Central Nervous System Stimulants Flashcards
What do CNS stimulants do
- increase the activity of CNS neurons
- can be the produced either through enhancement of excitation or suppression of inhibition
- in sufficient doses, all CNS stimulants can cause convulsions
- CNS stimulant have clinical usefulness in treatment of ADHD and Narcoplesy
- and they are used ( and abused) for non-therapuetic purposes
Caffeine
- a methylxanthine, similar structurally to purines
- theophylline and theobromine are very similar in structure and mechanism
MOA caffeine
- primary effect at normal caffeine doses: competitive antagonist of adenosine receptors
- postsynaptic adenosine receptors produce IPSPs (hyperpolarize)
- presynaptic adensosine receptors inhibit glutmate release
-caffeine inhibits these inhibitory effect (dis-inhibition) resulting in CNS stimulation
What does caffeine do at higher doses
- inhibits cAMP phosphodiesterase
- results in increased cAMP; responsible for its beneficial effects in the treatment of asthma (not as efficacious as other methylxanthines)
- induces the release of calcium from intracellular (ER) stores
pharmacological action of caffeine
- CNS stimulant
- peripheral effects
Caffeine as a CNS stimulant
- increased alertness; increased attention during sustained tasks
- decreased fatigue and drowsiness
- can cause nervousness, restlessness and tremors
- high doses stimulate medullary respiratory and cardiovascular centers
Caffeine peripheral effects
- positive inotropic and chronotropic effects (direct effects on the myocardium)
- dilates coronary and systemic blood vessels; constricts cerebral blood vessels (this may underlie the beneficial effects of caffeine in headache)
- produces diuresis
- increases gastric secretions
- modest bronchodilation
Therapeutic usefulness of caffeine
- primarily used to stay awake (various over the counter prescriptions)
- added to some aspirin preparations to treat headache (excedrin)
caffeine overdose
-excessive CNS stimulation: nervousness, insomnia, excitement
consequences of chronic use of caffeine
- tolerance: develops to the stimulant effects of caffeine
- physical dependence: develops to caffeine at the dose of two cups of coffee per day
-withdrawal symptoms include feelings of fatigue and sedation; headaches and nausea; vomiting (rare)
Sympathomimetic stimulants
- act through the enhancement of catecholaminergic neurotransmission
- cocaine
- amphetamine
- methylphenidate
Cocaine
- extracted from coca plant
- local anesthetic
- illicit use
- cacoaine is a weak base; therefore, unionized it is in the unprotonated form (B) which predominates at alkaline pH (native people chew leaves with soda lime
- 3 major forms: hydrochloride salt, purified free base, and impure base “crack”
How are free base cocaine and crack cocaine made
- extracting the hydrochloride salt from an alkaline solution into an organic solvent
- crack is made by adding bicarbonate to the hydrochloride salt
- both crack and free base are absorbed more quickly across membrane; but more importantly they are more volatile than the salt form and can be smoked
pharmacokinetics of coaine
- well absorbed through any mucous membrane
- time to peak effect and duration of action are depndent upon the route of administration (shortest are iv and smoke)
- metabolized in plasma and liver
- short plasma half life (50 min) even shorter CNS half life (10-30 min)
- urine screens detect metabolites
MOA cocaine
- potent inhibitor of the reuptake of NE, DA, 5-HT
- cocaine binds to the transporter itself and inhibits the binding of the neurotransmitter
- reinforcing effects are due to increased dopamine in the synapse
- increases the activity of tyrosine and tryptophan hydroxylase (due to loss of end product inhibition) -increase NT synthesis
- is a local anesthetic and vascosontrictor
Pharmacological effects of cocaine
- peripheral sympathomimetic effects (due to inhibition of NE reuptake in periphery)
- vasoconstriction, tachycardia
- increased alertness and vigilance (due to inhibition of NE reuptake in CNS synapses)
- euphoria elation, feeling of well being (due to inhibition of DA reuptake in the mesolimbic circuit
- as a result, cocaine has a high abuse liability
toxic effect of cocaine
- tolerance and physical dependence occur with heavy use, but they are mild
- mild withdrawal symptoms
- neurotoxicologic consequences to long term use: due to damage of dopaminergic neurons
- overdose can cause seizure;CV effect (myocardial infarction and arrhythmias)
- effects on developing fetus-more significant than alcohol
- premature labor, low birth weights, many learning and emotional problmes, attaachment disorder
Cocaine and its psychological dependence
- profound psychological dependence
- drug craving and seeking
- users crave the drug even 10 minutes after last dose
- abuse liability is greater with dosage forms that deliver drug rapidly to the CNS (smoking or iv)
- withdrawal symptoms: dysphoria, depression, sleepiness, fatigue
- cocaine cravings can be reduced by drugs that increase GABA including ganapentin, vigabatrin, baclofen
Amphetamine and methamphetamine
- structurally similar to Norepinephrine
- weak bases
- well absorbed orally; the free bas methamphetamine can be smoke (crystal meth)
- amphetamine is metabolized to a variety of metabolites and about 50% is excreted unchanged; methamphetamine is metabolized to amphetamine
- relatively long half lives (much longer than cocaine)
MOA for Amphetamine and Methamphetamine
- Potentiate NE, DA and 5HT signaling
- via actions at the trace amine associated receptor (TAAR1)
- TAAR1 is a GPCR, via cAMP/PKA phosphorylates reuptake carriers (DAT, NET, SERT( and VMAT2
- results in inhibition of uptake and reversal (release of the amines) from terminal or vesicles (VMAT2)
- partial agonist of alpha receptors
- MAO inhibitor at high doses
- more NE-like effects than cocaine
Pharmacological properties of amphetamine and methamphetamine
- arousal; increased wakefulness; decreased fatigue
- enhance athletic and intellectual performance (quantity is improved, not quality)
- elevated mood, increased self-confidence
- respiratory stimulant
- decreases appetite
- peripheral sympathomimetic
pharmacological properties amphetamine
-what is the active form
mixture of steroeisomers; active form is dextroamphetamine
pharmacological properties methylphenidate
-not technically an amphetamine, but structurally and mechanistically very similar
pharmacological properties methamphetamine
-gets into brain better, higher abuse liability
pharmacological properties lisdextrofetamine
-prodrug of dextroamphetamine
clinical uses amphetamine and methylphenidate
- Narcolepsy- use is complicated by risk of abuse and tolerance development
- Attention Deficit Hyperactivity Disorder: excessive motor activity, racing thoughts, difficulty in sustained attention; academic underachievement. is effective in many children
- exogenous obesity: obesity that is considered to be outside the control of the individual
side effects of amphetamine and metylphenidate taken at therapeutic doses
- insomnia
- abdominal pain
- anorexia, weight loss
- suppression of growth
- high body temperature
- facial tics
toxicity of amphetamines and methylphenidate (occurs at much higher doses than used for ADHD)
- acute toxicity: sympathomimetic effects; restlessness, dizziness, tremor
- psychosis due to excessive DA
- neurotoxicity: permanent intellectual problems; neuronal degeneration
- meth mouth: sever tooth decay, cause by a combination of dry mouth, lack of oral hygiene, increased consumption of sugared drinks, and teeth clenching and grinding
- abuse liability: esp iv or smoked methamphetamine; worse long term than cocaine
- sudden cardia death due to sympathetic activation
Nicotine-what is it and what is the mechanism of action
- naturally occurring alkaloid in tobacco products
- MOA: agonist of nicotinic cholinergic receptors
*NMJ: initially activates muscle contraction, but then desensitizes
- autonomic ganglia:
- sympathetic: release of epinephrine form adrenal
- parasympathetic: GI effects
- receptors in CNS:
- found in many brain regions; including nucleus accumbens (target of dopamine in the mesolimbic reward circuit)
- are monovalent cation channels; activation produces a membrane depolarization, thus produces excitation
Pharmacological actions of nicotine
- CNS stimulant-increases alertness
- Increases dopamine release in limbic, reward centers-is reinforcing
- muscle relaxant
- activates the chemoreceptor trigger zone and causes nausea (common with first exposure)
Explain why smoking is highly reinforcing
- reaches the brain very rapidly (lungs to brain in 7 sec)
- Increases dopamine signaling in the nucleus accumbens reward pathway
- each puff of smoke is a separate opportunity for the brain to associate smoking with reward; therefore it is highly addicting even though a single administration of nicotine is not as rewarding as a single administration of cocaine
what is the relationship between environmental factors or cues and smoking
Environmental factor or cues become associated with the reward as well
- setting (“I only smoke in bars”)
- time of day (“I only smoke after dinner”)
- preparation (“seeing an ashtray makes me want to smoke”)
can people really only be a social smoker
-not really because the number of administration perday (STRONG association between smoking and euphoria) and the environmental cues give it a high dependence liability
Describe nicotine tolerance`
- occurs over a very short period of time (hours: tachyphylaxis)
- therefore the first cigarette of the day is the best
nicotine withdrawal symptoms
- irritability, hostility, impatience
- anxiety
- depression
- difficulty concentrating
- increased appetite, weight gain
treatment of nicotine dependence
- Nicotine replacement: most widely used and there are many preparations
- active: nasal spray, gum, lozenge, sublingual tablet, inhaler
- passive: patches
-a large percent of patients using nicotine replacement are not smoking at 6 weeks but only 20% are abstinent for one year
Pharmacotherapies for smoking cessation
- bupropion
- Varenicline
bupropion
- antidepressant
- used as a sustained release preparation
- reduces craving and lessens some of the nicotine withdrawal symptoms (esp depression)
- side effects: insomnia, dry mouth
Varenicline
- partial agonist of nicotinic receptors
- rationale: reduce craving by activating the nicotinic achetylcholine receptor; will not desensitize like nicotine itself, also blocks the effects of nicotine if the person smoke (partial antagonist effect)
Side effects for varenicline
- nausea, headaches, constipation
- FDA concern for increase suicidal thoughts and depression
other drugs used to treat ADHD that are not classified as stimulants
- atomoxetine
- clonidine
atomoxetine
-selective norepinephrine reuptake inhibitor (SNRI); antidepressant
Clonidine
alpha 2 adrenergic receptor agonist
Guanfacine
alpha 2 adrenergic receptor agonist
