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Sedative-Hypnotic and Antianxiety Agents
Drugs Used to Treat Affective Disorders: Depression and
Bipolar syndrome
Antipsychotic Drugs
Antiepileptic Drugs
Pharmacological Mgt of Parkinson Disease
Skeletal Muscle Relaxants
Opioid Analgesics
Tight junctions between capillary endothelial cells;
CNS capillaries lack gaps and fenestrations seen in
peripheral capillaries

Astrocytes with the capillaries

Make up the BBB being an impermeable barrier.
A selective filter to protect the CNS by limiting
harmful substances that enter the brain and spinal
Nonpolar, lipid-soluble drugs -able to cross BBB by
passive diffusion.
Polar and lipophobic compounds -Unable to enter
the brain
Glucose - transported by facilitated diffusion
Other compounds including some drugs may be
able to cross BBB by active transport

A group of structurally similar CNS neurotransmitters that
include the catecholamines (dopamine, norepinephrine)
and 5-hydroxytryptamine (serotonin).
Catecholamines: Dopamine and Norepinephrine
Serotonin - Another monoamine
Substance -excitatory transmitter involved in spinal cord
pathways transmitting pain impulses
Endorphins, enkephalins, and dynorphins -endogenous
Excitatory transmitters in certain brain synapses that
inhibit painful sensations
Substance P

Endogenous opioids: enkephalins, endorphins,

Norepinephrine secreted by neurons that
originate in the locus caeruleus of the pons and
projects throughout the reticular formation.
An inhibitory transmitterbut overall effect is
excitation of the brain
Norepinephrine directly inhibits other neurons
that produce inhibition.
Called disinhibition - excitation by removing the
influence of inhibitory neurons.




Presynaptic action potential

Limits the amount of depolarization occurring in the
presynaptic terminal, will inhibit the synapse because
less neurotransmitter released.

Local anesthetics block propagation along neural axons

Referred to as presynaptic inhibition

Endogenous neurotransmitter GABA

2. Synthesis of neurotransmitter
If synthesis of neurotransmitters is blocked, impair
Ex: metyrosine (Demser) inhibits enzyme essential for
catecholamine biosynthesis in the presynaptic terminal.
Tx with metyrosine results in decreased synthesis of
transmitters such as dopamine and norepinephrine.

3. Storage of neurotransmitter
Example -antihypertensive drug
Reserpine (Serpalan, Serpasil) impairs the ability of adrenergic
terminals to sequester and store norepinephrine in
presynaptic vesicles.
4. Release
Either increase or decrease release of neurotransmitter from
the presynaptic terminal
Amphetamines increase presynaptic release of catecholamine
neurotransmitters (e.g., norepinephrine).
botulinum toxin (Botox) impair the release of acetylcholine
from the skeletal neuromuscular junction
5. Reuptake
Some chemical synapses terminate activity primarily by
transmitter reuptake.

Involves the movement of the transmitter molecule back

into the presynaptic terminal
Blocking reuptake actually increases activity at the synapse
Tricyclic antidepressants impair the reuptake mechanism
that pumps amine neurotransmitters back into the
presynaptic terminal, transmitter continues to prolong
activity at the synapse.
6. Degradation
Some synapses rely on enzymatic breakdown of the
transmitter to terminate synaptic activity.
Ex. inhibiting cholinesterase enzyme as a tx for myasthenia
Anticholinesterase drugs -neostigmine (Prostigmin) and
pyridostigmine (Mestinon) inhibit acetylcholine breakdown,
allowing more acetylcholine to continue its effects

7. Postsynaptic receptor
Antagonists can be used to block postsynaptic receptor to
decrease synaptic transmission.
Ex: beta blockers antagonists specific for the beta-adrenergic
receptors on the myocardium to treat hypertension
8. Presynaptic autoreceptors
There are also receptors on the Presynaptic terminal that
serve as a method of negative feedback in controlling
neurotransmitter release
The accumulation of neurotransmitter in the synaptic cleft
may allow binding to the presynaptic receptors and limit
further release of chemical transmitter
9. Membrane effects
Alter synaptic transmission by affecting membrane
organization and fluidity.

Sedative-Hypnotic and
Antianxiety Agents

Sedative implies calming effect

At higher doses, same drug can produce drowsiness and
initiate a relatively normal state of sleep (hypnosis).
At still higher doses, some sedative-hypnotics (especially
barbiturates) will eventually bring on a state of general
Sedative-Hypnotic Agents
Two general categories:
Benzodiazepines and nonbenzodiazepines
Benzodiazepines are typically used to promote normal
sedation and sleep, especially in relatively acute or shortterm situations.
Associated with treating anxiety (e.g., diazepam [Valium

Indicated specifically to promote sleep

Exert hypnotic effects similar to those of
nonbenzodiazepinessuch as the barbituratesbut
benzodiazepines are regarded as safer because of lesser
chance for lethal overdose
Prolonged use can also cause tolerance and physical
MOA : increasing the inhibitory effects at CNS synapses that
use the neurotransmitter gamma-aminobutyric acid (GABA).
Nonbenzodiazepines Barbiturates
Group of CNS depressants that share a common chemical
barbituric acid
Associated with a small therapeutic index
Very addictive, and has strong potential for addiction

Barbiturates function like -Potentiate the inhibitory effects of

At higher doses barbiturates -Directly increase the release of
inhibitory transmitters such as glycine, and increase the
release of excitatory transmitters such as glutamate.
At higher doses, barbiturates also depress neuronal
excitability in other areas of the brain and spinal cord
producing general anesthesia
Alcohol exert most of its effects by activating GABA a
receptors and increasing GABA-mediated inhibition in the
Alcohol decrease neuronal transmission causing CNS
Primary problem with sedative-hypnotic use is the residual
effects that can occur the day after administration.
Drowsiness and decreased motor performance the next day

Hangoverlike effects due to the drug being redistributed to

the CNS from peripheral storage sites or because the drug has
not been fully metabolized.
Long-term sedative-hypnotic drug use cause tolerance and
physical dependence.
Drug tolerance -The need to take more of a drug to exert the
same effect.
Dependence is described as the onset of withdrawal
symptoms if drug administration
Long-term use should be avoided,
Nonpharmacologic methods of reducing stress and promoting
relaxation (e.g., mental imagery, biofeedback) should be
Anxiety -fear or apprehension over a situation or event that
an individual feels is threatening.

Many drugsincluding sedative-hypnoticshave the ability

to decrease anxiety levels, but at the expense of increase in
Alleviating anxiety without producing excessive sedation is
desirable so one can function
Anxiolytic properties at doses that produce minimal sedation
are desirable
Benzodiazepines front-line drugs to treat anxiety
Diazepam (Valium) -prototypical antianxiety benzodiazepine
In anxiolytic dosages, diazepam and other benzodiazepines
decrease anxiety without major sedative effects.
Some sedation, however, may occur even at anxiolytic
These drugs can be used as sedativehypnotics simply by
increasing the dosage.

Benzodiazepines increase inhibition in the spinal cord,

causing skeletal muscle relaxation that contribute to their
antianxiety effects - the individual feels more relaxed.
Buspirone (BuSpar)
An antianxiety drug for treating general anxiety disorder.
Not a benzodiazepine but an azapirone
Does not act on the GABA receptor,
Its antianxiety effects by increasing the effects of 5hydroxytryptamine (serotonin) in certain areas of the
A serotonin agonist that stimulates certain serotonin
Buspirone produce less sedation and psychomotor
impairment than benzodiazepine agents

Use of Antidepressants in Anxiety

Many patients with anxiety also have symptoms of
Antidepressant drugs have direct anxiolytic effects
Sedation -the most common side effect of anxiolytic
Addiction and abuse - problems with chronic benzodiazepine
us; withdrawal is a problem
Anxiety can return to, or exceed, pretreatment levels when
benzodiazepines are suddenly discontinued- known as
rebound anxiety

Pharmacological Management
of Parkinson Disease

Parkinson disease No cure

Motor function slowly deteriorates
Dopamine-producing cells in the substantia nigra begin to
Loss of dopaminergic input into the corpus striatum
Lack of dopamine results in an activity increase in basal
ganglia cholinergic pathways
Normal: balance between dopaminergic and cholinergic
influence in the basal ganglia
Loss of dopaminergic influence in Parkinson disease appears
to allow cholinergic influence to dominate
Theories explaining the possible cause Parkinson Disease:
1. Genetic
2. Toxins
3. Free radical injury

Dopamine does not cross the blood-brain barrier.
The immediate precursor to dopamine,
dihydroxyphenylalanine- dopa crosses the blood-brain
barrier quite readily.
Dopa, or levodopa (the L-isomer of dopa),
Upon entering the brain, levodopa is transformed into
dopamine by decarboxylation from the enzyme dopa
The most effective single drug in the treatment of
Parkinson Disease
Most of the levodopa ends up as dopamine in the
peripheral circulation, and can cause gastrointestinal and
cardiovascular side effects

Levodopa is given in conjunction with a peripheral

decarboxylase inhibitor
Decarboxylase inhibitor -selectively inhibits the dopa
decarboxylase enzyme outside of the CNS enabling more
levodopa to reach the brain before being converted to
Carbidopa -a peripheral decarboxylase inhibitor given with
levodopa to prevent peripheral decarboxylation
Benserazide - another decarboxylase inhibitor used to
prevent peripheral conversion of levodopa to dopamine
Levodopa -always administered along with a decarboxylase
inhibitor such as carbidopa
These two drugs are often combined in the same pill
Levodopa with benserazide Madopar.

Problems and Adverse Effects of Levodopa Therapy

Gastrointestinal Problems- nausea and vomiting.
Can be severe during the first few days
This problem is greatly reduced if levodopa is given in
conjunction with a peripheral decarboxylase inhibitor such
as carbidopa.
Cardiovascular Problems
Cardiac arrhythmias may arise
Postural hypotension: PTs should always monitor BP and
avoid sudden postural adjustments
80 % of patients receiving chronic levodopa exhibit various
dyskinesias such as choreoathetoid movements, ballismus,
dystonia, myoclonus, and various tics and tremors

Behavioral Changes
Mental side effects have been reported; psychotic
symptoms, depression
Diminished Response to Levodopa
May be caused by a progressive increase in the severity of
Parkinson Disease rather than a decrease in drugs efficacy
Antihistamine drugs with anticholinergic properties are
also used
Less effective in treating parkinsonism, but have milder side
effects than their anticholinergic counterparts.
Amantadine (Symmetrel)
Originally developed as an antiviral drug
Ability to reduce parkinsonian symptoms discovered by

Help reduce dyskinesias and other motor complications

associated with levodopa
Primary adverse effects associated with amantadine are
orthostatic hypotension, CNS disturbance (e.g., depression,
confusion, hallucinations), and patches of skin discoloration
on the lower extremities (livedo reticularis).
Selegiline (Deprenyl, Eldepryl) is a drug that inhibits
monoamine oxidase type B (MAOB) enzyme.
This enzyme is responsible for breaking down dopamine. By
inhibiting this enzyme, selegiline prolongs the local effects of
dopamine at CNS synapses
Peak effects of drug therapy in patients receiving levodopa
occur approximately 1 hour after a dose of the medication
has been taken.
If possible, schedule therapy after the breakfast dose of

Monitor BP in patients receiving anti-Parkinson drugs to

check for orthostatic hypotension especially during the
first few days
Dizziness and syncope often occur because of a sudden
drop in BP
Susceptibility to falls is increased by the chance of
orthostatic hypotension.
Therapists must be especially careful to guard against falls
General Anesthetics
Anesthetics -general or local, depending on whether or
not the patient remains conscious when the anesthetic is
General anesthetics for more extensive surgical

Local anesthetics -when analgesia is needed in a

relatively small, well-defined area, or when the patient
needs to remain conscious during surgery
General anesthetics bind to CNS receptors that are
specific for gamma-aminobutyric acid (GABA).
GABA receptors contain a chloride ion channel that,
when activated by GABA, increases influx of chloride
ions into the neuron, thereby inhibiting that neuron.
By binding to GABA receptors, general anesthetics
increase the effects of GABA, thus enhancing CNS
inhibition throughout the CNS
This widespread CNS inhibition ultimately leads to a
state of general anesthesia.

Adjuvants in General Anesthesia: Neuromuscular Blockers

Another problem that therapists frequently deal with is
the tendency for bronchial secretions to accumulate in
the lungs of patients recovering from general anesthesia.
General anesthetics depress mucociliary clearance in the
airway, leading to a pooling of mucus, which may
Produce respiratory infections and atelectasis.
Therapists should prevent this accumulation of
pulmonary secretions by:
Encouraging the patients early mobilization
Respiratory hygiene protocols (i.e., breathing exercises
and postural drainage).
The caine suffix (lidocaine, procaine, and so on) usually
identifies local anesthetics.

Central neural blockade

Anesthetic is injected within the spaces surrounding the
spinal cord
Epidural nerve blockade injection of drug into the
epidural spacethat is, the space between the bony
vertebral column and the dura mater.
Caudal block - local anesthetic is injected into the
lumbar epidural space via the sacral hiatus
Spinal nerve blockade -injection within the subarachnoid
space that is, the space between the arachnoid
membrane and pia mater.
Also referred to as intrathecal anesthesia because the
drug is injected within the tissue sheaths surrounding the
spinal cord

Epidural and spinal blocks can be done at any level of

the cord, but are usually administered at L3-4 or L4-5
Central neural blockade -used when analgesia is
needed in a large region
Epidural and spinal routes are used frequently to
administer local anesthetics during obstetric
Procedures (including caesarean delivery) and for relief
of acute and chronic pain
Sympathetic block
Selective interruption of sympathetic efferent discharge
Useful in cases of complex regional pain syndrome
(CRPS) also known as reflex sympathetic dystrophy
syndrome (RSDS) and causalgia

Involves increased sympathetic discharge to an upper or

lower extremity causing severe pain and dysfunction in the
distal part of the extremity.
Differential Nerve Block
Refers to the ability of a local anesthetic to block specific
nerve fiber groups depending on the size (diameter) of the
The smallest diameter (type C) fibers that transmit pain are
usually the first sensory information blocked
Other sensory informationsuch as temperature, touch,
and proprioceptionis successively lost as the
concentration and effect of the anesthetic increases.
Finally, skeletal motor function is usually last to disappear
because efferent impulses to the skeletal muscle are
transmitted over the large type A-alpha fibers

Skeletal Muscle Relaxants

Upper motor neuron lesions interrupt the cortical control of
stretch reflex and alpha motor neuron excitability causing
Spasticity is not a disease but rather the motor sequela to
pathologies such as cerebral vascular accident (CVA), cerebral
palsy, multiple sclerosis (MS), and traumatic lesions to the
brain and spinal cord (including quadriplegia and paraplegia).
Skeletal muscle spasms describe increased tension seen
musculoskeletal injuries and inflammation (muscle strains,
nerve root impingements, etc.)
This tension is involuntary, so the patient is unable to relax
the muscle.
Spasms differ from spasticity because spasms typically arise
from an orthopedic injury to a musculoskeletal structure

Agents Used to Treat Muscle Spasms

An antianxiety drug
A muscle relaxant
Agents Used to Treat Spasticity
Dantrolene sodium
Two newer agents: gabapentin and tizanidine,
Bind preferentially to certain GABA receptors, which have
been classified as GABAb receptors enabling baclofen to act
as a GABA agonist, inhibiting transmission within the spinal
cord at specific synapses

Inhibitory to alpha motor neuron activity within the spinal

Inhibits excitatory neurons that synapse with the alpha
motor neuron (presynaptic inhibition), as well as directly
affecting the alpha motor neuron itself (postsynaptic
Results to decreased firing of the alpha motor neuron, with
relaxation of skeletal muscle.
Administered orally to treat spasticity
Does not cause generalized muscle weakness as directacting relaxants like dantrolene sodium
Baclofen is less effective in treating spasticity associated
with supraspinal lesions (stroke, cerebral palsy), because
baclofen does not readily penetrate the blood-brain barrier

Dantrolene Sodium
Only muscle relaxant available that exerts its effect
directly on the skeletal muscle
Impairs the release of calcium from the sarcoplasmic
reticulum within the muscle cell during excitation
Dantrolene is not prescribed to treat muscle spasms
caused by musculoskeletal injury.
Most common side effect of dantrolene - generalized
The use of dantrolene is sometimes counterproductive
because the increased motor function that occurs when
spasticity is reduced may be offset by generalized motor
Can cause severe hepatotoxicity

Effective in reducing spasticity as well as muscle spasms
because this drug increases the inhibitory effects of GABA in
the CNS.
Adverse effects: sedation
patients with spasticity who do not want a decrease in mental
alertness will not tolerate diazepam therapy very well.
Extended use cause tolerance and physical dependence thus
long-term treatment should be avoided
Developed originally as an antiseizure drug gabapentin
Decreases spasticity by inhibition in the spinal cord, thereby
decreasing excitation of the alpha motor neuron with
subsequent skeletal muscle relaxation.

Use of Botulinum Toxin as a Muscle Relaxant

Purified version of the toxin that causes botulism.
Systemic doses-extremely dangerous or fatal because
botulinum toxin inhibits the release of acetylcholine from
presynaptic terminals at the skeletal neuromuscular
Attracted to glycoproteins located on the surface of the
presynaptic terminal and inhibits proteins that are needed
for acetylcholine release
Botulinum toxin makes it impossible for the neuron to
release acetylcholine into the synaptic cleft
Removes spastic dominance so volitional motor function
can be facilitated
Results in improved gait and functional activities in cerebral
palsy, stroke, or traumatic brain injury

Muscles can be stretched or casted more

effectively, thus helping to prevent joint
contractures and decreasing the need for surgical
procedures such as heel-cord lengthening and
adductor release.
Long-term use of antispasm agents NOT
PRACTICAL because of the sedation and the
addictive properties that lead to tolerance and
physical dependence
Skeletal muscle relaxants are used to treat the
muscle spasms that result from musculoskeletal
injuries or spasticity that occurs following lesions
in the CNS