CNS: STIMULANTS

Introduction

š Pyschomotor stimulants
š Excitement
š Euphoria
š Increase motor activity
š Decrease fatigue
Methylxanthines
Methylxanthines

• Theophylline (found in tea)

• Theobromine (found in cocoa)

• Caffeine (coffee, tea, chocolate) ~ Most widely used stimulant in the

world!

• Primary MOA: blockade of adenosine receptors to indirectly increase

dopamine levels
Methylxanthines

Actions Therapeutic Uses Pharmacokinetics Adverse Effects

CNS: Mental alertness, Theophylline Metabolized by liver Insomnia
Decreased fatigue = used to treat (CYP1A2) Anxiety
asthma Agitation
CV: +Inotropic, Well absorbed orally,
(Beta2 agonists
+Chronotropic on the distributed Emesis
and/or
heart throughout body & Convulsions
corticosteroids are
BRAIN
Diuretic: Increased first line) PVCs/ Cardiac
urinary output of Na+, Cross placenta, arrythmias
Cl-, K+ expressed in breast
Death= lethal
milk
GI: Increased HCl acid dose is 10g (100
secretion cups of coffee)
Pulm: Relax smooth
muscle of bronchioles
Nicotine
Nicotine

š Active ingredient in tobacco

š 2nd most widely used CNS stimulant
š 2nd most abused drug
š Lipid soluble (BBB)
š MOA:
š Activates nicotinic receptors, inhibits monoamine oxidase
š low dose stimulates ganglia
š high dose blocks ganglia
Nicotine PK/PD
Nicotine

Actions Therapeutic Pharmacokinetics Adverse Effects

Uses
CNS: Highly lipid NONE (?) Metabolized by Irritability
soluble (crosses liver Tremor
blood brain GI cramps
Well absorbed
barrier) Diarrhea
orally, in lungs, GI
CV: Increases BP mucosa and skin Increased HR
& HR (worsens and BP
Clearance via
PVD, HTN)
lung, liver, & Increases rate
GI: appetite urinary excretion of metabolism
suppressant; for other drugs
*crosses placenta
+bowel activity
& secreted in
breast milk
Protective effects of smoking???

š Parkinson’s disease
š Alzheimer’s disease
š Endometrial cancer/ Endometriosis
š Ulcerative colitis
Smoking Cessation Varenicline (Chantix)

• Partial agonist at neuronal nicotinic Ach receptors in the CNS

• Produces less euphoric effects (b/c partial agonist)
• Attenuates rewarding effects of nicotine if pt relapses

MONITOR: Suicidal thoughts, vivid nightmares, mood changes

Cocaine

• Both psychostimulant and local anesthetic

• Increased addiction potential
• MOA: Blockade of reuptake of Norepinephrine, Serotonin,
Dopamine
• Potentiates and prolongs the CNS and peripheral actions
Cocaine AE:
 Other Psychomotor Stimulants

Amphetamine, Dextroamphetamine, Lisdexamfetamine, Modafinil,

Armodafinil, Methylphenidate, Dexmethylphenidate
MOA: increases the synaptic concentrations of norepinephrine and dopamine
Attention deficit hyperactivity disorder (ADHD)

š Adderall (Amphetamine)
š Atomoxetine (Straterra)
š Dexmethylphenidate (Focalin)
š Lisdexamfetamine (Vyvanse)
š Methylphenidate (Ritalin/Concerta)
Amphetamines: Adverse Effects
Modafinil (Provigil)
Armodafinil (Nuvigil)

š Rx indicated for Narcolepsy

š Promotes wakefulness
š Produces fewer psychoactive and euphoric effects typical of other CNS
stimulants
š MOA remains unclear
š Adverse effects: HA, nausea, nervousness
Local and General
Anesthetics
Selection of Anesthesia

š CV: Myocardial depression – heart and tissues cannot tolerate hypoperfusion;

Caution: CVD, ischemia, other heart disease
š Respiratory: Suppression of ventilation (IV anesthetics, opioids), Bronchodilation
(inhaled anesthetics) Caution: Asthma, other vent/perfusion disorders
š Liver/Kidney: clearance of agents, toxic
š Nervous System: Neurologic disorders (epilepsy, myasthenia gravis, etc),
Compromised cerebral circulation
š Pregnancy: Caution! (BZDs= oral clefts and Nitrous oxide= aplastic anemia in
fetus)
General Anesthesia

“A reversible state of CNS depression resulting in loss of response

to and perception of external stimuli.”
Benefits:
— Sedation & Anxiety reduction
— Lack of awareness and amnesia
— Skeletal muscle relaxant
— Suppression of reflexes
— Analgesia No one drug can do it all – General
anesthesia requires use of multiple
medications.
Preanesthesia Medications
Some functions of
adjuncts to anesthesia

š Anxiety – Benzodiazepines (BZD) Relieve anxiety

(benzodiazepines)

š Allergic Reactions – Antihistamines Prevent gastric acid

secretion
(H2 blockers)

š Nausea/Vomiting – Antiemetics / H2 Blocker

Prevent allergic reactions
(antihistamines)

š Analgesia – Opioids Prevent aspiration of

stomach contents and
postsurgical nausea

š Decrease Bradycardia/Secretions – Anticholinergics and vomiting

(antiemetics)

š Skeletal Muscle Relaxation – Neuromuscular Blockade

Provide analgesia
(opioids)

Prevent bradycardia and

secretion of fluids into the
respiratory tract
(anticholinergic drugs)

Facilitate intubation
and relaxation
(neuromuscular blocking agents)
Stages & Depth of Anesthesia

3 stages: Induction, maintenance, and recovery

1. Induction: time from administration of potent
anesthetic to development of effective
anesthesia.
2. Maintenance: provides sustained anesthesia
3. Recovery: time from discontinuation of
anesthetic until consciousness and reflexes
return
*Depth= degree to which the CNS is depressed.
Stages & Depth of Anesthesia

• Induction
• Maintenance of Anesthesia: Both inhalation and IV drugs
used, continuous monitoring of vital signs, opioids for
pain relief
• Recovery: Monitored for return of consciousness and
normal physiologic function (BP, HR, spontaneous resp)
• Depth (has 4 stages): I. Analgesia, II. Excitement, III.
Surgical anesthesia, IV. Medullary paralysis (severe
depression; ventilation must be supported to prevent
death.)
General Anesthesia: Inhaled Agents

š Used for maintenance of anesthesia

• Halothane š Decrease cerebrovascular resistance
• Desflurane (DES) š Decrease spontaneous ventilation
and hypoxic pulmonary
• Isoflurane (ISO) vasoconstriction
• Nitrous Oxide š MOA: bind to GABA receptor-
chloride ion channel complexes;
• Sevoflurane (SEV) increase chloride influx and
potassium efflux from the neurons
Halothane

š Potent anesthetic, weak

analgesic
š Metabolized to tissue-toxic
hydrocarbons (hepatitis)
š AE: bradycardia,
arrhythmia, hypotension,
malignant hyperthermia
Summary: Inhalation Anesthetics
General Anesthetics: IV

• Barbiturates
• Benzodiazepines š Cause rapid induction of anesthesia

• Ketamine š Can be used alone for short

procedures or to help maintain
• Opioids anesthesia for longer procedures
• Propofol (Diprivan)
Propofol

š Barbiturates (thiopental, methohexital)

š Generally 1st choice for inducing š Require supplementary analgesic

anesthesia (30-40s) administration

š Depresses the CNS, may cause some š SE: apnea, coughing, chest wall
excitatory phenomena such as muscle spasm, laryngospasm, bronchospasm
twitching, hiccups, etc š Benzodiazepines (midazolam, diazepam,
š Decreases BP and intracranial pressure lorazepam)

š Does NOT provide analgesia š Used in conjunction with anesthetics

for sedation
š Has some antiemetic effects
š Facilitate temporary anterograde
amnesia as well as sedation
š Metabolized by the liver
Other IV Anesthetics
š Opioids (fentanyl, sufentanil,
remifentanil)
š Commonly used in combination
with other anesthetics
š Can be administered IV,
epidurally, intrethecally
š SE: hypotension, respiratory
depression, muscle rigidity, and
nausea and vomiting
š Etomidate
š Only used with patients with CAD
or cardiovascular dysfunction
š Ketamine
š Dissociative anesthesia provides
sedation, amnesia, and immobility
š Patient may appear to be awake
š Increases BP and CO,
bronchodilator
š Mainly used in children and elderly
š Dexmedotmidine
š Used in ICU and surgery
š Provides sedation with respiratory
depression
š MOA: Alpha 2 receptor agonist
Summary: IV Anesthetics
Neuromuscular Blockers

š Used to abolish reflexes

• Cisatracurium
š MOA~ blockade of nicotinic
• Pancuronium acetylcholine receptors in the
neuromuscular junction
• Rocuronium
• Succinylcholine
• Vencuronium
*discussed in Ch.5 of textbook
Local Anesthetics

• Block sensation (low doses)

• Block motor activity (limited area of body – higher dose)
• MOA: block sodium ion channels to prevent action potential of
nerve membrane
• Applied or injected locally via
• Topical application
• Infiltration
• Ring blocks
• Peripheral nerve blocks
• Neuraxial blocks (spinal, epidural, caudal)
Local Anesthetics

• Lipophilic Carbon chain linked to either ESTER or AMIDE

• Most widely used are:
• Lidocaine (most commonly used)
• Bupivacaine (cardiotoxicity)
• Mepivacaine (do not use in Ob due to neonatal toxicity)
• Tetracaine
• Maximum dose based on weight should be calculated to prevent
overdose
• Epinephrine can be added to reduce toxicity and increase the duration
of action
Summary: Local Anesthetics
t
1SPDBJOF

t
5FUSBDBJOF
t
-JEPDBJOF t
.FQJWBDBJOF
CHARACTERISTIC ESTERS t
$IMPSPQSPDBJOF
t
$PDBJOF AMIDES t
#VQJWBDBJOF t
1SJMPDBJOF
t
3PQJWBDBJOF
Metabolism Rapid by plasma cholinesterase Slow, hepatic
Systemic toxicity Less likely More likely
Allergic reaction Possible- PABA derivatives form Very rare
Stability in solution Breaks down in ampules (heat, sun) Very stable chemically
Onset of action Slow as a general rule Moderate to fast
pKa's Higher than physiologic pH (8.5–8.9) Close to physiologic pH (7.6–8.1)

DRUG POTENCY ONSET DURATION

1SPDBJOF Low Rapid Short
$IMPSPQSPDBJOF Low Rapid Short
5FUSBDBJOF High Slow Long (spinal)
-JEPDBJOF Low Rapid Intermediate
.FQJWBDBJOF Low Moderate Intermediate
#VQJWBDBJOF High Slow Long
3PQJWBDBJOF High Moderate Long