of cyclooxygenase
cyclooxygenase (COX)
(COX)
–– Enzyme
Enzyme responsible
responsible for
for synthesis
synthesis of:
of:
Prostaglandins
Prostaglandins
–Pain
–Painresponse
response
–Suppression
–Suppressionof
ofgastric
gastricacid
acidsecretion
secretion
–Promote
–Promotesecretion
secretionof
ofgastric
gastricmucus
mucusand
andbicarbonate
bicarbonate
–Mediation
–Mediationof
ofinflammatory
inflammatoryresponse
response
–Production
–Productionof
offever
fever
–Promote
–Promoterenal
renalvasodilation
vasodilation(⇑
(⇑blood
bloodflow)
flow)
–Promote
–Promoteuterine
uterinecontraction
contraction
Thromboxane
ThromboxaneAA22
–Involved
–Involvedininplatelet
platelet
–aggregation
–aggregation
Aspirin
Aspirin Effects
Effects
Good
Good
•• Pain
Pain relief
relief
•• ⇓⇓ Fever
Fever
•• ⇓⇓ Inflammation
Inflammation
Bad
Bad
•• GI
GI ulceration:
ulceration:
–– ⇑⇑Gastric
Gastricacidity
acidity
–– ⇓⇓GI
GIprotection
protection
••
••
••
⇑⇑ Bleeding
Bleeding
⇓⇓ Renal
Renal elimination
elimination
⇓⇓ Uterine
Uterine contractions
contractions
during
during labor
labor
®
Acetaminophen
(Tylenol
Acetaminophen (Tylenol®))
••
••
NSAID
NSAID similar
similar to
to aspirin
aspirin
Only
Only inhibits
inhibits synthesis
synthesis of
of CNS
CNS
prostaglandins
prostaglandins
–– Does
Does not
not have
have peripheral
peripheral side
side effects
effects of
of ASA:
ASA:
•• Gastric
Gastriculceration
ulceration
•• ⇓⇓Platelet
Plateletaggregation
aggregation
•• ⇓⇓Renal
Renalflow
flow
•• ⇓⇓Uterine
Uterinecontractions
contractions
Acetaminophen
Acetaminophen Metabolism
Metabolism
Major Pathway
Non-toxic
Non-toxic
metabolites
metabolites
Acetaminophen
Acetaminophen
Induced
Inducedby
by
ETOH
ETOH
P-450
Toxic
Toxic
metabolites
metabolites
Minor Pathway
Depleted
Depletedby
byETOH
ETOH&
&
APAP
APAPoverdose
overdose
Glutathione
Non-toxic
Non-toxic
metabolites
metabolites
Anesthetics
Anesthetics
•• Loss
Loss of
of all
all sensation
sensation
–– Usually
Usually with
with loss
loss of
of consciousness
consciousness
–– ⇓⇓ propagation
propagation of
of neural
neural impulses
impulses
•• General
General anesthetics
anesthetics
–– Gases
Gases
®®), halothane, ether
•• Nitrous
oxide
(Nitronox
Nitrous oxide (Nitronox ), halothane, ether
–– IV
IV
®®), methohexital (Brevitol®®),
•• Thiopental
(Pentothal
Thiopental (Pentothal ), methohexital (Brevitol ),
®
diazepam
diazepam(valium®),
(valium®),remifentanil
remifentanil(Ultiva
(Ultiva®))
Anesthetics
Anesthetics
•• Local
Local
–– Affect
Affect on
on area
area around
around injection
injection
–– Usually
Usually accompanied
accompanied by
by epinephrine
epinephrine
®
•• Lidocaine
Lidocaine(Xylocaine
(Xylocaine ®),),topical
topicalcocaine
cocaine
Anti
-anxiety &
Anti-anxiety
& Sedative
Sedative-hypnotic
hypnotic Drugs
Drugs
••
••
••
Sedation:
Sedation: ⇓⇓ anxiety
anxiety &
& inhibitions
inhibitions
Hypnosis:
Hypnosis: instigation
instigation of
of sleep
sleep
Insomnia
Insomnia
–– ⇑⇑Latent
Latentperiod
period
–– ⇑⇑Wakenings
Wakenings
•• Classes:
Classes:
–– Barbiturates
Barbiturates
–– Benzodiazepines
Benzodiazepines
–– Alcohol
Alcohol
Chemically
Chemicallydifferent,
different,
Functionally
Functionallysimilar
similar
Mechanism
Mechanism of
of action
action
•• Both
Both promote
promote the
the effectiveness
effectiveness of
of GABA
GABA
receptors
receptors in
in the
the CNS
CNS
–– Benzodiazepines
Benzodiazepines promote
promote only
only
–– Barbiturates
Barbiturates promote
promote and
and (at
(at high
high doses)
doses)
stimulate
stimulate GABA
GABA receptors
receptors
•• GABA
GABA == chief
chief CNS
CNS inhibitory
inhibitory
neurotransmitter
neurotransmitter
–– Promotes
Promotes hyperpolarization
hyperpolarization via
via ⇑⇑ Cl
Cl-- influx
influx
Benzodiazepines
Benzodiazepines vs.
vs.
Barbiturates
Barbiturates
Criteria
BZ
Barb.
Relative Safety
High Low
Maximal CNS depression
Low High
Respiratory Depression
Low High
Suicide Potential
Low High
Abuse Potential
Low High
Antagonist Available?
Yes
No
Benzodiazepines
Benzodiazepines
Benzodiazepines
Benzodiazepines
®®)
•• diazepam
(Valium
diazepam (Valium )
®®)
•• midazolam
(Versed
midazolam (Versed )
•• alprazolam
alprazolam (Xanax
(Xanax®®))
•• lorazepam
lorazepam (Atiavan
(Atiavan®®))
•• triazolam
triazolam (Halcion
(Halcion®®))
“Non-benzo
“Non-benzo benzo”
benzo”
®®)
•• zolpidem
(Ambien
zolpidem (Ambien )
®®)
•• buspirone
(BusPar
buspirone (BusPar )
Barbiturates
Barbiturates
Subgroup
Prototype
Typical
Indication
Ultra-short
acting
thiopental
(Pentothol®)
Anesthesia
Short acting
secobarbital
(Seconal®)
Insomnia
Long acting
phenobarbital
(Luminal®)
Seizures
Barbiturates
Barbiturates
••
••
••
••
••
®®)
amobarbital
(Amytal
amobarbital (Amytal )
®®)
pentobarbital
(Nembutal
pentobarbital (Nembutal )
®®)
thiopental
(Pentothal
thiopental (Pentothal )
®®)
phenobarbital
(Luminal
phenobarbital (Luminal )
®®)
secobarbital
(Seconal
secobarbital (Seconal )
Anti
-seizure Medications
Anti-seizure
Medications
••
••
Seizures
Seizures caused
caused by
by hyperactive
hyperactive brain
brain areas
areas
Multiple
Multiple chemical
chemical classes
classes of
of drugs
drugs
–– All
All have
have same
same approach
approach
–– Decrease
Decrease propagation
propagation of
of action
action potentials
potentials
++, Ca++
•• ⇓⇓Na
Na , Ca++influx
influx(delay
(delaydepolarization/prolong
depolarization/prolong
repolarization)
repolarization)
•• ⇑⇑Cl
influx(hyperpolarize
(hyperpolarizemembrane)
membrane)
Cl-influx
Anti
-Seizure Medications
Anti-Seizure
Medications
Benzodiazepines
Benzodiazepines
•• diazepam
diazepam (Valium®)
(Valium®)
®®)
•• lorazepam
(Ativan
lorazepam (Ativan )
Barbiturates
Barbiturates
•• phenobarbital
phenobarbital
®®)
(Luminal
(Luminal )
Ion
Ion Channel
Channel Inhibitors
Inhibitors
•• carbamazepine
carbamazepine
(Tegretol
(Tegretol®®))
•• phenytoin
phenytoin (Dilantin®)
(Dilantin®)
Misc.
Misc. Agents
Agents
•• valproic
valproic acid
acid
(Depakote®)
(Depakote®)
Ion
Ion Diffusion
Diffusion
••
••
Key
Key to
to neurophysiology
neurophysiology
Dependent
Dependent upon:
upon:
–– Concentration
Concentration gradient
gradient
–– Electrical
Electrical gradient
gradient
•• Modified
Modified by:
by:
–– ‘Gated
‘Gated ion
ion channels’
channels’
Where
Where Does
Does Diffusion
Diffusion Take
Take the
the
Ion?
Ion?
+
Na
Na+
150
150mM
mM
KK++
55mM
mM
Cl
ClHigh
High
Exterior
II
NN
++
Na
Na
15
15mM
mM
O
O
UU
TT
KK++
150
150mM
mM
II
NN
Interior
-Cl
Cl
Low
Low
Action
Action Potential
Potential Components
Components
Membrane Potential (mV)
Depolarization!
Depolarization!
+
Na
Na+equilibrium
equilibrium
Action
Action
Potential
Potential
+30
0
Threshold
Threshold
Potential
Potential
-50
-70
Hyperpolarized
Hyperpolarized
Time (msec)
Resting
RestingMembrane
Membrane
Potential
Potential
0
Na + Influx
+30
K+ Efflux
Membrane Potential (mV)
Membrane
Membrane Permeability
Permeability
Threshold
Threshold
Potential
Potential
-50
-70
Resting
RestingMembrane
Membrane
Potential
Potential
Time (msec)
0
Na + Influx
+30
K+ Efflux
Membrane Potential (mV)
-What
Happens
to
the
Membrane
If
Cl
What Happens to the Membrane If Cl
Rushes
Rushes Into
Into the
the Cell
Cell During
During Repolarization?
Repolarization?
It
It gets
gets
hyperpolarized!
hyperpolarized!
Threshold
Threshold
Potential
Potential
-50
-70
Resting
RestingMembrane
Membrane
Potential
Potential
Time (msec)
Membrane Potential (mV)
What
What Happens
Happens to
to the
the Frequency
Frequency of
of Action
Action
Potentials
Potentials IfIf the
the Membrane
Membrane Gets
Gets
Hyperpolarized?
Hyperpolarized?
+30
0
It
It
decreases!
decreases!
-50
-70
Time (msec)
Clinical
Clinical Correlation
Correlation
•• Remember
Rememberthat
thatititisisthe
therate
rateof
ofaction
actionpotential
potentialpropagation
propagation
that
thatdetermines
determinesneurologic
neurologicfunction.
function.
–– Determined
Determinedby
byfrequency
frequencyof
ofaction
actionpotentials.
potentials.
What
What
What isis aa seizure?
seizure?
What would
would be
be the
the
effect
effect on
on the
the membrane
membrane
-- influx
of
⇑
Cl
of ⇑ Cl influx
Hyperpolarization &
during
during aa seizure?
seizure?
⇓ seizure
activity!
Cl
Cl -
Gamma
Gamma Amino
Amino Butyric
Butyric Acid
Acid
Receptors
Receptors
GABA
GABA
Receptor
Receptor
Exterior
Hyperpolarized!
Hyperpolarized!
Interior
Cl
Cl -
GABA+Bz
GABA+Bz Complex
Complex
Bz
Bz
Receptor
Receptor
GABA
GABA
Receptor
Receptor
Profoundly
Profoundly
Hyperpolarized!
Hyperpolarized!
Exterior
Interior
Are
Are You
You Ready
Ready for
for aa Big
Big
Surprise?
Surprise?
Many CNS drugs act on GABA
receptors to effect the frequency
and duration of action potentials!
SNS
SNS Stimulants
Stimulants
•• Two
Two general
general mechanisms:
mechanisms:
–– Increase
Increase excitatory
excitatory neurotransmitter
neurotransmitter release
release
–– Decrease
Decrease inhibitory
inhibitory neurotransmitter
neurotransmitter release
release
•• Three
Three classes:
classes:
•• Amphetamines
Amphetamines
•• Methylphendidate
Methylphendidate
•• Methylxanthines
Methylxanthines
Amphetamines
Amphetamines
amphetamine
amphetamine
methamphetamine
methamphetamine
dextroamphetamine
dextroamphetamine
®®)
(Dexedrine
(Dexedrine )
MOA:
MOA:
promote
promote release
release of
of
norepinephrine,
norepinephrine,
dopamine
dopamine
Indications
Indications
•Diet
•Diet suppression
suppression
•⇓
•⇓ Fatigue
Fatigue
•⇑
•⇑ Concentration
Concentration
Side
Side Effects
Effects
•Tachycardia
•Tachycardia
•Hypertension
•Hypertension
•Convulsion
•Convulsion
•Insomnia
•Insomnia
•Psychosis
•Psychosis
®
Methylphenidate
(Ritalin
Methylphenidate (Ritalin®))
•• Different
Different structure
structure than
than other
other stimulants
stimulants
–– Similar
Similar mechanism
mechanism
–– Similar
Similar side
side effects
effects
•• Indication:
Indication: ADHD
ADHD
–– Increase
Increase ability
ability to
to focus
focus &
& concentrate
concentrate
Methylxanthines
Methylxanthines
•• Caffeine
Caffeine
•• Theophylline
Theophylline (Theo-Dur®)
(Theo-Dur®)
•• Aminophylline
Aminophylline
Mechanism
Mechanism of
of action
action
•• Reversible
Reversible blockade
blockade of
of adenosine
adenosine receptors
receptors
AA patient
patient is
is taking
taking theophylline
theophylline and
and
becomes
becomes tachycardic
tachycardic (SVT).
(SVT). You
You want
want to
to
give
give her
her adenosine.
adenosine. Is
Is there
there an
an interaction
interaction
you
you should
should be
be aware
aware of?
of? How
How should
should you
you
alter
alter your
your therapy?
therapy?
Methylxanthines
Methylxanthines blocks
blocks
adenosine
adenosine receptors.
receptors. A
A
typical
typical dose
dose of
of adenosine
adenosine
may
may not
not be
be sufficient
sufficient to
to
achieve
achieve the
the desired
desired
result.
result.
Double
Double the
the
dose!
dose!
News
…
News You
You Can
Can Use
Use…
Source
Amount of Caffeine
Coffee
•Brewed
•Instant
Decaffeinated Coffee
40 – 180 mg/cup
30 – 120 mg/cup
2 - 5 mg/cup
Tea
20 – 110 mg/cup
Coke
40 – 60 mg/12 oz
Psychotherapeutic
Psychotherapeutic
Medications
Medications
•• Dysfunction
Dysfunction related
related to
to neurotransmitter
neurotransmitter
imbalance.
imbalance.
–– Norepinephrine.
Norepinephrine.
–– Dopamine.
Dopamine.
–– Seratonin.
Seratonin.
Monoamines
•• Goal
Goal isis to
to regulate
regulate excitory/inhibitory
excitory/inhibitory
neurotransmitters.
neurotransmitters.
Anti
-Psychotic Drugs
Anti-Psychotic
Drugs
(Neuroleptics)
(Neuroleptics)
•• Schizophrenia
Schizophrenia
–– Loss
Loss of
of contact
contact with
with reality
reality &
& disorganized
disorganized
thoughts
thoughts
–– Probable
Probable cause:
cause: increased
increased dopamine
dopamine release
release
–– Tx.
Tx. Aimed
Aimed at
at decreasing
decreasing dopamine
dopamine activity
activity
Two
Two Chemical
Chemical
Classes:
Classes:
•• Phenothiazines
Phenothiazines
••
®
chlorpromazine
chlorpromazine(Thorazine
(Thorazine ®))
••
haloperidol
haloperidol(Haldol
(Haldol®))
•• Butyrophenones
Butyrophenones®
Other
Other Uses
Uses for
for Antipsychotics
Antipsychotics
••
••
••
••
••
Bipolar
Bipolar depression
depression
Tourette’s
Tourette’s Syndrome
Syndrome
Prevention
Prevention of
of emesis
emesis
Dementia
Dementia (OBS)
(OBS)
Temporary
Temporary psychoses
psychoses from
from other
other illness
illness
Antipsychotic
Antipsychotic MOA
MOA
••
••
Mechanism
Mechanism isis similar
similar
Strength
Strength ([])
([]) vs.
vs. Potency
Potency (‘oomph’)
(‘oomph’)
–– Phenothiazines
Phenothiazines––low
lowpotency
potency
–– Butyrophenones
Butyrophenones––high
highpotency
potency
•• Receptor
Receptor Antagonism
Antagonism
–– Dopamine
Dopamine22in
inbrain
brain
–– Muscarinic
Muscariniccholinergic
cholinergic
–– Histamine
Histamine
–– Norepi
Norepiatatalpha
alpha1
1
Therapeutic effects
Uninteded effects
Antipsychotic
Antipsychotic Side
Side Effects
Effects
••
••
••
Generally
Generally short
short term
term
Extrapyramidal
Extrapyramidal symptoms
symptoms (EPS)
(EPS)
Anticholinergic
Anticholinergic effects
effects (atropine-like)
(atropine-like)
••
••
••
••
Orthostatic
Orthostatic hypotension
hypotension
Sedation
Sedation
Decreased
Decreased seizure
seizure threshold
threshold
Sexual
Sexual dysfunction
dysfunction
–– Dry
Drymouth,
mouth,blurred
blurredvision,
vision,photophobia,
photophobia,tachycardia,
tachycardia,
constipation)
constipation)
Extrapyramidal
Extrapyramidal Symptoms
Symptoms
Reaction
Onset
Features
Acute dystonia
Hours to 5 days
Spasm of tongue, neck, face &
back
Parkinsonism
5 – 30 days
Tremor, shuffling gait, drooling,
stooped posture, instability
Akathesia
5 – 60 days
Compulsive, repetitive motions;
agitation
Tarditive
dyskinesia
Months to years
Lip-smacking, worm-like tongue
movement, ‘fly-catching’
Treatment
Treatment of
of EPS
EPS
•• Likely
Likely caused
caused by
by blocking
blocking central
central
dopamine
receptors responsible
responsible for
for
dopamine22 receptors
movement
movement
•• Anticholinergic
Anticholinergic therapy
therapy rapidly
rapidly effective
effective
®®)
–– diphenhydramine
(Benadryl
diphenhydramine (Benadryl )
Antipsychotic
Antipsychotic Agents
Agents
••
••
••
••
chlorpromazine
chlorpromazine (Thorazine®)
(Thorazine®)
thioridazine
thioridazine (Mellaril®)
(Mellaril®)
trifluoperazine
trifluoperazine (Stelazine®)
(Stelazine®)
haloperidol
haloperidol (Haldol®)
(Haldol®)
Antidepressants
Antidepressants
••
••
Likely
Likely cause:
cause: inadequate
inadequate monoamine
monoamine levels
levels
Treatment
Treatment options:
options:
–– Increasing
Increasing NT
NT synthesis
synthesis in
in presynaptic
presynaptic end
end
bulb
bulb
–– Increasing
Increasing NT
NT release
release from
from end
end bulb
bulb
–– Blocking
Blocking NT
NT ‘reuptake’
‘reuptake’ by
by presynaptic
presynaptic end
end
bulb
bulb
Tricyclic
Tricyclic Antidepressants
Antidepressants
(TCAs)
(TCAs)
•• Block
Block reuptake
reuptake of
of both
both NE
NE &
& serotonin
serotonin
–– Enhance
Enhanceeffects
effects
•• Similar
Similar side
side effects
effects to
to phenothiazines
phenothiazines
TCA
TCA Side
Side Effects
Effects
••
••
••
••
Orthostatic
Orthostatic hypotension
hypotension
Sedation
Sedation
Anticholinergic
Anticholinergic effects
effects
Cardiac
Cardiac toxicity
toxicity
–– Ventricular
Ventricular dysrythmias
dysrythmias
Selective
Selective Serotonin
Serotonin Reuptake
Reuptake
Inhibitors
Inhibitors (SSRIs)
(SSRIs)
•• Block
Block only
only serotonin
serotonin (not
(not NE)
NE) reuptake
reuptake
–– Elevate
Elevate serotonin
serotonin levels
levels
•• Fewer
Fewer side
side effects
effects than
than TCS
TCS
–– No
No hypotension
hypotension
–– No
No anticholinergic
anticholinergic effects
effects
–– No
No cardiotoxicity
cardiotoxicity
•• Most
Most common
common side
side effect
effect
–– Nausea,
Nausea, insomnia,
insomnia, sexual
sexual dysfunction
dysfunction
Monoamine
Monoamine Oxidase
Oxidase Inhibitors
Inhibitors
((MAOIs)
MAOIs)
•• Monoamine
Monoamine oxidase
oxidase
–– Present
Present in
in liver,
liver, intestines
intestines &
& MA
MA releasing
releasing
neurons
neurons
–– Inactivates
Inactivates monoamines
monoamines
–– Inactivates
Inactivates dietary
dietary tyramine
tyramine in
in liver
liver
•• Foods
Foodsrich
richin
intyramine:
tyramine:cheese
cheese&
&red
redwine
wine
MAOI
MAOI Side
Side Effects
Effects
•• CNS
CNS Stimulation
Stimulation
–– Anxiety,
Anxiety, agitation
agitation
••
••
Orthostatic
Orthostatic hypotension
hypotension
Hypertensive
Hypertensive Crisis
Crisis
–– From
From increased
increased tyramine
tyramine consumption
consumption
•• Excessive
Excessivearteriole
arterioleconstriction,
constriction,stimulation
stimulationof
ofheart
heart
MAOI
MAOI &
& Dietary
Dietary Tyramine
Tyramine
Antidepressant
Antidepressant Mechanism
Mechanism
TCAs &
SSRIs
Block Here
Antidepressants
Antidepressants Agents
Agents
TCAs
TCAs
••
••
••
®
imiprimine
imiprimine(Tofranil
(Tofranil®))
®
amitriptyline
amitriptyline(Elavil
(Elavil®))
®
nortriptyline
nortriptyline(Pamelor
(Pamelor ®))
SSRIs
SSRIs
••
••
••
®
fluoxetine
fluoxetine(Prozac
(Prozac®))
®
paroxetine
paroxetine(Paxil
(Paxil®))
®
sertraline
sertraline(Zoloft
(Zoloft®))
MAOIs
MAOIs
®®)
•• phenelzine
(Nardil
phenelzine (Nardil )
Atypical
Atypical Antidepressants
Antidepressants
®
•• bupropion
bupropion(Wellbutrin
(Wellbutrin®))
Parkinson
’s Disease
Parkinson’s
Disease
•• Fine
Fine motor
motor control
control dependent
dependent upon
upon balance
balance
between
between excitatory
excitatory and
and inhibitory
inhibitory NT
NT
–– Acetylcholine
Acetylcholine == excitatory
excitatory
–– Dopamine
Dopamine =inhibitory
=inhibitory
GABA=
GABA= inhibitory
inhibitory
Control GABA
release
Parkinson
’s Disease
Parkinson’s
Disease
Parkinson
’s Symptoms:
Parkinson’s
Symptoms:
••
••
Similar
Similar to
to EPS
EPS
Dyskinesias
Dyskinesias
–– Tremors,
Tremors, unsteady
unsteady gait,
gait, instability
instability
••
••
Bradykinesia
Bradykinesia
Akinesia
Akinesia in
in severe
severe cases
cases
Parkinson
’s Treatment
Parkinson’s
Treatment
•• Dopaminergic
Dopaminergic approach
approach
–– ⇑⇑ Release
Release of
of dopamine
dopamine
–– ⇑⇑ [Dopamine]
[Dopamine]
–– ⇓⇓ Dopamine
Dopamine breakdown
breakdown
•• Cholinergic
Cholinergic approach
approach
–– ⇓⇓ Amount
Amount of
of ACh
ACh released
released
–– Directly
Directly block
block ACh
ACh receptors
receptors
•• All
All treatment
treatment isis symptomatic
symptomatic and
and temporary
temporary
Levodopa
Levodopa
••
••
••
Sinemet
Sinemet ®
® == levodopa
levodopa ++ carbidopa
carbidopa
Increase
Increase central
central dopamine
dopamine levels
levels
Side
Side effects:
effects:
–– Nausea
Nausea and
and vomiting
vomiting
–– Dyskinesia
Dyskinesia (~80%
(~80% of
of population)
population)
–– Cardiovascular
Cardiovascular (dysrythmias)
(dysrythmias)
Levodopa
Levodopa Mechanism
Mechanism
Other
Other Agents
Agents
®®)
•• amantadine
(Symmetrel
amantadine (Symmetrel )
–– ⇑⇑ release
release of
of dopamine
dopamine from
from unaffected
unaffected neurons
neurons
®®)
•• bromocriptine
(Parlodel
bromocriptine (Parlodel )
–– Directly
Directly stimulated
stimulated dopamine
dopamine receptors
receptors
®®, Eldepryl®®)
•• selegiline
(Carbex
selegiline (Carbex , Eldepryl )
–– MAOI
MAOI selective
selective for
for dopamine
dopamine (MAO-B)
(MAO-B)
®®)
•• benztropine
(Cogentin
benztropine (Cogentin )
–– Centrally
Centrally acting
acting anticholinergic
anticholinergic
Drugs
Drugs That
That Affect
Affect the
the
Autonomic
Autonomic Nervous
Nervous System
System
Word
Word of
of Warning
Warning
Carefully
Carefully review
review the
the A&P
A&P material
material &
&
tables
tables on
on pages
pages 309
309 –– 314
314 and
and 317
317 –– 321!
321!
PNS
PNS Drugs
Drugs
•• Cholinergic
Cholinergic
–– Agonists
Agonists &
& Antagonistis
Antagonistis (Anticholinergics)
(Anticholinergics)
–– Based
&
Based on
on response
response at
at nicotinic
nicotinic(N&M)
(N&M) &
muscarinic
muscarinic receptors
receptors
Acetylcholine
Acetylcholine Receptors
Receptors
Figure 9-8, page 313, Paramedic Care, V1
Cholinergic
Cholinergic Agonists
Agonists
Cholinergic agents
cause SLUDGE!
HINT!
These effects are
predictable by knowing
PNS physiology (table 9-4)
Salivation
Salivation
Lacrimation
Lacrimation
Urination
Urination
Defecation
Defecation
Gastric
Gastric motility
motility
Emesis
Emesis
Direct
Direct Acting
Acting Cholinergics
Cholinergics
•• bethanechol
bethanechol (Urecholine)
(Urecholine) prototype
prototype
–– Direct
Direct stimulation
stimulation of
of ACh
ACh receptors
receptors
–– Used
Used for
for urinary
urinary hesitancy
hesitancy and
and constipation
constipation
Indirect
Indirect Acting
Acting Cholinergics
Cholinergics
•• Inhibit
Inhibit ChE
ChE (cholinesterase)
(cholinesterase) to
to prolong
prolong the
the
duration
duration of
of ACh
ACh stimulation
stimulation in
in synapse
synapse
•• Reversible
Reversible
•• Irreversible
Irreversible
Reversible
Reversible ChE
ChE Inhibitors
Inhibitors
®®)
•• neostigmine
(Prostigmine
neostigmine (Prostigmine )
–– Myasthenia
Myasthenia Gravis
Gravis at
at nicotinic
nicotinicMM receptors
receptors
–– Can
Can reverse
reverse nondepolarizing
nondepolarizing neuromuscular
neuromuscular
blockade
blockade
•• physostigmine
physostigmine (Antilirium®)
(Antilirium®)
–– Shorter
Shorter onset
onset of
of action
action
–– Used
Used for
for iatrogenic
iatrogenic atropine
atropine overdoses
overdoses @
@
muscarinic
muscarinic receptors
receptors
Irreversible
Irreversible ChE
ChE Inhibitors
Inhibitors
••
••
Very
Very rarely
rarely used
used clinically
clinically
Very
Very common
common in
in insecticides
insecticides &
& chemical
chemical
weapons
weapons
–– VX
VX and
and Sarin
Sarin gas
gas
–– Cause
Cause SLUDGE
SLUDGE dammit
dammit and
and paralysis
paralysis
®®)
•• Tx:
atropine
and
pralidoxime
(2-PAM
Tx: atropine and pralidoxime (2-PAM )
–– Anticholinergics
Anticholinergics
Anticholinergics
Anticholinergics
•• Muscarinic
Muscarinic
antagonists
antagonists
–– Atropine
Atropine
•• Ganglionic
Ganglionic antagonists
antagonists
–– block
blocknicotinic
nicotinicNN
receptors
receptors
–– Turns
Turnsoff
offthe
theANS!
ANS!
–– trimethaphan
trimethaphan
®®)
(Arfonad
(Arfonad )
•• Hypertensive
Hypertensivecrisis
crisis
•• Atropine
Atropine Overdose
Overdose
–– Dry
Drymouth,
mouth,blurred
blurred
vision,
vision,anhidrosis
anhidrosis
Hot
Hotas
asHell
Hell
Blind
Blindas
asaaBat
Bat
Dry
Dryas
asaaBone
Bone
Red
Redas
asaaBeet
Beet
Mad
Madas
asaaHatter
Hatter
Neuromuscular
Neuromuscular Blockers
Blockers
•• Nicotinic
Nicotinic Cholinergic
Cholinergic Antagonists
Antagonists
–– Given
Given to
to induce
induce paralysis
paralysis
•• Depolarizing
Depolarizing
–– succinylcholine
succinylcholine (Anectin
(Anectin®®))
•• Nondepolarizing
Nondepolarizing
–– tubocurarine
tubocurarine from
from curare
curare
–– rocuronium
rocuronium (Zemuron
(Zemuron®®))
–– vecuronium
vecuronium (Norcuron
(Norcuron®®))
Warning!
Warning!
•• Paralysis
Paralysis without
without loss
loss of
of consciousness!
consciousness!
–– MUST
MUST also
also give
give sedative-hypnotic
sedative-hypnotic
–– Common
Common agents:
agents:
®
•• fentanyl
fentanyl(Sublimaze
(Sublimaze®))
®®)
•• midazolam
(Versed
midazolam (Versed )
SNS
SNS Drugs
Drugs
•• Predictable
Predictable response
response based
based on
on knowledge
knowledge of
of
affects
affects of
of adrenergic
adrenergic receptor
receptor stimulation
stimulation
•• HINT:
HINT: Know
Know table
table 9-5,
9-5, page
page 321
321
•• Each
Each receptor
receptor may
may be:
be:
–– Stimulated
Stimulated (sympathomimetic)
(sympathomimetic)
–– Inhibitied
Inhibitied (sympatholytic)
(sympatholytic)
Alpha
Alpha11 Agonists
Agonists
•• Profound
Profound vasoconstriction
vasoconstriction
–– Increases
Increases afterload
afterload &
& blood
blood pressure
pressure when
when
given
given systemically
systemically
–– Decreases
Decreases drug
drug absorption
absorption &
& bleeding
bleeding when
when
given
given topically
topically
Alpha
Alpha11 Antagonism
Antagonism
•• Inhibits
Inhibits peripheral
peripheral vasoconstriction
vasoconstriction
–– Used
Used for
for hypertension
hypertension
–– prazosin
prazosin (Minipress
(Minipress®®))
–– doxazosin
doxazosin (Cardura
(Cardura®®))
–– phentolamine
phentolamine (Regitine
(Regitine®®))
•• Blocks
receptors
Blocksalpha
alpha1&2
1&2 receptors
Beta
Beta11 Agonists
Agonists
•• Increases
Increases heart
heart rate,
rate, contractility,
contractility, and
and
conductivity
conductivity
Beta
β Blockers)
Beta Antagonists
Antagonists ((β
Blockers)
••
••
••
Frequently
Frequently used
used
Lower
Lower Blood
Blood Pressure
Pressure
Negative
Negative chronotropes
chronotropes &
& inotropes
inotropes
Beta
Beta11Selective
SelectiveBlockade
Blockade
®
•• atenolol
atenolol(Tenormin
(Tenormin®))
®®)
•• esmolol
(Brevibloc
esmolol (Brevibloc )
®
•• metoprolol
metoprolol(Lopressor
(Lopressor®))
Nonselective
Nonselective
®
•• propranolol
propranolol(Inderal
(Inderal®))
®®,
•• labetalol
(Normodyne
labetalol (Normodyne ,
®®)
Trandate
Trandate )
®
•• sotalol
sotalol(Betapace
(Betapace®))
Adrenergic
Adrenergic Receptor
Receptor Specificity
Specificity
Drug
Epinephrine
Ephedrine
Norepinephrine
Phenylephrine
Isoproterenol
Dopamine
Dobutamine
terbutaline
α1
α2
β1
β2
Dopaminergic
Web
Web Resources
Resources
•• Web
Web based
based synaptic
synaptic transmission
transmission project
project
–– http://www.williams.edu/imput/index.html
http://www.williams.edu/imput/index.html
Thank
Thank You!
You!
•• To
To Temple
Temple College
College EMS
EMS Professions
Professions for
for
permission
permission to
to use
use their
their materials
materials