CNS stimulants

Question 1

general properties of CNS stimulants

Answer 1

increase activity of CNS neurons, can either enhance excitation or suppress inhibition in sufficient doses, all stimulants can produce convulsions, CNS stimulants have limited clinical (therapeutic) usefulness (Attention-deficit, hyperactivity disorder, narcolepsy)

Question 2

Caffeine

Answer 2

methylxanthine compound in coffee. It is also found in cocoa and the kola nut. other natural methylxanthine include theophylline and theobromine. A cup or mug of coffee may have 80 to 200 mg of caffeine

Question 3

MOA: caffeine

Answer 3

1. MOA: block adenosine receptor (equilibrium-competitive antagonist) currently thought to be mechanism for CNS stimulation

postsynaptic adenosine receptors produce IPSPs
Presynaptic adenosine receptors inhibit glutamate release
Caffeine blocks both of these inhibitory effects–> CNS stimulation

2. MOA: inhibition of phosphodiesterase–> results in increased cAMP concentration (beneficial to asthma)
3. MOA: induces release of calcium from intracellular stores (endoplasmic reticulum)

Question 4

pharmacological actions of caffeine

Answer 4

CNS stimulant: increased alertness, and capacity for tasks requiring sustainted attention, decreased fatigue and drowsiness, nervousness, restlessness and tremors, high doses can stimulate medullary respiratory, vasomotor and vagal centers

PNS: stimulates myocardium positive chronotropic and inotropic effects, dilates coronary and constrics cerebral blood vessels. DIuretic effect, increases gastric secretion, modest bronchodilator activity

Tolerance develops to stimulant effects of caffein (physical dependence develops at a dose of 2 cups of coffee a day)

Question 5

sympathomimetic stimulants

Answer 5

compounds that act through the enhancement of catecholaminergic neurotransmission. includes cocaine, the amphetamines and non amphetamines stimulants such as methylphenidate

Question 6

cocaine

Answer 6

psychoactive alkaloid present in the coca plant

Chemistry: weak base, unprotanated form is unionized (predominates at alkaline pH), used in 2 major form

cocaine hydrochloride: water soluble
Cocaine free base: lipid soluble, volatile

Question 7

pharmacokinetics and metabolism of cocaine

Answer 7

well absorbed through most mucous membranes including the lungs, time to peak dependent of route of admin

metabolized primarily by serum and liver esterases, very short halflife (50 minutes)

test for cocaine: look for metabolites in urine

Question 8

mechanism of action cocaine

Answer 8

cocaine: potent inhibitor of reuptake of NE, dopamine, and serotonin

cocaine receptor on transporter for dopamine, competes for binding of the endogenous ligand resulting in increased ligand in the synapse

central reinforcing effects believed due to an action on dopamine synapses in the ventral striatum, increases tyrosine and tryptophan hydroxylase (due to loss of end-product inhibition)

local anesthetic, vasoconstrictor

Question 9

pharmacological effects of cocaine

Answer 9

peripheral symapthomimetic- due to increased norepinephrine (Vasoconstriction, tachycardia)

increased alertness: vigilance (increased NE in CNS)

Produces euphoria, feelings of elation, well being and competency (due to increase in Dopamine in mesolimbic circuit), high abuse potential- very reinforcing

toxicity and chronic use- tolerance, occurs and withdrawal syndrome is mild

fetal effects worse than cocaine

therapeutic uses: local anesthesia in upper respiratory tract

Question 10

amphetamine and amphetamine like drugs chemistry

Answer 10

most are a- methyl phenethylamine derivatives

weak base

Question 11

amphetamine (and -like) pharmacokinetics and metabolism

Answer 11

well absorbed orally, longer duration of action than cocaine (4-6 hours)
metabolism: deamination to benzoic acid (predominant route), also excreted unchanged as amphetamine-base excretion increased in acid urine

Question 12

amphetamine MOA

Answer 12

releases norepinephrine, dopamine, and serotonin

blocks transmitter uptake into presynaptic terminals (like cocaine)

direct partial agonist of alpha-adrenergic receptors

MAO inhibition at high doses

Question 13

amphetamine properties

Answer 13

wakefulness, alertness, decreased fatigue (more done but more errors), enhances athletic and intellectual performance, elevation of mood, increased self confidence, increase in motor and speech activities, speed, respiratory stimulation, decreased appetite, peripheral sympathomimetic effects

Question 14

specific agents of amphetamine class

Answer 14

all have similar effects, however intensity of central effects vary

Amphetamine: also some prodrugs that result in the production of amphetamine

Methamphetamine- better CNS bioavailability, more CNS effect, higher abuse liability

Methylphenidate- not actually an amphetamine but structurally and mechanistically very similar

Question 15

clinical uses of amphetamines

Answer 15

narcolepsy: day time sleepiness, amphetamine

ADHD: amphetamine, methylphenidate, excessive motor activity, racing thoughts, difficulty in sustained attention, academic underachievement

there are several non stimulant drugs being used to treat ADHD:

Atomoxetine: selective norepinephrine reuptake inhibitor
Clonidine and guanfacine: alpha 2 agonists

Question 16

Side effects of amphetamines

Answer 16

insomnia, abdominal pain, anorexia, weight loss, supression of growth, fever

Question 17

toxicity of amphetamines and methylphenidate

Answer 17

acute toxicity: sympathomimetic effects, restlessness, dizziness, tremor

psychosis due to excessive dopamine

neurotoxicity: abuse can lead to permanent intellectual problems

Abuse liability- very high
particularly for IV or smoked methamphetamine abuse liability is similar to cocaine, clinical deterioration is worse because of neurotoxicity

Question 18

nicotine

Answer 18

nicotine is self administered via use of tobacco- smoking chewing snuff

mechanism of action: agonist of nicotinic cholinergic receptors
NMJ- not as affected
autonomic ganglia: sympathetic ganglia activation results in release of epinephrine
parasympathetic ganglia activation is predominant , results in GI effects (nausea, increased motility)

CNS receptors: found in many brain regions, results in membrane depolarization (excitation)

Question 19

Pharmacological actions of nicotine

Answer 19

CNS stimulant: increased alertness, activates dopamine signaling in nucleus accumbens, therefore it is reinforcing, muscle relaxant

Question 20

tolerance and physical dependance on nicotine

Answer 20

tolerance and physical dependence: nicotine is absorbed readily through mucous membranes, lungs to brain in 7 seconds. Nicotine is reinforcing, it activates neuronal systems designed to maintain behaviors that are important for survival (each puff= reinforcing signal)

peripheral factors associated with nicotine (setting, preparation, time of day)

tolerance occurs throughout the day first cigarette is the best

nicotine withdrawal symptoms (irritability, impatience, hostility, anxiety, depression, difficulty concentrating, increased appetite, weight gain)

Question 21

treatment of nicotine dependence

Answer 21

nicotine replacement therapy (most widely used), replace nicotine partially, formulations nasal spray, gum etc)

Question 22

bupropion

Answer 22

MOA: unknown enhances noradrenergic and dopaminergic signaling

adverse effects: drymouth, insomnia

moderately effective, reduces craving and nicotine withdrawal symptoms

Question 23

varenicline

Answer 23

partial agonist of CNS nicotinic receptors, activates nicotinic receptors alone enough to reduce craving and withdrawal, reduces the effects of the full agonist, nicotine

produces significant increase in abstinence compared to placebo

adverse effects: nausea, insomnia, headache, constipation

increases thoughts of suicide and depression