Block 3 Drugs Flashcards
parenterally administered anesthetic barbiturate quick action, short duration, long half-life
sodium thiopental activates GABA A receptors
barbiturate side effects
CNS depression (can be good) cardiovascular (vasodilation, venodilation) respiratory depression (must intubate)
parenteral general anesthetic used to induce & maintain anesthesia antiemetic 3.5 hr half life
propoforl GABA A mechanism
propofol side effects
pain on injection (inject w/ lidocaine into larger vein) initial excitation on induction CV: severe BP reduction AND decr myocardial contractility respiratory depression (more than thiopental)
used to induce anesthesia in patients at risk for hypotension
etomidate
etomidate side effects
lots of pain w/ injection, myoclonus nausea & vomiting suppression of adrenocortical response to stress only used w/ patients w/ hemodynamic problems CNS same as thiopental CV FAR less than thiopental Respiratory less than thiopental
produces dissociative anesthesia analgesia, amnesia doesn’t affect respiration, bronchodilator
ketamine NMDA receptor antagonist
ketamine side effects
nystagmus, salivation, lacrimation, spontaneous movement/increased muscle tone increase cerebral blood flow → increased intracranial pressure emergence delirium (less in kids) hypertension
ketamine’s usefulness
patients with bronchospasm kids for short, painful procedures
short-acting benzodiazepine GABA A activator use alone for conscious sedation, short procedures induction agent (less so), decreases anxiety
midazolam
midazolam pharmacokinetics
slower induction time, longer duration than thiopental metabolized to active metabolite
midazolam side effects
resp depression/arrest (esp IV) use w/ caution in patients w/ neuromuscular disease, parkinsons’, bipolar CV similar to thiopental
commonalities of inhalation general anesthetics
low therapeutic indices gaseous or volatile
factors that affect induction with a gaseous anesthetic
anesthetic concentration in inspired air pulmonary ventilation pulmonary blood flow arteriovenous concentration gradient
anesthesia achieved when?
when brain partial pressure is equal to MAC
moderate blood:gas PC, not quick recovery excreted unchanged into expired air uses: inhaled induces and especially maintains anesthesia, used with NO
isoflurane
isoflurane side effects
respiratory: airway irritant, coughing, decreases tidal vol, increase resp rate, depresses respiration, increases PaCO2 cardio: myocardial depression, decreased BP, arrhythmias, cerebral vessel vasodilation → increased intracranial pressure
volatile and RT; low solubility in blood, rapid induction and recovery; excreted unchanged used in outpatient surgeries, maintenance not induction, causes skeletal relaxation
desflurane
desflurane side effects
CV same as isoflurane resp: worse as irritant, bronchospasm
low blood:gas PC; 5% metabolized to fluoride ion in liver; degraded to compound A by absorbants inpatient and outpatient; induce and maintain; kids and adults; not resp irritant
sevoflurane
sevoflurane side effects
similar to isoflurane, not as much respiratory depression
rapid equilibration; used to enhance induction; weak anesthetic, don’t get MAC sedation, analgesia; use with others to reduce dose
nitrous oxide when emerging, use 100% O2
nitrous oxide side effects
CI w/ pneumothorax; negative inotrope (decr HR); sympathomimetic (helps increase HR); minimal resp effects besides O2 dilution; abuse liability
injection of local anesthetic around individual nerves/nerve plexuses
nerve block anesthesia
local anesthesia mechanism of action
act directly on nerve cells to block ability to conduct impulses bind directly to voltage-dependent sodium channel higher affinity for inactive channel than unopened channel
co-administration of local anesthetic with vasoconstrictors (eg epinephrine)
decrease rate of absorption into circulation, increasing duration of anesthesia less potential for systemic toxicity
order of CNS toxicity for local anesthetics
CNS stimulation first then CNS depression at higher doses death due to respiratory depression
cardiovascular toxicity of local anesthetics
general depression of CV after CNS effects: decreased contractility, decreased BP, decreased rate of conduction (arrhthmias), arteriolar vasodilation cardiac arrest
how are ester local anesthetics inactivated?
by plasma esterases
how are amide local anesthetics metabolized?
by the liver
local anesthetic; blocks pre-synaptic NE uptake potent vasoconstrictor topical anesthesis of upper respiratory tract
cocaine
short acting, synthetic local anesthetic low potency, slow onset, short duration
procaine
long acting, more potent, longer duration ester anesthetic spinal anesthesia, topical and opthalmic preparations
tetracaine
low water solubility so low toxicity applied to wounds and ulcerated surfaces
benzocaine
amide, intermediate duration of action; faster, longer lasting and more extensive anesthesia often used with vasoconstrictors
lidocaine
long acting amide, prolonged anesthesia, more sensory than motor block, more cardiotoxic
bupivicaine
long acting amide, S-enantiomer, less cardiotoxicity, motor sparing epidural and regional anesthesia
ropivacaine
amides
metabolized by liver not associated with allergic reactions
esters
metabolized by plasma cholinesterases rare allergic reactions
neuropsych drugs pt 1
amitriptyline clomipramine fluoxetine sertraline buproprion mirtazapine duloxetine phenelzine chlorpromazine clozapine thioridazine fluphenazine haloperidol olanzapine risperidone quetiapine aripiprazole
Which drugs are used in the treatment of depressive disorders?
SSRIs, SNRIs, Atypical drugs, Tricyclic antidepressants, MAOIs
5-HT uptake inhibitors
SSRIs- fluoxetine, sertraline
SSRI side effects
nausea, insomnia, and sexual dysfunction no food rxns, but dangerous “serotonin reaction” (hyperthermia, muscle rigidity, CV collapse) can occur if given with MAOIs
Do SSRIs have fewer or more adverse effects than TCAs and MAOIs?
less, so overdose risk is reduced
Symptoms of SSRI withdrawal
-dizziness, light-headedness, vertigo or feeling faint, shock-like sensation, paresthesia, anxiety, diarrhea, fatigue, gait instability, headache, insomnia, irritability, nausea or vomiting, tremor, visual disturbances -symptoms begin within 1-7 days after stopping an SSRI
SSRI approved uses
Major Depression OCD Panic disorder Social Anxiety Disorder PTSD Generalized Anxiety disorder PMS (now PDD) Hot flashes associated with menopause
effects on drug metabolism, long half-life active metabolite (7 days or more). now available as a sustained release product. used to treat PMS
fluoxetine
used to treat OCD, PTSD, Panic attacks; less effects on metabolism than fluoxetine, shorter half life.
sertraline
block both 5-HT and NE reuptake, side effect profile is more SSRI-like than TCA-like
SNRI drugs
12-18 hr half-life. also approved for neuropathic pain syndromes, fibromyalgia, back pain, and osteoarthritis pain. What is the drug and which patients to do you have to use caution with?
duloxetine -use caution in patients with liver disease
neuropsych drugs pt 1
amitriptyline clompiramine fluoxetine sertraline buproprion mirtazapine duloxetine phenelzine chlorpromazine clozapine thioridazine fluphenazine haloperidol olanzapine risperidone quetiapine aripiprazole
drugs without typical TCA structure of SSRI or SNRI action. May or may not block catecholamine uptake
Atypical antidepressants
weakly blocks NE and dopamine uptake. No weight gain or sexual dysfunction. what is the drug and what is it also approved for?
bupropion -also approved for nicotine withdrawal and seasonal affective disorder
blocks presynaptic alpha2 receptors in the brain. increases appetite
mirtazapine -good for AIDS patients with AIDS wasting syndrome
blocks NE and 5-HT reuptake; first highly effective drugs for the treatment of depression; now used secondarily to SSRIs and other newer compounds
tricyclic antidepressants
pharmacokinetics of TCAs
rapidly absorbed after parenteral or oral administration; relatively high concentrations are found in the brain and heart.
demethylated to active metabolites which are used as drugs themselves; long plasma half-life (8-100 hrs)
amitriptyline
side effects of TCAs
sedation cardiac abnormalities (due to anticholinergic effects and increased NE concentrations–>palpitations, tachycardia, and arrhythmias) overdoses: acute toxicity (symptoms include hyperpyrexia, hyper- or hypotension, seizures, coma, and cardiac conduction defects)
side effects of TCAs
sedation cardiac abnormalities (due to anticholinergic effects and increased NE concentrations–>palpitations, tachycardia, and arrhythmias) overdoses: acute toxicity (symptoms include hyperpyrexia, hyper- or hypotension, seizures, coma, and cardiac conduction
contraindications for TCAs?
recent MIs
TCAs and drug interactions?
TCAs effect absorption and metabolism of other drugs TCAs block guanethidine uptake sympathomimetic drugs; particularly indirect acting agents
therapeutic uses of TCAs
major depressive disorder (3rd choice) enuresis in childhood- imipramine chronic pain (neuropathic pain that opiates do not handle as well)- amitriptyline OCD- clomipramine and SSRIs
non-selective MAOI
phenelzine
produces mood elevation in depressed patients; may progress to hypomania particularly in bipolar disease; corrects sleep disorders in depressed patients; may produce stimulation in normals; antidepressant action takes about 2 weeks
MAOIs
symptoms of actue toxicity of MAOIs
agitation, hallucinations, hyperpyrexia, convulsions, and changes in bp
what do you have to restrict in patients on MAOIs?
dietary intake of tyramine
therapeutic uses of MAOIs
major depression (not first drug of choice, however) narcolepsy
other treatments for depression
electroconvulsive shock therapy (ECT) transcranial magnetic stimulation (TMS) cortical and subcortical electrical stimulation (still experimental)
nonspecific blockers of NE and 5-HT reuptake
amitriptyline
selective serotonin reuptake inhibitors (SSRIs)
fluoxetine, sertraline
serotonin-norepinephrine reuptake inhibitors (SNRIs)
duloxetine
monamine oxidase inhibitors (MAOI)
phenelzine
drugs with other monamine mechanisms
bupropion, mirtazapine
SSRI-like; used to treat OCD
clomipramine
actions of antipsychotic drugs
(treatments are not curative) decrease in psychotic behavior (negative symptoms of schizophrenia are not well treated by older typical agents) sedation
actions of antipsychotic drugs
decrease in psychotic behavior (negative symptoms of schizophrenia are not well treated by older typical agents) sedation extrapyramidal effects (biggest concern; dystonias, parkinsonism, akathisia, tar dive dyskinesia)
side effects of antipsychotic drugs. How can the long-term side effects be prevented?
extrapyramidal effects (biggest concern; dystonias, parkinsonism, akathisia, tardive dyskinesia); tardive dyskinesia can be prevented by “drug holidays” anticholinergic (dry mouth, blurred vision, urinary retention) orthostatic hypotension neuroendocrine effects (result of dopamine receptor blockade; prolactin effects and gynocomastia) allergic and idiosyncratic effects (liver, blood, and cutaneous) cardiac effects (thioridazine) decreased seizure threshold (particularly phenothiazines) weight gain (diabetes related events are more common with atypicals, particularly olanzapine, risperidone, clozapine, and quetiapine)
what is the potentially lethal side effect of antipsychotic drugs and what does it involve? How do you treat this?
neuroleptic malignant syndrome; potentially lethal hypodopaminergic side effect) hyperthermia, parkinson-like symptoms (muscular rigidity and tremor), mutism, and possible death treatment: cooling and hydration, bromocriptine and dantrolene (muscle relaxants, most common when used with SSRIs or SRNIs
original antipsychotics, currently less commonly used
phenohiazines
phenothiazine; aliphatic side chain; low to medium potency, sedative, pronounced anticholinergic actions
chlorpromazine
phenothiazine; piperidine side chain; low potency, sedative, less exrapyramidal actions, anticholinergic
thioridazine
phenothiazine; piperazine side chain; high potency, less sedative, more exrapyramidal reactions, less cholinergic
fluphenazine
why are atypical antipsychotics used over older typical antipsychotics?
need for better antipsychotic drugs, more acceptable side-effect profile, more efficacious in treating negative symptoms of schizophrenia in general, atypical antipsychotics have lower incidence of extrapyramidal symptoms (better compliance), possible lower incidence of tardive dyskinesia, improve negative symptoms, improve positive symptoms in many antipsychotic-resistant or refractory patients, less impact on cognitive functioning (??), more cost effective (???)
why are atypical antipsychotics used over older typical antipsychotics?
need for better antipsychotic drugs, more acceptable side-effect profile, more efficacious in treating negative symptoms of schizophrenia
atypical antipsychotic agents (5)
clozapine, olanzapine, risperidone, quetiapine, aripiprazone
blocks D4 and 5-HT2 receptors, little effect of D2, muscarinic antagonist, improves positive symptoms even in patients not helped by other drugs, improves negative symptoms
clozapine
side effects of clozapine
lowers seizure thresholds more than other antipsychotics (5-10% incidence) can cause fatal agranulocytosis, which requires monitoring!!
potent 5-HT2 antagonist, D1 and D2 antagonist, some D4, few extrapyramidal symptoms (5-HT>D)
olanzapine
side effects of olanzapine
weight gain and diabetes related adverse events reports of olanzapine abuse no agranulocytosis less seizure incidence than clozapine
combined D2 and 5-HT2 antagonist, greater reduction in negative symptoms and less extrapyramidal symptoms than traditional antipsychotics; paliperidone is the active metabolite, both are available as intramuscular depot preparations
risperidone
side effects of risperidone worse or better than clozapine?
less seizure activity and less antimuscarinic than clozapine
structurally related to clozapine, similar to risperidone and olanzapine in effects on schizophrenia symptoms and side effects; shorter half-life; approved for augmentation in depression. any abuse?
quetiapine; some reports of abuse
partial D2 agonist and 5-HT2 antagonist; also approved as an adjunct in depression (augmentation)
aripiprazole
uses of antipsychotic drugs
acute psychotic episodes (no matter what the cause) chronic schizophrenia manic episodes, bipolar disorder (aripiprazole, olanzapine, quetiapine, risperidone) schizoaffective disorder (paliperidone) augmentation in depression (aripiprazole, olanzapine, quetiapine) Tourette’s syndrome (haloperidol, pimpozide) antiemesis (not thioridazine)
monovalent cation, blocks manic behavior, no behavioral effects in “normals” inhibits phosphatase that converts IP2 to IP1 unbound to plasma proteins, 95% of dose eliminated in urine narrow therapeutic window
lithium levels raised by diuretics, ACE inhibitors, Ang II receptor blockers
lithium side effects
fatigue, tremor, GI symptoms, ataxia higher levels cause hyperactive deep reflexes, rigidity, coma
CI of lithium
pregnancy
clinical uses of lithium
mania, prevent recurrences of bipolar disease, cluster headaches
alternatives to lithium
carbamazepine, valproic acid for initial control of manic symptoms: haloperidol
blocks sodium channels, no interaction with GABA unpredictable absorption, hepatic enzyme induction used for partial seizures
carbamazepine
blocks repetitive neuronal firing, can reduce some Ca currents, increases GABA concentrations bound to plasma protein, in extracellular fluid used as first line drug in bipolar disease, sedating
valproic acid inhibits metabolism of drugs including carbamazepine
treatment of depressive episodes associated with bipolar disease (drug combination)
olanzapine and fluoxetine
carbamazepine side effects
CNS side effects such as sedation, confusion and ataxia, diplopia
valproic acid side effects
GI upset, weight gain, hair loss not dose related: hepatotoxicity and teratogenic (spinal bifida)
somatic correlates of anxiety
ANS arousal, voluntary muscle activation (jitteriness, tremor) complications: substance abuse
treatment of anxiety and insomnia
benzodiazepines, SSRIs, buspirone, classical antihistamines, EtOH, cannabis, opiates, barbiturates
benzodiazepine receptor agonists
diazepam, zolpidem
benzodiazepine receptor antagonists
flumazenil
partial agonist for 5-HT 1A, also binds to dopamine receptors delayed onset, little sedation, no dependence or cross-tolerance used for GAS
buspirone
benzodiazepines used to treat anxiety
diazepam, alprazolam, lorazepam
rapid onset of action, long duration used as hypnotic
flurazepam
fast onset of action, high lipid solubility, rapid redistribution muscle relaxant due to actions in spinal cord
diazepam
less lipophilic, slower absorption and onset of action, longer duration of action after single dose used as hypnotic
lorazepam
CNS effects of benzodiazepines
decreased anxiety, sedation, hypnosis, muscle relaxation, anterograde amnesia, anticonvulsant action, minimal CV/resp actions alone
benzodiazepine drug interactions
produce additive CNS depression with other depressants, can affect hepatic metabolism of drugs like cimetidine
clinical uses of benzodiazepines
anxiety states, sleep disorders, seizure treatment, IV sedation and anesthesia some used for alcohol withdrawal, acute manic episodes
benzo used for alcohol withdrawl
chlordiazepoxide
benzo used for acute manic episodes
clonazepam
symptoms of benzo withdrawal
anxiety, insomnia, irritability, headache, hyperacusis, hallucinations, seizures
other treatments for anxiety
SSRIs & SNRIs, beta-blockers, other sedatives (rarely)
hypnotic that binds to BDZ receptor on GABA complex weak anxiolytic, muscle relaxant and anticonvulsant preserves stage 3 and 4 sleep, duration 5-6hr
zolpidem
adverse effects of hypnotic effects
daytime sedation, ataxia, rebound insomnia, tolerance and dependence, occasional idiosyncratic excitement and stimulation
act at GABA A, rapidly absorbed and distributed, highly lipid soluble, renal excretion, additive with other CNS depressants used as anticonvulsant
barbiturate
barbiturate side effects
general CNS depression, anticonvulsant, respiratory depression tolerance (not uniform) physical dependence with withdrawal symptoms (seizures)
skeletal muscle relaxants
used to reduce muscle tone associated with spasticity related to MS injuries/other musculoskeletal disorders
GABA-mimetic agent working at GABA B receptors, interferes with release of NT used to reduce spasticity less sedation
baclofen
alpha2 adrenergic agonist, relieves muscle spasm side effects include drowsiness, hypotension, dry mouth interacts with CYP1A2 inhibitors
tizanidine
other agents used as muscle relaxants
botulinum toxin, dantrolene
what is the single “dose” size for alcohol. What is the dosing for beer, wine, and 80 proff liquor?
about 14 grams
this is the amount in:
12 ounces of beer
5 ounces of wine
1.5 ounces of 80 proof liquor
when a 70 kg person consumes 14 g of alcohol what does their blood alcohol become?
30 mg/dl
30mg%
0.03% w/v
This is equal to 7mM concentration
pharmacokinetics of alcohol
primary route of administration is oral
rapid absorption
primarily from the sall intestine, but can be absorbed through the GI tract
what factors effect the absorption of alcohol?
increased by gastric emptying
enhanced by carbonated beverages
decreased by the presence of food
what is effects the rate of absorption of alcohol
ethanol concentration
rate of ethanol consumption
distribution of ethanol?
does it cross membranes?
distribution to organs?
total body water
thus, Vd is equal to the volume of body water; essentially equal to the body weight
crosses membranes freely (including INTO the alveolae from the lung capillaries=basis for the brethalizer test of expired air)
distribution to individual organs depends on the degree of tissue vascularization and the amount of blood flow
what is ethanol metabolized to?
90-98% of ethanol that is ingested is metabolized to acetaldehyde by two enzymatic routes (the remainder is eliminated unchanged in the breath, sweat, and saliva)
does ethanol undergo a first pass effect?
Yes, ethanol has a significant first pass effect by both gastric and liver alcohol dehydrogenases
what is the primary, rate-limiting pathway of alcohol metabolism?
what type of kinetics does this enzyme undergo?
alcohol dehydrogenase
primarily in liver and GI tract
zero order kinetics (ex. 10g/hr in 70kg person-since one drink is 14g, takes about 1.5 hours to metabolize one drink)
what pathway does alcohol get shunted to once the alcohol dehydrogenase pathway becomes overwhelmed?
mixed function oxidase system (MFOS) through CYP2E1
pharmacokinetics for CYP2E1 pathway of ethanol metabolism?
high Km for ethanol (low affinity)
induced in chronic alcoholics
results in important drug interactions
what enzyme converts acetaldehyde to acetic acid during ethanol metabolilsm?
aldehyde dehyrdogenase
what are some properties of aldehyde dehydrogenase?
mitochondrial enzyme
inhibited by disulfiram
genetic polymorphisms in the gene that are very prevalent in Asian cultures
what are two consequences of alcohol metabolism?
and what do these two things cause/lead to?
increased NADH (causes inhibition of the TCA cycle; reduced gluconeogenesis; reduced fatty acid oxidation)
increased acetaldehyde (protein adduct formation; results in inflammation; inhibition of microtubules which can interfere with cellular and liver function; depletion of glutathione)
metabolic changes from alcohol metabolism can cause what side effects?
fatty liver
hepatic inflammation
induction of CYP2E1 (metabolism of xenobiotics to carcinogenic agents)
–>Bad news for the liver!!
what can heavy ethanol loads produce?
heavy alcohol load produces transient hypogylcemia (due to insulin secretion)
alcohol-induced ketoacidosis (increased serum ketones along with a mild increase in glucose; when our bodies start to use fat as fuel we get acid-base and metabolic dysfunction)
what are the CNS effects of ethanol?
several ion channels are sensitive to the presence of ethanol
most important is the GABAAreceptor-ligand gated chloride channel (causes a hyperpolarization)
disturbs the balance between excitatory and inhibitory neurotransmission in the brain; promotes inhibition
acute effects of ethanol?
dose-dependent; CNS depressant
effects from alcohol:
sedation, “euphoria”, increased reaction time, poor motor function, ataxia, emesis, stupor, coma, and death
chronic ethanol effects?
(Liver and GI specific effects)
Liver and GI effects:
steatosis (fatty liver)
Hepatitis C (often a co-morbid disease)
cirrhosis (due to liver necrosis and chronic inflammation)
gastritis, pancreatitis, malabsorption of vitamins
chronic diarrhea
cancers, including esophageal, liver, and bladder
chronic ethanol effects on the CNS?
tolerance occuring due to: adaptive neuronal changes (chronic ethanol–>CNS depression–>up-regulation of excitatory transmission to compensate) and metabolic tolerance (due to up-regulation of CYP2E1)
both psychological (craving) and physical dependence (withdrawal can be dangerous, especially because of seizures if metabolic imbalance occurs)
alcohol addiction
how prevalent is alcoholism?
alcohol addicition occurs in 5-10% of men and 3-5% of women
what are the effects of neurotoxicity of alcoholism?
neuralgias and peripheral nerve injury
memory impairment; blackouts
thiamine deficiency associated with chronic use can produce: cerebral/cerebellar atrophy, Wericke’s encephalopathy, Korsakoff’s psychosis
what are the teratogenic effects of alcohol?
associated with chronic maternal alcohol abuse
traid of symptoms in new born:
retarted body growth
facial abnormalities
CNS dysfunction
Ethanol and/or acetaldehyde affect embryonic cell proliferation
dose-dependent, but minimum dose is not known
do alcohol/ drug interactions occur?
Yes
CNS depressants are additive (barbituates; benzodiazepines; opiates; neuroleptics)
interactions with drug metabolism (acute, high doses can inhibit CYP-mediated metabolism; chronic ethanol induces CYP2E1, therefore accelerates metabolism of some drugs)
acetaminophen toxicity (is worse in alcoholics of when intoxicated because glutathione is depleted)
clinical pharmacology of ethanol-actue toxicity?
how can you treat acute alcohol toxicity?
acute intoxication:
generally 400mg/dl is lethal
(12 drinks)
support respiration and prevent aspiration of vomit
correct any metabolic problems (ex. dehydration, hypoglycemia, ketosis, electrolyte imbalance)
what are the signs of alcohol withdrawal and how do you treat alcohol withdrawal?
signs: alcohol craving, agitation, anxiety, insomnia, seizures, mood swings, sweating, tachycardia
goal: prevent seizures, delirium, arrythmias
therapy: short acting benzodiazepines: diazepam and chlordiazepoxide (subtutes for alcohol, then can taper off gradually; remember that the brain has increased excitatory transmission in response to chronic alcohol; atenolol is used to prevent cardiac arrythmias)
pharmacologic treatment of alcholism?
naltrexone, acamprosate, disulfiram (antabuse)
mu opiate receptor antagonist, can reduce craving, increase self-control in alcoholics, best when used in combo with psychosocial therapy
naltrexone
GABAA agonist, decreased drinking frequency and relapse, thought to normalize dysregulated neurotransmission (remove ethanol, left with unopposed increase in excitation)
acamprosate
SE of acamprosate?
diarrhea
inhibitor of alcohol dehydrogenase, results in the accumulation of acetaldehyde (very uncomfortable for the patient)
used as aversion therapy in alcoholics
disulfiram (antabuse)
(not very effective, requires considerable will-power to conform)
what is the role of CNS stimulants on CNS neurons?
what is a SE of all CNS stimulants at sufficient doses?
increase activity of CNS neurons
(can be produced either through enhancement of excitation or suppression of inhibition)
in sufficient doses all CNS stimulants can produce convulsions
what is the clinical usefulness of CNS stimulants?
attention-deficity, hyperactive disorder
narcolepsy
a methylxanthine, similar structure to purines, competitive antagonist of adenosine receptors.
where is this compound found?
caffeine
found in coffee beans, cocoa beans and kola nuts, is also added to OTC stimulants and analgesics (ex. Excedrin)
compounds with similar structure to caffeine found in tea
theophylline and theobromine
mechanism of action of caffeine?
primary effect at normal caffeine doses: competitive antagonist of adenosine receptors (postsynaptic adenosine receptors produce IPSPs–>hyperpolarize the membrane; presynaptic adenosine receptors inhibit glutamate release)
=>caffeine inhibits these inhibitory effects (dis-inhibition) resulting in CNS stimulation and excitation
what effects does caffeine have at higher doses?
at higher doses, caffeine inhibits cAMP phosphodiesterase (results in increased cAMP; responsible for its beneficial effects in the treatment of asthma-not as efficacious as other methylxanthines, however)
at higher doses, it also induces the release of calcuim from intracellular (ER) stores
pharmacological actions of caffeine when delivered in caffeine-containing drinks?
CNS stimulant
increased alertness, increased attention during sustained tasks
decreased fatigue and drowsiness
can cause nervousness, restlessness, tremors
high doses stimulate medullary respiratory and CV centers; can get tachycardia
peripheral effects of caffeine?
positive ionotropic 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 as an aid to stay awake in various OTC preparations
added to some aspirin preparations to treat headache (Excedrin)
toxicity and consequences of chronic use of caffeine?
“overdose” results in excessive CNS stimulation (nervousness, insomnia, excitement)
consequences of chronic use:
- 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)
what are the three sympathomimetic stimulants that act through enhancement of catecholaminergic neurotransmission?
cocaine, amphetamines, methylphenidate
extracted from the coca plant, major use is illicit, weak base (unionized in the unprotonated form [B] which predominates at alkaline pH)
cocaine
two major forms of cocaine
hydrochloride salt and free base forms
how is free base cocaine formed?
what is the benefit of having a free base form of cocaine for users?
free base cocaine (crack cocaine that can be smoked) is made by extracting the hydrochloride salt from an alkaline solution into ether or another organic solvent
free base is absorbed more quickly across membranes; but more importantly it is volatile and can be smoked
pharmacokinetics of cocaine?
well absorbed through any mucous membrane
time to peak effect and duration of action are dependent upon the route of administration (shortest are i.v. and smoked)
metabolized in plasma and liver
short plasma half-life (50 min); CNS half-life is even shorter (10-30 min)
urine screens detect metabolites
mechanism of action of cocaine?
potent inhibitor of the reuptake of norepinephrine, dopamine, and serotonin
cocaine binds to the transporter itself and inhibits the bindng of the neurotransmitter (reinforcing effects are due to increased dopamine in the synapse)
increases the activity of tyrosine and tryptophan hydroxylases (due to loss of end-product-monamine- inhibition)
is a loca anesthetic and vasoconstrictor
