Pharm: Alcohol and Drugs of Abuse Flashcards
psychological dependence
dependency of the mind - cravings, irritability, insomnia, depression, anorexia
= “addiction”
sensitization
i) An increase in response with repetition of the same dose of the drug (also known as reverse tolerance)
ii) Conditioning is a form of sensitization
iii) The dose-response curve shifts to the left
iv) Example drug: cocaine (repeated daily administration of cocaine to rats produces an increase in motor activity that increases over several days even though the dose remains constant)
mesolimbic DA system
a) Mesolimbic DA system
i) Prime target of addictive drugs
ii) Originates in the ventral tegmental area (VTA), a tiny structure at the tip of the brainstem, which projects to the nucleus accumbens, the amygdala, the hippocampus, and the prefrontal cortex
iii) Most projections of the VTA are DA-producing neurons: large quantities of DA are released in the nucleus accumbens and the prefrontal cortex when the DA neurons of the VTA are activated
iv) As a general rule, all addictive drugs activate the mesolimbic DA system
Dopamine hypothesis of addiction (DA reward pathway)
i) Dependence-producing drugs activate the mesolimbic DA system, releasing DA
ii) The pleasure-related (hedonic) effect results from activation of this pathway, rather than from a subjective appreciation of the diverse other effects (such as alertness or disinhibition) that the drugs produce
LSD
nonaddictive DOA - targets cortical and thalamic circuits
i) Lysergic acid diethylamine (LSD), mescaline, psilocybin
(1) Repetitive exposure leads to rapid tolerance (tachyphylaxis)
(2) Animals will not self administer hallucinogens, suggesting they are not addictive in nature
** LSD can cause flashbacks of altered perception years after consumption
PCP
nonaddictive DOA - targets cortical and thalamic circuits
Phencyclidine (PCP) and ketamine
(1) Developed as general anesthetics (ketamine is still used for this purpose)
(2) Club drugs sold under names such as angel dust, Special K, Hog
(3) Psychedelic effects last for about 1 hour and also include increased blood pressure, impaired memory function, disorientation, nystagmus, and visual alterations
(4) Classification of these NMDA antagonist as nonaddictive agents has been questioned due to animal research that shows that PCP can increase mesolimbic dopamine concentrations and has some reinforcing properties in rodents
** PCP may lead to irreversible schizophrenia-like psychosis
naloxone
(i) MOA: pure opioid antagonist that reverses effects of a dose of opiates within minutes
(ii) Provokes an acute withdrawal syndrome in situations where a dependent person has opiates in their system
Withdrawal symptoms include intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, fever
NOTE: naloxone is rapid acting, naltrexone is longer onset
methadone
- Long-acting opioids used for substitution therapy (half-life 25-52 hrs) for opioid dependence
Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
Abrupt discontinuation precipitates a withdrawal syndrome
buprenorphine
mixed agonist/antagonist (partial agonist at opioid receptors)
used for opioid dependence
methadone
- (i) Long-acting opioids used for substitution therapy (half-life 25-52 hrs)
(ii) Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
(iii) Given with supervised intake
(iv) Abrupt discontinuation precipitates a withdrawal syndrome
opioids
GPCR drugs: cause disinhibition of DA neurons
=Drugs that activate Gio-coupled receptors: cause disinhibition of DA neurons
(2) In the VTA, µ opioids cause an inhibition of GABAergic inhibitory interneurons, which leads to a disinhibition of dopamine neurons (see figure below)
(3) µ receptors cause euphoria when activated and are implicated in the reward effects of opiates (commonly abused µ opioids are morphine, heroin, codeine, oxycodone, and meperidine)
Withdrawal symptoms include intense dysphoria, nausea or vomiting, muscle aches, lacrimation, rhinorrhea, mydriasis, piloerection, sweating, diarrhea, yawning, fever
tx for OD: naloxone
tx for substitution therapy: methadone, buprenorphine
buprenorphine
- (i) Long-acting opioids used for substitution therapy (half-life 25-52 hrs)
(ii) Tolerance and physical dependence develop more slowly in comparison to other opioids (e.g., morphine)
(iii) Given with supervised intake
(iv) Abrupt discontinuation precipitates a withdrawal syndrome
cannabinoids
GPCR drugs: cause disinhibition of DA neurons
(3) The exogenous cannabinoid Δ9-tetrahydrocannabinol (THC) causes disinhibition of DA neurons by presynaptic inhibition of GABA neurons in the VTA (similar to opioids)
(4) Effects of THC include euphoria, relaxation, feelings of well-being, grandiosity, and altered perception of passage of time
(5) The THC-induced effects of increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain have led to the use of cannabinoids in medical therapy
(6) Chronic exposure leads to dependence with a mild and short-lived withdrawal syndrome (includes restlessness, irritability, mild agitation, insomnia, nausea, cramping)
dronabinol
(a) FDA-approved THC analog used for anorexia and weight loss in AIDS patients and cancer-chemotherapy induced nausea and vomiting
Nabilone
(a) THC analog used for the treatment of refractory nausea and vomiting associated with cancer chemotherapy and as an adjunct in chronic pain management
Gamma-hydroxybutyric Acid (GHB)
GPCR drugs: cause disinhibition of DA neurons
(1) GHB is produced during the metabolism of GABA, but the endogenous function is unknown
(2) Activates the GABAB receptor with low affinity and produces euphoria, enhanced sensory perceptions, feelings of social closeness, and amnesia before causing sedation and coma (originally introduced as a general anesthetic)
(3) Also known as liquid ecstasy or the date rape drug (has been used in date rapes because it is odorless, readily dissolved in beverages, reaches maximal plasma concentration 20-30 minutes after ingestion, and has an elimination half-life of 30 minutes)
(4) Recreational use only inhibits GABA neurons but at higher doses GHB hyperpolarizes DA neurons and inhibits DA release
(5) GHB targets GABAB receptors on both GABA and DA neurons, but those on GABA neurons are more sensitive to GHB and lead to disinhibition of DA neurons when activated
nicotine
(a) MOA: selective agonist of the nicotinic acetylcholine receptor (nAChR)
(b) Neuronal nAChRs are expressed on DA neurons in the VTA; activation fulfills the DA requirement of addictive drugs
(c) Though highly addictive, withdrawal is mild compared with opioid withdrawal and involves irritability and sleeplessness
buproprion
(i) Antidepressant with unknown mechanism of action
(ii) Used alone or in combination with nicotine-replacement therapy and/or behavioral therapy
varenicline
“chantix”
(i) Derivative of the plant-extract cytisine
(ii) Partial neuronal nAChR agonist
(iii) Only approved for treating smoking cessation
(iv) Prevents nicotine stimulation of mesolimbic dopamine system associated with nicotine addiction
cocaine
- MOA:
- peripheral nervous system, cocaine inhibits voltage-gated sodium channels and can be used as a local anesthetic
- CNS: Blocks the DAT and increases the DA concentrations in the nucleus accumbens (rewarding effects)
- CNS: Blocks the NET and activates the sympathetic nervous system, which leads to an acute increase in arterial pressure, tachycardia, ventricular arrhythmias, and pupil dilation
Sx: of use include loss of appetite, hyperactivity, and lack of sleep while overdose may lead to hyperthermia, coma, and death
Caution: !! Exposure increases risk for intracranial hemorrhage, ischemic stroke, myocardial infarction, and seizures !!
Withdrawal syndrome not as strong as that observed with opioids
(7) Reverse tolerance can occur (sensitization to small doses of cocaine)
(8) Susceptible individuals may become dependent and addicted after only a few exposures
(9) No antidote; intoxication management remains supportive with agents to control heart rate/rhythm (β-adrenergic receptor antagonist propranolol) and seizures (sedative-hypnotic diazepam)
amphetamines
(1) MOA: cause the release of endogenous biogenic amines by reversing the action of biogenic amine transporters at the plasma membrane
- Amphetamines are taken up into the cell by the DAT
- Amphetamines block the intracellular VMAT and deplete synaptic vesicles of their neurotransmitter content, which causes levels of DA and other amines (serotonin, norepinephrine) to increase in the cytoplasm
- Increasing levels of amines in the cytoplasm cause the DAT, SERT, and NET to work in reverse and release amines into the synapse!
Amphetamines are neurotoxic (dependent on the NMDA receptor and affects mainly serotonin and DA neurons)
Withdrawal consists of dysphoria, drowsiness (insomnia in some cases), and general irritability
Ecstasy
(MDMA; methylenedioxymethamphetamine)
MOA: similar to amphetamines (reverses the action of biogenic amine transporters)
- Preferential affinity for the SERT and strongly increases the extracellular concentration of serotonin
- Heavy users of MDMA report long-term cognitive impairment due
Acute toxic effects include hyperthermia, dehydration, serotonin syndrome (mental status change, autonomic hyperactivity, neuromuscular abnormalities), and seizures
Withdrawal consists of a mood “offset” characterized by depression lasting up to several weeks, possible increased aggression
schedule I
The drug or other substance has a high potential for abuse.
The drug or other substance has no currently accepted medical use in treatment in the United States.
There is a lack of accepted safety for use of the drug or other substance under medical supervision.
All research use is illegal under federal law
Examples = heroin, lysergic acid diethylamide (LSD), marijuana, and methaqualone.
schedule III
The drug or other substance has less potential for abuse than the drugs or other substances in schedules I and II.
The drug or other substance has a currently accepted medical use in treatment in the United States.
Abuse of the drug or other substance may lead to moderate or low physical dependence or high psychological dependence.
Prescription must be rewritten after six months or five refills.
Anabolic steroids, codeine and hydrocodone with aspirin or acetaminophen, and some barbiturates are examples of Schedule III substances.
schedule IV
The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule III.
The drug or other substance has a currently accepted medical use in treatment in the United States.
Abuse of the drug or other substance may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule III.
Prescription must be rewritten after six months or five refills; differs from Schedule III in penalties for illegal possession.
Examples of drugs included in schedule IV are propoxyphene plus aspirin (Darvon), pentazocine, meprobamate, diazepam, and alprazolam.
schedule V
The drug or other substance has a low potential for abuse relative to the drugs or other substances in Schedule IV.
The drug or other substance has a currently accepted medical use in treatment in the United States.
Abuse of the drug or other substances may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule IV.
As any other nonopioid prescription drug; may also be dispensed without prescription unless additional state regulations apply.
Cough medicines with codeine are examples of Schedule V drugs.
PK of ethanol
chemistry:
i) Alcohols are amphipathic compounds and have both hydrophilic (polar, water-soluble) and hydrophobic (nonpolar, water-insoluble) portions in their chemical structures
ii) The amphipathic quality of alcohols greatly enhances their ability to cross membranes and increases their extent of absorption and distribution
- EtOH is widely distributed to total body
- Alcohol crosses the blood-brain barrier and its distribution is proportional to total blood flow (concentration rises quickly due to total blood flow to the CNS)
** peak blood levels reached 30 mins after ingestion - absorption occurs through SI
Ethanol undergoes extensive first-pass metabolism by gastric and liver alcohol dehydrogenase (ADH)
metabolism of alcohol
zero order kinetics
- Alcohol dehydrogenase pathway
* Primary pathway for alcohol metabolism
- ADH catalyzes the conversion of ethanol to acetaldehyde and is located predominantly in the liver
- NAD+ is required to convert ethanol to acetaldehyde (this produces NADH, of which excess production may contribute to the metabolic disorders that accompany chronic alcoholism and to the lactic acidosis and hypoglycemia that frequently accompany acute alcohol poisoning) - Acetaldehyde metabolism
- Mitochondrial NAD+-dependent ALDH catalyzes the reaction of acetaldehyde to acetic acid, which is further metabolized to carbon dioxide and water
- NAD+ is required to convert acetaldehyde to acetic acid (produces NADH)
- thus 2 mol of NAD+ are required to convert 1 mol of ethanol to acetic acid (required by both ADH and ALDH)
- the body is only able to metabolize about 7-10 g of alcohol per hour (zero-order metabolism)
- Microsomal ethanol oxidizing system (MEOS)
- Mixed function oxidases (cytochrome P450s) use NADPH as a cofactor in the metabolism of ethanol to acetaldehyde
- At higher concentrations of ethanol (when NAD+ is depleted and the alcohol dehydrogenase system becomes saturated) there is increased contribution from the P450s, particularly 2E1, 1A2, and 3A4
- Chronic alcohol consumption induces MEOS activity (2E1) and can result in the enhanced activation of toxins, free radicals, and hydrogen peroxide
- Genetic polymorphism of ALDH
- Some individuals of primarily Asian descent have a low activity level of mitochondrial ALDH
- When these individuals drink alcohol, they develop high acetaldehyde concentrations and may experience facial flushing, light headedness, palpitations, nausea, and general “hangover” symptoms
- Appears to protect against alcohol dependence and abuse
- Individuals with the polymorphism in ALDH who are chronic heavy drinkers and/or alcohol dependent have an increased risk of severe liver disease due to the toxic effects of acetaldehyde
fomepizole
inhibits ADH and is used in the treatment of acute methanol or ethylene glycol poisoning (see below)
aspirin
inhibits gastric ADH and can increase ethanol bioavailability
levels of alcohol intoxication?
ALCOHOL IS A CNS DEPRESSANT!
intoxication = 80 mg/dL = .08% BAC
50-100 = sedation, “high”, slower reaction times
100-200 = impaired motor fn, slurred speech, ataxia
200-300 = emesis, stupor
300-400 = coma
> 500 = resp. depression + death
ion channels affected by alcohol?
1 - N-methyl-D-aspartate (NMDA) subtype of glutamate receptors
- Glutamate is the primary excitatory neurotransmitter in the CNS
- Receptor activation is implicated in many aspects of cognitive function including learning and memory
- Alcohol inhibits the ability of glutamate to open the cation channel of the NMDA receptor and leads to an increased depression of the CNS
- *Memory loss that occurs with high levels of alcohol (i.e., blackouts) most likely results from inhibition of NMDA receptor activation
- γ-aminobutyric acid (GABA) receptor
(a) GABA is the primary inhibitory neurotransmitter in the CNS
(b) Alcohol (like other sedative-hypnotics) enhances the effects of GABA on the GABAA receptor and leads to an increased depression of the CNS
** As concentrations of alcohol increase, individuals experience slurred speech, ataxia, impaired judgment, and disinhibited behavior
systemic effects of alcohol?
- respiratory depression d/t CNS depression
- heart: Depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol
smooth mm:
i) Ethanol causes vasodilation, likely due to CNS effects (depression of the vasomotor center) and smooth muscle relaxation caused by the metabolite acetaldehyde
ii) In severe overdose situations, ethanol can cause hypothermia caused by vasodilation
iii) Ethanol causes uterine muscle relaxation and was used intravenously for suppression of premature labor before the introduction of more effective and safe medications (e.g., calcium blockers, magnesium ion, β2-adrenergic receptor agonists)
GI effects of chronic alcohol use?
esophagus - reflux, barretts, mallory-weiss tears, esophageal cancer
stomach - gastritis
intestines - chronic diarrhea and poor absorption esp. of vitamin B –> can cause osteoporosis and increased brain injuries
pancreas - chronic and acute pancreatitis
liver - leading cause of liver cirrhosis! fatty infiltration!!
alcohol w/drawal sx?
seizures:
- Expression of NMDA receptors and voltage-sensitive Ca2+ channels are up-regulated, which may underlie the seizures that accompany alcohol withdrawal syndrome
- GABAA receptors are down-regulated, which leads to a continued hyperexcited state of the CNS during withdrawal
toxic psychosis
delirium tremens: delirium, hallucinations, fever, tachycardia
Neuro effects of chronic alcohol use?
- Degenerative changes of the nervous system occur with chronic alcohol abuse and include the following symptoms:
- Generalized symmetric peripheral nerve injury, which begins with distal parathesias of the hands and feet (most common neurologic abnormality of chronic alcoholics)
- Gait disturbances and ataxia
- Dementia and demyelinating disease (rare) - Wernicke-Korsakoff syndrome
- Paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death
- Associated with thiamine deficiency and rarely seen in the absence of alcoholism
- Treatment with thiamine will improve ocular problems, ataxia, and confusion, but most patients are left with a chronic disabling memory disorder known as Korsakoff’s psychosis - Painless blurring of vision occurs over several weeks of heavy alcohol consumption, with changes typically bilateral and symmetric (optic nerve degeneration may follow)
CV effects of chronic alcohol use?
- cardiomyopathy, ventricular hypertrophy, fibrosis –> heart failure
- arrhtymias
- HTN
- stroke
other systemic affects of alcohol use chronically?
- mild anemia d/t folic acid deficiency
- electrolyte imbalance, gynecomastia and testicular atrophy
- decreased mm. strength
- sweating (d/t vasodilation) and internal body temperature falls
- decreased libido
FAS
Fetal alcohol syndrome (FAS)
- Chronic alcohol abuse during pregnancy can have teratogenic effects (apoptotic neurodegeneration)
- Alcohol is a leading cause of mental retardation and congenital malformation
FAS includes:
(1) Intrauterine growth retardation
(2) Microcephaly
(3) Poor coordination
(4) Underdevelopment of midfacial region
(5) Minor joint abnormalities
Ethanol crosses the placenta and the fetal liver has little or no alcohol dehydrogenase activity and must rely on the mother’s liver for elimination
increased risk of what cancers w/ alcohol abuse?
increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver and may increase the risk of breast cancer in women (though alcohol is not a carcinogen)
Acetaldehyde and reactive oxygen species produced by increased CYP450 activity can damage DNA
management of acute alcohol intox?
i) Goals include the prevention of severe respiratory depression and aspiration of vomitus
ii) Glucose can treat metabolic alterations such as hypoglycemia and ketosis
iii) Thiamine is provided to protect against the Wernicke-Korsakoff syndrome
iv) Potassium may be required in the event of severe vomiting (if renal function is normal), along with electrolyte solutions
management of alcohol w/drawal syndrome?
- Moderate forms of alcohol withdrawal syndrome, characterized by tremor, anxiety, and insomnia, occur 6-8 hours after alcohol consumption is stopped and usually abate in 1-2 days
- Major pharmacological objective is to prevent seizures, delirium, and arrhythmias and include electrolyte rebalancing and thiamine therapy
- severe cases = use long-acting sedative-hypnotic drug for alcohol and then gradually tapering the dose
1. Long-acting benzodiazepines (chlordiazepoxide, clorazepate, diazepam)
- severe cases = use long-acting sedative-hypnotic drug for alcohol and then gradually tapering the dose
- Benefits: less frequent dosing and built-in tapering effect
- Disadvantages: pharmacologically active metabolites may accumulate, especially in patients with compromised liver function
2. Short-acting benzodiazepines (lorazepam, oxazepam) - Rapidly converted to inactive metabolites and are useful in patients with liver disease
Tapering of sedative-hypnotic medications can occur over several weeks with complete alcohol detoxification requiring several months of abstinence for restoration of normal CNS function
Diazepam
use - alcohol w/drawal sx of seizures
Long-acting benzodiazepines (chlordiazepoxide, clorazepate, diazepam)
- Benefits: less frequent dosing and built-in tapering effect
- Disadvantages: pharmacologically active metabolites may accumulate, especially in patients with compromised liver function
Lorazepam
use - alcohol w/drawal sx of seizures
Short-acting benzodiazepines (lorazepam, oxazepam)
- Rapidly converted to inactive metabolites and are useful in patients with liver disease
Oxazepam
use - alcohol w/drawal sx of seizures
Short-acting benzodiazepines (lorazepam, oxazepam)
- Rapidly converted to inactive metabolites and are useful in patients with liver disease
Naltrexone
** Approved for the treatment of alcohol and opiate dependence
MOA: µ opioid receptor antagonist (long-acting)
- Reduces the craving for alcohol and the rate of relapse to either drinking or alcohol dependence for the short term (12 weeks)
CI: in patients with acute hepatitis or liver failure
- Causes dose-related hepatocellular injury; avoid combination of naltrexone and disulfiram (also hepatotoxic)
Acamprosate
MOA: weak NMDA-receptor antagonist and GABA¬A receptor agonist (also affects serotonergic, noradrenergic, and dopaminergic systems)
Reduces short-term and long-term (more than 6 months) relapse rates when combined with psychotherapy
** caution in patients with kidney disease
AE: nausea, vomiting, diarrhea, and rash
Can be used in combination with naltrexone or disulfiram
Disulfiram
- MOA: irreversibly inhibits aldehyde dehydrogenase and causes extreme discomfort in patients who drink alcoholic beverages (flushing, throbbing headache, nausea, vomiting, sweating, hypotension, confusion due to the accumulation of aldehyde)
- effects start within minutes of alcohol consumption and last 30 minutes to several hours; effects may occur when alcohol is consumed up to 14 days after a previous dose
- Hepatotoxic and inhibits the metabolism of other therapeutic agents (phenytoin, oral anticoagulants, isoniazid, caffeine, barbiturates)
** Not a cure for alcohol dependence and must be used in patients who are highly motivated and have supportive therapy
**Not commonly used due to low compliance; evidence from clinical trials for its effectiveness is weak
Naltrexone
(1) Approved for the treatment of alcohol and opiate dependence
(2) MOA: µ opioid receptor antagonist (long-acting)
(3) Reduces the craving for alcohol and the rate of relapse to either drinking or alcohol dependence for the short term (12 weeks)
(4) Extensive first-pass metabolism; contraindicated in patients with acute hepatitis or liver failure
(5) Causes dose-related hepatocellular injury; avoid combination of naltrexone and disulfiram (also hepatotoxic)
ehtylene glycol ingestion
- Accidental overdose in pets and children due to the sweet taste of ethylene glycol in antifreeze (also in heat exchangers and industrial solvents)
- Metabolized to toxic aldehydes and oxalate
Treatment:
(1) Hemodialysis
(2) Ethanol infusion
(3) Fomepizole
Acamprosate
(1) MOA: weak NMDA-receptor antagonist and GABA¬A receptor agonist (also affects serotonergic, noradrenergic, and dopaminergic systems)
(2) Reduces short-term and long-term (more than 6 months) relapse rates when combined with psychotherapy
(3) Eliminated in urine as an uncharged drug; use caution in patients with kidney disease
(4) Most common adverse effects are nausea, vomiting, diarrhea, and rash
(5) Can be used in combination with naltrexone or disulfiram
methanol
- Poisonings can occur from accidental ingestion of methanol-containing products or when it is used by alcoholics as an ethanol substitute
** Most common characteristic symptom in methanol poisoning is blurred vision (“like being in a snowstorm”)
Treatment:
(1) Respiratory support
(2) Suppression of metabolism by ADH (ethanol and fomepizole)
(3) Hemodialysis to enhance methanol removal
(4) Alkalinization to counteract metabolic acidosis (bicarbonate)
* * Ethanol has a higher affinity than methanol for ADH and is often used intravenously as treatment for methanol poisoning
Fomepizole inhibits ADH and is approved for the treatment of methanol poisoning
ehtylene glycol ingestion
- Accidental overdose in pets and children due to the sweet taste of ethylene glycol in antifreeze (also in heat exchangers and industrial solvents)
- Metabolized to toxic aldehydes and oxalate
Treatment:
(1) Hemodialysis
(2) Ethanol infusion
(3) Fomepizole
which receptors does EtOH target?
Ionotropic receptors:
- N-methyl-D-aspartate (NMDA) glutamate receptors
- Cation channel (Na+ and Ca2+)
- Glutamate is the primary excitatory neurotransmitter in the CNS (memory)
- Alcohol inhibits NMDA receptor channel opening - GABAA receptors
- Anion channel (Cl-)
- GABA is the primary inhibitory neurotransmitter in the CNS
- Alcohol enhances GABA’s effects on the GABAA receptor
decreased NMDA function, increased GABAa function!
how do drugs that activate GPCR work?
Opioids, cannabinoids, GHB
Inhibiting Ca2+ influx and increasing outflow of K+ decreases the likelihood of an action potential and GABA release
Blocks the inhibitory effects of GABAergic neurons
Dopamine levels are increased because of dopamine neuron disinhibition
which drugs bind ionotorpic receptors?
Nicotine, alcohol, benzodiazepines, barbiturates, phencyclidine, ketamine
