PHARMACOLOGY: NEUROTROPIC DRUGS

By CJEVC

APPLICATION OF DRUGS AFFECTING THE NERVOUS SYSTEM • 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

BLOOD-BRAIN BARRIER • 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 cord.

• 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

MONOAMINES: • A group of structurally similar CNS neurotransmitters that

include the catecholamines (dopamine, norepinephrine) and 5-hydroxytryptamine (serotonin).

• Catecholamines: Dopamine and Norepinephrine • Serotonin - Another monoamine

PEPTIDES: • Substance -excitatory transmitter involved in spinal cord

pathways transmitting pain impulses • Endorphins, enkephalins, and dynorphins -endogenous

opioids, • Excitatory transmitters in certain brain synapses that

inhibit painful sensations • Substance P

• Endogenous opioids: enkephalins, endorphins, dynorphins

• 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.

CNS DRUGS ACT BY MODIFYING SYNAPTIC

TRANSMISSION

1. 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

transmission • 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

gravis. • 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 anesthesia.

Sedative-Hypnotic Agents Two general categories:

• Benzodiazepines and nonbenzodiazepines • Benzodiazepines are typically used to promote normal

sedation and sleep, especially in relatively acute or short-term situations.

Benzodiazepines • Associated with treating anxiety (e.g., diazepam [Valium

• Indicated specifically to promote sleep • Exert hypnotic effects similar to those of

nonbenzodiazepines—such as the barbiturates—but benzodiazepines are regarded as safer because of lesser chance for lethal overdose

• Prolonged use can also cause tolerance and physical dependence

• 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 GABA.

• 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 CENTRAL NERVOUS SYSTEM

• Alcohol decrease neuronal transmission causing CNS depression

• 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 instituted

• Anxiety -fear or apprehension over a situation or event that an individual feels is threatening.

• Many drugs—including sedative-hypnotics—have the ability to decrease anxiety levels, but at the expense of increase in sedation.

• 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

dosages • 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 5-

hydroxytryptamine (serotonin) in certain areas of the brain.

• A serotonin agonist that stimulates certain serotonin receptors

• Buspirone produce less sedation and psychomotor impairment than benzodiazepine agents

Use of Antidepressants in Anxiety • Many patients with anxiety also have symptoms of

depression. • Antidepressant drugs have direct anxiolytic effects • Sedation -the most common side effect of anxiolytic

benzodiazepines • 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

degenerate • 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

Levodopa • 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 decarboxylase

• 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 dopamine.

• 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 Sinemet.

• 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 Dyskinesias

• 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 drug’s 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

chance

• 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 levodopa

• 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 administered.

• General anesthetics for more extensive surgical procedures.

• 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 patient’s 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 space—that 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 fibers.

• The smallest diameter (type C) fibers that transmit pain are usually the first sensory information blocked

• Other sensory information—such as temperature, touch, and proprioception—is 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

• 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 • Diazepam

– An antianxiety drug – A muscle relaxant

Agents Used to Treat Spasticity • Baclofen • Diazepam • Dantrolene sodium • Two newer agents: gabapentin and tizanidine,

Baclofen • 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 cord.

• Inhibits excitatory neurons that synapse with the alpha motor neuron (presynaptic inhibition), as well as directly affecting the alpha motor neuron itself (postsynaptic inhibition)

• 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 direct-

acting 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

muscle • The use of dantrolene is sometimes counterproductive

because the increased motor function that occurs when spasticity is reduced may be offset by generalized motor weakness.

• Can cause severe hepatotoxicity

Diazepam • 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 Gabapentin

• Developed originally as an antiseizure drug gabapentin (Neurontin)

• 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 junction

• 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