PHARMA LECTURE 2: PHARMACOLOGY OF THE CNS Ia

GENERAL PRINCIPLES OF CNS PHARMACOLOGY CNS ORGANIZATION

● Specific chemical from neuron to neuron

CNS ORGANIZATION
● Propagate via synapses
● Generally excitatory or inhibitory
● Central Nervous System

○ Brain
■ Cerebrum Neurotransmitters
■ Brainstem
Group Transmitter Specific Transmitter General Effect
● Midbrain
● Pons Acetylcholine Acetylcholine Excitation
● Medulla
Monoamines
■ Cerebellum
○ Spinal Cord Catecholamine Dopamine Inhibition
● Limbic System - functional
5-hydroxytryptamine Serotonin Inhibition

Amino Acids

Glycine Inhibition

Gamma-aminobutyric acid
Inhibition
(GABA)

Aspartate Excitation

Glutamate Excitation

Peptides

Substance P Excitation
● Blood-Brain Barrier:
○ Tight Junctions between capillary endothelial cells Endorphin
○ Highly selective semipermeable Endogenous Opioids Enkaphalin Excitation
■ Nonpolar, lipid-soluble via passive diffusion Dynorphin
■ Glucose via facilitate diffusion Galanin
■ Some via active transport or endocytosis Leptin
Neuropeptide Y
Vasoactive intestinal
polypeptide (VIP)
Pituitary adenylate
cyclase-activating
polypeptide (PACAP)

Others

Adenosine
Purines
Adenosine Triphosphate

Histamine

Nitric Oxide

Vasopressin

Oxytocin
 GENERAL MECHANISMS OF CNS DRUGS
● CNS-related drugs:
○ Modify neuronal activity
○ Increase/decrease synaptic transmission (synapse is the
junction between two neurons)
■ Neurotransmitter quantity at pre-synapse
■ Receptor at post synapse
■ Both
○ Alter arousal levels (levels of consciousness)
● Sites that drugs may modify synaptic transmission (Sites drug act
on)
1. Action potential
● Block propagation along axon → not reach
presynaptic terminal
● Limit depolarization amount at presynaptic terminal
(presynaptic inhibition) → dec neurotransmitter
release (e.g. GABA)
2. Synthesis
● Block synthesis → deplete amount at presynaptic
terminal → impair transmission (e.g. metyrosine)
3. Storage
● Impair presynaptic vesicles → decrease prolonged
synaptic transmission (e.g. reserpine)
4. Release
● Increase/decrease presynaptic neurotransmitter
release → increase/decrease synaptic activity (e.g.
norepinephrine, botulinum toxin)
5. Reuptake
● Impair reuptake movement → transmitter remain at
synaptic cleft → continue effect → increase
synaptic activity (tricyclic antidepressants)
6. Degradation
● Inhibition of enzymatic breakdown → transmitter
remain at synaptic cleft → increase synaptic
activity (neostigmine)
7. Postsynaptic receptor
● Block postsynaptic receptor → decrease synaptic
activity (beta blockers)
● Affect receptor → increased neurotransmitter
binding or improved receptor-effector coupling or
both (benzodiazepines)
8. Presynaptic autoreceptor
● Bind to presynaptic receptors → impair release of
neurotransmitters (e.g. clonidine); relatively new
9. Membrane
● Affect membrane organization and fluidity → alter
receptor environment → alter presynaptic vesicles’
neurotransmitter fusion and release →
increase/decrease synaptic transmission (e.g.
alcohol)
ANTIEPILEPTIC DRUGS
EPILEPSY & ITS CLASSIFICATIONS
● Epilepsy
○ Chronic neurological disorder
○ Recurrent seizures
○ Due to spontaneous discharge of hyperexcitable cerebral
neurons
■ neuronal damage (stroke, tumor, head trauma)
■ systemic metabolic disorder (infection,
hypoglycemia, hypoxia, uremia)
● Seizure
○ Sudden, transient cerebral rapid and synchronized
excitation
○ Self-limiting
● Convulsion
○ Involuntary, paroxysmal skeletal muscle contractions
● Status epilepticus
○ Series of seizures without period of recovery in between
○ Continuous > 30 minutes
○ Unconsciousness between series of seizures
○ Due to:
■ Sudden drug withdrawal (antiepileptic, alcohol,
addictive drugs)
■ Cerebral infarction
■ Systemic or intracranial infections
○ Fatal if untreated, severe, and/or resistant to treatment
● Focal Seizures
○ Simple partial - full consciousness during seizure
○ Complex partial - altered consciousness
○ Secondarily Generalized - also known as focal becoming
generalized

Classification of Seizures
Seizure Classes & Subclasses Typical Symptoms
Generalized Seizures
Tonic-clonic Major convulsions of entire body;
sustained contraction of all muscles
(tonic phase) followed by powerful
rhythmic contractions (clonic phase);
loss of consciousness
Absence (petit mal) seizures Sudden, brief loss of
Typical consciousness; motor signs may be
Atypical absent or may range from rapid
Absence with special features eye-blinking to symmetrical jerking
Myoclonic absence movements of entire body
Eyelid myoclonia
Myoclonic seizure Sudden, brief, “shocklike”
Myoclonic contractions of muscles in the face
Myoclonic atonic and trunk or in one or more
Myoclonic tonic extremities; contractions may be
single or multiple; consciousness
may be impaired
Clonic seizures Rhythmic, synchronized
contractions throughout the body;
loss of consciousness
Tonic seizures Generalized sustained muscle
contractions throughout body; loss
of consciousness
Atonic seizures Sudden loss of muscle tone in the
head and neck, one limb, or
throughout the entire body;
consciousness may be maintained
or lost briefly
Focal Seizures
Simple partial seizures Consciousness remains intact, but
there are observable motor or
autonomic responses, including
convulsions confined to one limb or
specific sensory hallucinations
Complex partial seizures Consciousness or awareness is
impaired and may include a wide
variety of other manifestations and
bizarre behaviors
Secondary generalized seizures Symptoms progressively increase to
a bilateral, convulsive seizure,
including tonic, clonic, or
tonic-clonic components
● Tonic - total body
● Clonic - total body
● Myoclonic - only affects certain extremities, trunk, head
● Atonia - loss of tone
● Epilepsy cascade
○ Excessive neuronal excitation → harmful protein
production at neurons → damage neuronal mitochondria
→ apoptosis affected neuron → structural and functional
neuronal pathway changes → increased seizure
susceptibility
ANTISEIZURE DRUGS
● Drug therapy rationale:
○ Suppress affected neuronal excitability
■ Increase CNS inhibitory neurons (GABA)
■ Decrease CNS excitatory neurons (glutamate,
aspartate)
■ Stabilize opening and closing of neuronal Na or Ca
channels
● Other drug therapy uses:
○ Loss of consciousness
○ Falls
○ Cardiac irregularities
■ Arrhythmias
○ Social interaction
● Drug therapy success:
○ 50% elimination for seizures
○ 25% reduction for epileptic seizures
First Generation Second Generation
Definition Original drugs, primary Newer drugs, adjunct
agents agents
Advantages Monotherapy ● Mild side effects
● Few side effects ● Predictable
● Low cost pharmacokinetic
● No interaction with properties
other drugs ● For unresponsive to
● Better patient single first generation
adherence drugs and resistant
● Better seizure control seizure types
Examples Barbiturates ● Felbamate (Felbatol)
● Pentobarbital ● Gabapentin (Neurontin)
(Nembutal) ● Lacosamide (Vimpat)
● Phenobarbital ● Lamotrigine (Lamictal)
(Solfoton) ● Levetiracetam (Keppra)
● Primidone (Mysoline) ● Pregabalin (Lyrica)
Benzodiazepines ● Rufinamide (Banzel)
● Clonazepam (Klonopin) ● Tiagabine (Gabitril)
● Clorazepate (Tranxene) ● Topiramate (Topamax)
● Diazepam (Valium) ● Vigabatrin (Sabril)
● Lorazepam (Ativan) ● Zonisamide (Zonegran)
Hydantoins
● Fosphenytoin
(Cerebyx)
● Phenytoin (Dilatin)
Iminostilbenes
● Carbamazepine
(Tegretol)
 ● Oxcarbazepine Iminostil Carbamazepi All except Inhibit Na ● Dizziness
(Trileptal) bene ne (Tegretol) absence channels to ● Drowsiness
Succinimides Primary for reset from ● Ataxia
● Ethosuximide partial, inactive to ● Blurred
(Zarontin) tonic-clonic active p AP vision
Valproates Equivalent firing → ↑ ● Anemia
● Valproic acid to phenytoin time ● Water
(Depakene) between AP retention
● Valproate Na Oxcarbazepi Partial in until normal ● Cardiac
(Depacon) ne (Trileptal) adults and 4 firing rate → arrhythmia
● Divalproex (Depakote) -16 ↓ Na entry ● Congestive
y/o into neurons heart
Adjunct in > Inhibit ● failure
2 y/o, Off presynaptic
First Generation Antiseizure Drugs -label for uptake
neuropathic and release
Chemic Generic and Indication Mechanism Side pain of
al Trade of Action Effect/Issue norepinephri
Class Name ne

Barbitur Pentobarbital Severe, ↑ GABA ● Sedation Succini Ethosuximide Absence ↓ Ca influx to ● Nausea
ate (Nembutal) uncontrollabl inhibitory ● Nystagmus mide (Zarontin) thalamic ● Vomiting
Very e effect and/or ● Ataxia neurons ● Headache
Effectiv seizures; via Inhibit Ca ● Folate, Vit K ● Dizziness
e; IV entry at deficiency Methsuximid Not clinically - ● Fatigue
Cheap presynaptic ● Skin e (Celontin) used ● Lethargy
Phenobarbita Primary; All terminal problems ● Dyskinesia
l adult ↓ glutamate ● Small ● Bradykinesi
(Solfoton) seizures release therapeutic Phensuximid a
(tonic- index e (Milontin) ● Skin rashes
clonic, focal) ● ↑ seizures and itching
and
Primidone Tonic hyperactivit Valproat Valproic acid Absence ↓ Na entry ● GI distress
(Mysoline) -clonic, y in some e (Depakene) simple ↑ K efflux ● Temporary
Complex children And → neuron hair loss
partial, Valproate complex Hyperpolariz ● Weight gain
Focal sodium Complex ation → or loss
seizures did (Depacon) partial ↓ excitability ● Impaired
not Acute manic ↑ GABA platelet
respond to phase of ● function
other drugs Divalproex bipolar
sodium d/o
Benzodi Clonazepam Akinetic ↑ GABA ● Tolerance (Depakote) Off-label
azepine (Klonopin) Myoclonic inhibitory ● Sedation
For migraine
Effectiv Specific effect ● Ataxia
headaches
e absence ● Behavioral
● changes
Clorazepate Simple
(Tranxene) partial

Diazepam Status Second Generation Antiseizure Drugs

(Valium) epilepticus
acute Generic and Indication Mechanism of Side
Lorazepam treatment Trade Action Effect/Issue
(Ativan) Name

Hydant Phenytoin Primary for Inhibit Na ● GI irritation Pregabalin Adjunct in adult Inhibit Ca ● Dizziness
oin (Dilantin, many channels to ● Confusion (Lyrica) partial-onset channels → ● Drowsiness
Phenytek) epileptic reset from ● Sedation Chronic pain limit Ca ● Peripheral
types (tonic inactive to ● Dizziness Fibromyalgia entry edema
-clonic, active p AP ● Headache Diabetic ↓ glutamate ● All
partial) firing →↑ ● Nystagmus peripheral release disappear <
Off-label for Time ● Ataxia neuropathy 2 weeks of
neuropathic between AP ● Dysarthria Postherpetic ● continuous
pain until normal ● Gingival neuralgia use
firing rate → Hyperplasia
↓ Na entry ● Hirsutism Rufinamide Adjunct in adult Enhances slow ● Dizziness
into neurons ● Skin (Banzel) Lennox imactivation ● Drowsiness
At ↑ dose: disorders -Gastaut of ● Headache
K and Ca and >4 y/o Na channels ● Nausea
channels → prolong Na ● Fatigue
influenced channel
↑ GABA inactivation
→ limit Na
Phosphenyto Status Probably entry to
in epilepticus same effect neurons
(Cerebyx) acute on Na
treatment channels Tiagabine Adjunct in Inhibit reuptake ● Dizziness
Severe (Gabitril) partial seizures of GABA from ● Weakness
seizures; via not traditional in presynaptic ● Slight
IM or IV adults and >12 terminal → tendency
for <5 days y/o GABA for anxiety
active in and
Ethotoin Avoided d/t synaptic cleft depression
(Peganone) high toxicity for
longer period
Mephenytoin
 ● Must be:
Topiramate Mono or Inhibit Na ● Sedation
(Topamax) adjunct in channel ● Dizziness ○ Under close medical supervision
adults and opening ● Fatigue ○ Tapered off for 3-6 months
children c Stimulate GABA ● Ataxia ● Requirements:
partial, tonic receptors ○ Seizure-free at least 2 years while on meds
-clonic, ↓ ○ Good control of seizures within 1 year of onset
Lennox responsiveness
○ Normal neurological exam before withdrawal
-Gastaut of receptors
Prevent for glutamate ○ Childhood initial onset
migraine ● Pregnancy
headaches ○ Risk for congenital malformation, still birth, MR (mental
retardation), delays, infantile seizures:
Vigabatrin Adjunct in adult Inhibit enzyme ● Possible
■ 1 dose during pregnancy: 2x
(Sabril) complex breakdown damage to
■ > 2 doses during pregnancy: 3x
partial not GABA → retina
responsive to prolong ● Confusion ○ If discontinued, increased risk for uncontrolled seizures
other inhibition ● Drowsiness ○ For mothers:
drugs ● Fatigue ■ Use monotherapy of lowest effective dose
Infantile spasm ● Incoordinati ■ Avoid valproates
<2 y/o on ○ For babies, check:
● Weight gain
■ Developmental delays
● Joint pain
■ Withdrawal symptoms
Zonisamide Partial seizures Limit Na entry ● Well ● Status epilepticus
(Zonegran) in adults to neurons tolerated ○ Benzodiazepine (Ativan or Valium) → c or p, phenytoin or
→ Stabilize Na ● Sedation
fosphenytoin → phenobarbital or valproic acid → general
channel ● Ataxia
Inhibit Ca entry ● Loss of anesthesia via IV; slowly tapered off over 12 hrs.
to neurons appetite ● Rehabilitation patients
→ ↑ GABA ● Fatigue ○ Thorough medical history
release and
○ Note for seizure type, frequency, aura, triggers
inhibit
release ○ Note antiseizure meds, side effects, efficacy
glutamate. ■ Headaches
■ Dizziness
■ Sedation
Selection of a Specific Antiepileptic Agent ■ Nausea
● Patient by patient basis ■ Vomiting
● Trial and error ■ Ataxia
● Drugs altered periodically throughout lifetime for optimal results ■ Skin conditions
● Mono → mono alternative → adjunct with second gen drugs ○ Consider all as with risk for seizure
○ Timing: varies from patient to patient

PHARMACOLOGICAL MANAGEMENT OF PARKINSON’S

PARKINSON’S DISEASE

● Movement disorder
○ Resting tremor
○ Bradykinesia
○ Rigidity
○ Postural instability
● Due to slow, progressive degeneration of dopamine-secreting
neurons at basal ganglia
○ Dopamine at substantia nigra
○ Acetylcholine at corpus striatum
○ GABA and glutamate at: intra BG synapses, BG neurons
to thalamus, thalamic neurons to cortex
○ Serotonin and norepinephrine
● Drug therapy does not cure but alleviate motor symptoms

THERAPEUTIC AGENTS IN PARKINSONISM

● Levodopa
○ Cornerstone > 40 yrs.
○ Improves all, especially bradykinesia and rigidity
○ Taken orally c meals to decrease GI irritation
○ Dose progressively increased until noticeable sx reduction
or side effects apparent
○ Precursor of dopamine
○ Attempt to increase dopamine in basal ganglia o Direction
administration ineffective d/t BBB (blood brain barrier)
○ Must provide precursor to dopamine
SPECIAL CONSIDERATIONS ○ Premature conversion of levodopa in peripherals;
carbidopa
○ More levodopa crossing BBB → more dopamine at brain
● Medication withdrawal
● After, 60-70% seizure-free
 ■ With close medical supervision
■ To recover from drug toxicity or tolerance
■ Uncommon in late PD

Other Drugs to Treat Parkinson’s Disease

Drug Indication Mechanism of Side

Action Effect/Issue

Dopamine ● Apokyn: Longer half life ● Nausea

Agonist severe Steady → ● Vomiting
● Apomorphin akinetic/off prolonged ● Orthostatic
e (Apokyn) period in effect on ● hypotension
● Bromocripti late PD via dopaminergic ● Confusion
ne (Parlodel) SC receptors and
● Cabergoline ● Adjunct ↑Delay/prevent hallucinatio
(Dostinex) levodopa (↓ dopaminergic n in chronic
● Pramipexole levodopa neuron use
(Mirapex) effect, degeneration →
● Ropinirole end-of normalize
(Requip) -dose endogenous
● Rotigotine akinesia, dopamine
(Neupro) on-off ax
phenomeno
n)
● Mono in
mild to
moderate
early PD if
levodopa is
poorly
● Dopa decarboxylase inhibitors at periphery: tolerated; (-)
○ Carbidopa dyskinesia
○ Benserazide
● Sinemet
○ Carbidopa + Levodopa
○ 1:4 ratio in early PD; 1:10 ratio in late PD
● Madopar
○ Carbidopa + Levodopa + Benserazide
● Levodopa
○ Side effects:
■ Nausea and severe vomiting (reduced c carbidopa)
■ Cardiac arrhythmias
■ Orthostatic hypotension
■ Others occurring with carbidopa
● Decreased plasma pH
● Psychosis, depression, anxiety, confusion,
impulsiveness
■ Dyskinesia (choreoathetoid, ballismus, dystonia,
myoclonus, tics, tremors)
● In 80% chronic (3 months-3 yrs.) users
● Maybe d/t short half-life and erratic
absorption → intermittent stimulation of
dopamine receptors by endogenous
dopamine and levodopa
● Adjust dose and schedule; use other
anti-PD meds or serotonin and glutamate ANESTHETICS
● Fluctuating response to levodopa
○ Diminished response 3-4 yrs
Anesthetics
■ Drug tolerance
■ Progressive course of PD General Local
○ End-of-dose akinesia
Area Extensive Well-defined
■ Drug effect wear off before next dose
■ Resolve by sustained release (Sinemet CR) or Consciousness (-), no recollection (+)
frequent small doses of drug
○ On-off phenomenon Recovery Slower Faster
■ Off: sudden decrease of drug effectivity Residual More Less
■ On: sudden increase or increase after drug Effects
administration
■ Due to low plasma levels, poor GI motility, Use Surgical & Diagnostic Surgical & Nonsurgical
Procedures Procedures
competition c large amino acids for transport in
intestine Target Entire Body Specific; Doesn’t affect
■ Resolve by sustained release (Sinemet CR) or other organs
taken c low-protein small meals or alter oral dose
sched
○ Drug holiday
■ Gradual drug removal for 3 days - 3 weeks
 GENERAL ANESTHETIC REQUIREMENTS

1. Rapid onset of anesthesia

● Includes loss of sensation
2. Skeletal muscle relaxation
● Muscle relaxants
● Neuromuscular blockers
3. Inhibition of sensory and autonomic reflexes
4. Easy dosage adjustment during procedure
● Adjusted using valves
● Masks, injections
5. Minimum toxic side effects
6. Rapid, uneventful recovery p administration termination
● Anesthetic effects should wear off within 24 to 48 hrs.
after administration termination
7. Amnesia
● Loss of memory during the surgery (not an
illness/condition)

GENERAL ANESTHETIC INDUCTION STAGES

1. Analgesia
● Decreased somatic sensation, (+) consciousness and
awareness
2. Excitement/Delirium
● Decreased /(-) somatic sensation, (-) consciousness and
awareness, agitated and restless
3. Surgical Anesthesia
● Onset of regular, deep respiration
● RR and reflex activity
○ Determine RR and motor response
○ Breathing is regular, not much motor activity
4. Medullary Paralysis
● (-) of respiratory control at medulla oblongata → (-)
Spontaneous respiration (might result to death)
● (-) vasomotor center at medulla oblongata →
cardiovascular collapse
○ Vasomotor center regulates blood pressure
● Provide cardiorespiratory support (i.e. mechanical
ventilator) to avoid death
Note: This happens in order. 4th Stage (medullary paralysis)
should be prevented
Goals:
● Reach stage III ASAP
● Maintain stage III during the surgical procedure
● Taper off dose toward end
○ Slowly lessen the concentration of the drug, so that the
less favorable effects of the anesthesia are minimized
when the patient wakes up

Read:
Chapter 5 General Principles of CNS Pharmacology
Chapter 9 Antiepileptic Drugs
Chapter 10 Pharmacological Management of Parkinson’s Disease
Chapter 11 General Anesthetics
Chapter 12 Local Anesthetics