FOBS Exam II Pharm Flashcards
Drugs of ADHD
Methylphenidate Amphetamines Lys-dexamphetamine Pemoline Atomoxetine
Amphetamines are CNS Stimulants that act to
How are they diff in adults and children?
enhance DA in the synapse, enhanced NE neurotransmission in the CNS
Adults - euphoria, insomnia, appetite suppression, and shift to paranoia
Children - calm hyperactive behavior
Mechanism of amphetamines
run the DA re uptake transporter (DAT) in reverse (synaptic concentration of DA are increased)
reverse the action of the re-uptake transporter at catecholamine synapses (NE and DA levels are elevated)
children with ADHD have a DAT that runs
in reverse - extrudes DA (ADHD sx)
so amphetamines cause them to start fxning to take up DA (slowing behavior)
Methylphenidate mechanism
facilitation of release of central DA and NE
mechanism in ADHD is unknown though
Methylphenidate metabolism
hepatic metabolism
2.5 h 1/2 life
dosing in the morning and during school hours
penetration to CNS is slower compared with cocaine or amphetamine (lower abuse potential)
Methylphenidate toxicity and contraindications (CI)
insomnia
anorexia
weight loss and growth retardation (long term therapy)
CI in HTN, glaucoma, anxiety, seizure disorder
Methylphenidate XL
Extended release
effects last 12-14 hours (dont need to give during school hours)
Methylphenidate transdermal patch
Slow onset - delayed 1 hr, good for kids who can’t swallow pills
Approximately 8 - 10 hr effect
Take off patch!!
Amphetamine Combinations
d-amphetamine saccharate
amphetamine aspartate
amphetamine sulfate
d-amphetamine sulfate
different salts contribute to more sustained effects because the salts have diff rates of going into solution in GI tract
Most likely to be abused ADHD formulation?
Amphetamine combination (adderall)
Lys-dexamfetamine
Children or adults?
Both children and adults - decreased the abuse potential of the d-amphetamine (bound to lysine that has to be split off in liver)
amphetamine side effects
insomnia, weight loss, emotional lability (adults - elated/out going to angry/withdrawn, emotions not seen so much in children)
High doses in adults can cause paranoia
Major problem with prescribing amphetamines
high abuse potential
Schedule II agents
Pemoline
Duration of action
Toxicity
Abuse
Equal to methylphenidate in effectiveness
Long duration of action
HEPATOTOXICITY
No abuse potential
Atomoxetine
Duration of action
Toxicity
Abuse
NE selective reuptake inhibitor
Non-stimulant, long acting
Anticholinergic effects - BPH males are not good candidates
Low abuse potential
BZD Agonists
Diazepam Alprazolam Lorazepam Oxazepam Flurazepam Triazolam Estazolam Temazepam
BZD antagonist
Flumazenil
BZD-1 Selective Binding Drugs
Eszopicolone
Zolpidem
Zaleplon
Sedative definition
diminish awareness
cause drowsiness
diminish motor activity
Hypnotic definition
promotes sleep and inhibits wakefulness
GABAa receptor complex effected by what anxiolytics/sedative-hypnotics
BZD
Barbiturates
Ethanol
Alpha unit binds
Alpha/beta junction binds
Gamma unit used for
GABA
BZD
Gamma unit present for BZD to modulate GABA
When GABA binds the channel opens to release
Cl- ions
Increased Cl- conductance inhibits neural firing
Decrease Cl- conductance excites neurons (seizures –> why local anestheics can cause seizures because they effect the small unmyelinated fibers first which GABA neurons are small unmyelinated)
BZD as an hypnotic
Problem with combining with other hypnotics?
Dependence?
Efficacious hypnotic with fast onset SAFE by themselves When combined with sedative-hypnotics such as etoh or barb, lethality is enhanced Dependence is a serious problem Long half lives = hangover
BZD Overdose
Usually not a problem
If mixed with EtOH or opioids –> severe respiratory depression
Diazepam
Actions
Half life
anxiolytic, hypnotic, muscle relaxant, pre-anesthetic
blocks convulsions in EtOH or BZD withdrawal
Terminates status epilepticus (second to lorazepam which is more water soluble)
Long half life = 50+ hrs
Alprazolam
Actions
Side effects
Anxiolytic, hypnotic
Intermediate acting
Early morning awakening, tolerance/dependence if over-used, less sedative than other BZD
Lorazepam
Anxiolytic and hypnotic
DOC for status epilipticus - better water solubility
Oxazepam
Beneficial for people w/ this dz?
Anxiolytic and for sleep induction
Live dz patients and elderly because better pharmacokinetics (changes in Phase 1 metabolism)
Also seen in Temazpeam and Lorazepam
Drug interactions with BZDs
Additive: EtOH, BZDs, opioids, antipsychotics, TcA, antihistamines
BZD Abstinence Syndrome (withdrawal signs and sx)
Signs: tremor, seizures
Sx: anxiety, insomnia, nausea, malaise
BZD tolerance
More tolerance with sedative than anxiolytic
Many pts escalate the dose to treat anxiety or insomnia
Higher the dose, more frequent the dose, longer the dose is taken = greater the tolerance
Greater the physical dependence = nastier the withdrawal syndrome
BZD dependence problem with anxiety
Initial anxiety returns during withdrawal
Additional anxiety occurs because of withdrawal
= intolerable anxiety
Sx occur BEFORE signs of withdrawal
BZD Dependence
Cross dependence with other sedative hypnotics - EtOH and barbs
“Dependence of the sedative-hypnotic type”
Limit the # of pills in a prescription and counsel the pt
Shorter elimination 1/2 life drugs give what kind of s/sx of withdrawal
Nastier
Longer are less severe but more protracted (consider giving a long acting BZD if withdrawal s/sx seem to be intolerable)
Two problems with insomnia
getting to sleep
staying to sleep
BZD as sedative-hypnotics
Problem with long, short, intermediate acting?
Problem with all BZDs?
Effective
Hangover with long-acting BZDs
Rebound insomnia and anxiety in short acting
Early morning awakening in short/intermediate acting
Tolerance/dependence/withdrawal
Triazolam
1/2 life
SE
Short half life = 3-4 hours
No hangover
SE: rebound insomnia and other withdrawal signs with continued use (some even with 1 dose), amnesia, tolerance
Zolpidem Binds what? As efficacious as BZD? 1/2 life? Abuse? Rebound insomnia?
Binds a subset of BZD receptors (BZD1) - not a BZD!!
Nearly as efficacious in producing sleep as a BZD but less anxiolytic, anticonvulsant, muscle relaxant
Short 1/2 life = 3-5 hrs (less hangover)
Abuse/dependence = lower than BZD
No rebound insomnia
Eszopiclone
Zolpidem
Zaleplon
All work on what receptor
Selectively to GABA receptors containing the alpha1 subunit (BZD1)
Zaleplon
Binds?
Use PRN for what?
Binds BZD1 receptors
Shorter half life than zolpidem = 1 hr
Used for before bedtime or awakening in the middle of the night (4+ hr remaining)
Eszopiclone
d-isomer of zopiclone, not a BZD but binds BZD1
Melatonin
Hormone from?
Used for?
CI in what?
Pineal gland hormone that regulates sleep/wake cycle
Useful for sleep problems related to jet lag, changing day/night working hours
Variable dose - can get OTC, no dependence problems
Depression is Contraindicated
Ramelteon
Binds?
Abuse?
Withdrawal?
Binds melatonin receptors (MT1 and MT2)
No dependence of abuse liability
No rebound insomnia or withdrawal
Can’t use Ramelteon with
Fluvoxamine - bc it binds CYP1A2 inhibiting its metabolism
Caution in administering any hypnotic to a pt with a hx of
Depression
Barbiturates
Pentobarbital
Secobarbital
Phenobarbital
Barbiturates Therapeutic Index
Poor
Phenobarbital for seizure control and the other two are supervised (hospital) as sleep agents (seco/pentobarbital)
BZD + Barbiturates
Profound CNS depression, anesthesia, coma
Respiratory depression
Abuse potential
BZD vs Barbiturates
Both facilitate GABA but neither bind GABA site directly
Barb directly increase Cl- flux at high doses
No dose of BZD ever directly affects Cl- flux
Other OTC Agents that aren’t melatonin as hypnotic
Antihistamine and block muscarinic receptors - limited dose range (if too high can be more sedative)
Less efficacious and tolerance occurs more rapidly
Drugs for Control of Appetite
Low-efficacy CNS stimulants Topiramate Phetermine + Topirmate Fluoxetine Orlistat Fenfluramine
Weight-control programs
EXERCISE
Restriction of energy intake (anorexiant medication)
Behavioral modification
Criteria for anorexiant medication
BMI > or equal to 30
OR
BMI > or equal to 27 with HTN, DM, hyperlipidemia
Amphetamine anorexiant MOA
Modification of NE and DA neurotransmission (reverse reuptake transporter)
Appetite-control areas of the hypothalamus - NE mechanism, DA in mesolimibic also of interest
What amphetamines can’t be prescribed for weight loss?
Schedule II agents
Therapeutic effects of amphetamine related anorexiants
Decrease in appetite Less interest in food Less pleasure from eating Increased satiety with eating Decrease in total energy intake
ONLY LOW EFFICACY CNS STIMULANTS ARE PERMITTED (high efficacy would also give euphoria, and abuse potential)
Amphetamine related anorexiants effectiveness:
Tolerance?
Limited by tolerance (2-3 weeks)
Should discontinue before reaches tolerance
Weight loss then plateau (thereafter, weight gain is likely)
Amphetamine related anorexiants precautions
Unusual reactivity to sympathomimetics (amphetamine, epi, isoproternol, phenylephrine, pseudoephedrine, terbutaline)
Dental problems - reduce salivary flow –> exacerbating periodontal disease
Amphetamine related anorexiants side effects
Insomnia (avoid 4-6 h before bed) Increased BP Anxiety Tremor Potential for abuse (psychosis, dependence)
Amphetamine related anorexiants overdose
Arrhythmia, confusion, diarrhea, fever
Assaultive behavior, hallucinations (shift toward paranoid thinking, typically high dose of Schedule II)
Circulatory collapse, coma before DEATH
Amphetamine related anorexiants contraindications
CVD Glaucoma HTN - moderate or severe Hyperthyroid Psychosis Alcoholism Hx of drug abuse/dependence
Amphetamine related anorexiants drug interactions
Thyroid hormones
MOAI
Amphetamine related anorexiants names, their classes and specific problems
Benzphetamine (class III, CI in preg) Diethylpropion (class IV, blood dyscrasias) Phentermine (class IV, long acting/most precscribed)
Topiramate
Other uses
Untoward effects
Anticonvulsant
Dizziness, drowsiness, tiredness, attention/memory issues
Phentermine + Topiramate
Sympathomimetic + anti-seizure
Efficacy is good - over 1 yr pts lost weight on a monthly basis
Fluoxetine
Other use
How does it help with weight loss?
Tolerance?
SSRI - mood disorders
Appetite reduction - SATIETY
Tolerance develops within days or weeks
Orlistat
MOA?
SE?
Tetrahydrolipstatin - bonds and inhibits gastric and pancreatic lipases (prevents hydrolysis of triglycerides to absorable free FA)
Need to supplement fat-soluble nutrients
SE: flatulence, loose stools - esp after high fat meals
Herbal/Nutritional supplements that haven’t been shown effective
Hydroxy citric acid
Fat binding fiber
Ginkgo, Biloba, vitamin E
BZD + Barbiturates
Profound CNS depression, anesthesia, coma
Respiratory depression
Abuse potential
BZD vs Barbiturates
Both facilitate GABA but neither bind GABA site directly
Barb directly increase Cl- flux at high doses
No dose of BZD ever directly affects Cl- flux
Other OTC Agents that aren’t melatonin as hypnotic
Antihistamine and block muscarinic receptors - limited dose range (if too high can be more sedative)
Less efficacious and tolerance occurs more rapidly
Drugs for Control of Appetite
Low-efficacy CNS stimulants Topiramate Phetermine + Topirmate Fluoxetine Orlistat Fenfluramine
Weight-control programs
EXERCISE
Restriction of energy intake (anorexiant medication)
Behavioral modification
Criteria for anorexiant medication
BMI > or equal to 30
OR
BMI > or equal to 27 with HTN, DM, hyperlipidemia
Amphetamine anorexiant MOA
Modification of NE and DA neurotransmission (reverse reuptake transporter)
Appetite-control areas of the hypothalamus - NE mechanism, DA in mesolimibic also of interest
What amphetamines can’t be prescribed for weight loss?
Schedule II agents
Therapeutic effects of amphetamine related anorexiants
Decrease in appetite Less interest in food Less pleasure from eating Increased satiety with eating Decrease in total energy intake
ONLY LOW EFFICACY CNS STIMULANTS ARE PERMITTED (high efficacy would also give euphoria, and abuse potential)
Amphetamine related anorexiants effectiveness:
Tolerance?
Limited by tolerance (2-3 weeks)
Should discontinue before reaches tolerance
Weight loss then plateau (thereafter, weight gain is likely)
Amphetamine related anorexiants precautions
Unusual reactivity to sympathomimetics (amphetamine, epi, isoproternol, phenylephrine, pseudoephedrine, terbutaline)
Dental problems - reduce salivary flow –> exacerbating periodontal disease
Amphetamine related anorexiants side effects
Insomnia (avoid 4-6 h before bed) Increased BP Anxiety Tremor Potential for abuse (psychosis, dependence)
Amphetamine related anorexiants overdose
Arrhythmia, confusion, diarrhea, fever
Assaultive behavior, hallucinations (shift toward paranoid thinking, typically high dose of Schedule II)
Circulatory collapse, coma before DEATH
Amphetamine related anorexiants contraindications
CVD Glaucoma HTN - moderate or severe Hyperthyroid Psychosis Alcoholism Hx of drug abuse/dependence
Amphetamine related anorexiants drug interactions
Thyroid hormones
MOAI
Amphetamine related anorexiants names, their classes and specific problems
Benzphetamine (class III, CI in preg) Diethylpropion (class IV, blood dyscrasias) Phentermine (class IV, long acting/most precscribed)
Topiramate
Other uses
Untoward effects
Anticonvulsant
Dizziness, drowsiness, tiredness, attention/memory issues
Phentermine + Topiramate
Sympathomimetic + anti-seizure
Efficacy is good - over 1 yr pts lost weight on a monthly basis
Fluoxetine
Other use
How does it help with weight loss?
Tolerance?
SSRI - mood disorders
Appetite reduction - SATIETY
Tolerance develops within days or weeks
Orlistat
MOA?
SE?
Tetrahydrolipstatin - bonds and inhibits gastric and pancreatic lipases (prevents hydrolysis of triglycerides to absorable free FA)
Need to supplement fat-soluble nutrients
SE: flatulence, loose stools - esp after high fat meals
Herbal/Nutritional supplements that haven’t been shown effective
Hydroxy citric acid
Fat binding fiber
Ginkgo, Biloba, vitamin E
Nicotine epidemiological factors Education Social Mental Illness Death rate Dollars Cancer
Lower education - no high school (37%)
Heavy drinkers (12.6%), illicit drugs (13.8%)
Mental illness 50% psych, 70% bipolar, 90% schizo
400,000 premature deaths in US each year
60% health care dollars
30% cancer deaths
Nicotine MOA
1/2 life
Agonist at the nicotinic subtype of the ACh –> 25% from smoke enters blood and within 15 seconds into the brain
Half life = 2 hrs
DA reward system - binds to cell bodies in the VTA and the dopaminergic terminal of the nucleus accumbens
Stimulates the release of DA and glutamate
Smokers are at reduced risk for
Parkinson’s
Alzheimer’s
Ulcerative colitis
Stimulatory effects of nicotine
improved attention, learning, reaction time, problem solving ability
lifts mood, decreases tension, lessens depressive feelings
Nicotine in cerebral blood flow
Short term - nicotine exposure increases the CBF without changing cerebral O2 metabolism
Long term - decreases the CBF, skeletal muscle relaxant
Nicotine dependence
develops quickly due to VTA dopaminergic activity (same as cocaine and amphetamines)
positive reinforcement is the process by which certain consequences of a response increase –> how nicotine works
Acute nicotine intoxication
At least one of these: Insomnia Bizarre dreams Lability of mood Derealization Interference with personal fxning AND at least one of these: Nausea/vomiting Sweating Tachycardia Cardiac arrhythmias
Nicotine Dependence syndrome
Three or more of for 1 month or w/i 12 month period:
1. a strong desire or sense on compulsion to take substance
2. impaired capacity to control substance taking (termination - longer period of time, onset - persistent desire, level of use - larger amnts)
3. physiological withdrawal when reduced/ceased
4. evidence of tolerance - increased amnts needed
5, preoccupation with substance use
6. persistent substance use despite clear evidence of harmful consequences
Nicotine withdrawal
Onset
Sx
Develops with 2 hours and peaks within 24-48
Sx: craving, tension, anxiety, dysphoric mood, irritability, difficulty concentrating, drowsiness, trouble sleeping, decreased HR/BP, increase appetite, weight gain, malaise, decreased motor, increased muscle tension
Overdose of Nicotine
60 mg fatal to adults (0.5 mg from common cigarette)
Signs: N/V, salivation, pallor, weakness, ab pain, diarrhea, dizzy, HA, increase BP/HR, tremor, cold sweats, inability to concentrate, confusion, sensory disturb, decreased REM, low birth weight in preg, increase risk of pulm HTN
Tx of Nicotine addiction
Abstinence
First line: patch, gum, patch + gum
Second line: nasal spray, inhaler, medications
Varenicline
Targets?
Length of tx?
SE?
Target nicotine dependence
Prescribed for 12 weeks
SE: N/V, gas, HA, insomnia, change in behavior, hostility, agitation, depressed mood, suicidal thought/action
Bupropion
Smoking cessation drug
Safer than Varenicline
Contraindicated in eating disorder
Behavioral therapy for nicotine
discover high risk relapse situations create aversion to smoking self-monitoring of smoking behavior competing coping responses figure out how to perform common daily activities without smoking** and cope with dysphoria/weight gain
Best tx for nicotine?
Combo of systemic nicotine admin and behavioral counseling (60% sustained abstinence rate)
How can smoker women reduce risk of low birth weight babies?
Stop smoking before pregnancy or during first 3 to 4 months to reduce risk
One drink =
14 g EtOH
1.5 oz 80 proof whiskey
12 oz beer
4 oz glass of wine
1-2 drinks produces a BEC of 0.025 g/dL or 0.025% or 0.25 mg%
EtOH Pharmacokinetics
Peak BEC when?
Absorbed where?
Distribution?
Absorbed rapidly/completely
Peak BEC ~ 30 min (longer with food)
Small intestine primary site
Rapid, passes easily through membranes, distributes total body water, females have smaller volume of distribution = higher BEC
EtOH metabolism and elimination
Small, predictable amounts excreted through lungs/urine/sweat (breathalyzer)
Metabolized by oxidation in liver
ZERO ORDER KINETICS
Zero Order Metabolism of EtOH
Independent of concentration
Varies slightly with body weight/liver weight
7 to 10 g/hr
Primary route of EtOH metabolism
EtOH –> acetaldhyde by Alcohol dehydrogenase that requires an NAD+ to NADH
(90 to 98% ingested EtOH)
Cytosol
What may be responsible for HA in hangover?
Acetaldehyde
Secondary route of EtOH metabolism
Ethanol –> Acetaldhyde by MEOS using NADP+ to NADPH
Microsomal EtOH Oxidizing System
Microsomes of smooth ER
When EtOH is high and NAD is inadequate
Acetaldhyde metabolism
Acetaldhyde –> acetate via aldehyde dehydrogenase with NAD
Cytosol and mitochondria
Acetate –> acetyl CoA –> TCA
Chronic alcoholics have too much acetate –> acetoacetate –> ketosis
EtOH induced metabolic disorders
Reduced gluconeogensis
Hypoglycemia
Ketoacidosis
Increase triglyceride synthesis from free FA
bc excess NADH and NADPH
Acute EtOH of liver
Increased O2 utilization
Decreased gluconeogensis
Increased lactate production
Decreased oxidation of FA - increased fat accumulation (blocking blood flow in the liver causing cirrhosis)
EtOH effects on Ion channels
Chloride - GABA gated is facilitated
Calcium - Glutamate gated is inhibited (NMDA)
Acute EtOH on cardiovascular
Vasodilation - hypothermia producing effects of EtOH (smooth muscle relaxation by acetaldhyde, depression of vasomotor system in CNS)
Depression of myocardial contractility
Acute EtOH on endocrine
Diuresis - inhibition of antidiuretic hormone release (all ADH release is prevented)
BEC = 50 - 100 sx
Sedation
Subjective “high”
Increased time to react to stimuli
2-4 quick drinks
BEC = 100 - 200 sx
Impaired motor fxn
Slurred speech
Ataxia
BEC = 200 - 300 sx
Emesis
Stupor
BEC = 300 - 400 sx
Coma
BEC > 500 sx
Respiratory depression
Death
Acute tolerance to EtOH
Intoxication more pronounced when BEC is rising than when falling
BEC rising –> brain DA in mesolimbic released –> stimulating
BEC falling –> drowsiness
Acute/Chronic ETOH on CNS
Blackouts - anterograde amnesia
Fragmentation of sleep patterns - diminish REM sleep early
Relaxes muscles in pharynx - snoring, sleep apnea
Management of acute alcohol intox
Prevent respiratory depression
Prevent aspiration of vomitus
GIVE THIAMINE before glucose (avoid Wernicke’s encephalopathy)
Glucose for hypoglycemia/ketosis
May need to tx electrolyte/phosphate levels
How do you get Wernicke’s in acute alcohol intox?
Increased NADH favors the conversion of pyruvate to L-lactate instead of to glucose and if thiamine deficient and only given glucose –> lacticacidemia
Chronic EtOH signs
Wernicke-Korsakoff, neuropathy, cerebeller degen
Myopathy
Hyperlipidemia/uricemia, anemia, thrombocytopenia
Isolated wrist drop
Gastritis, pancreatitis, malabsorption, malnutrition
Chronic EtOH liver disease
Steatosis - reversible - 90%
Hepatits/fibrosis - 40%
Cirrhosis/failure - 15-30% (fibrous nodules and loss of normal structure of the liver tissue w/ fxnal decline; women > men; hep B/C to make worse)
Chronic EtOH GI signs
pancreatitis - 3x higher than general public
gastritis
reversible SI injury - diarrhea, weigh loss, vit deficiencies
blood & plasma protein loss
Chronic EtOH & cancer
Cancer - 10x increase carcinoma
Chronic EtOH & heart
Cardio - dose/dependent HTN (~15% of all HTN is related to heavy alcohol consumption),
cardiomyopathy (dilated, ventricular hypertrophy/fibrosis)
arrhythmias
increased HDL cholesterol
Chronic EtOH tolerance
Adaptive changes such that proteins, cells, tissues, organs, systems and individuals are less affected by EtOH
Increased MEOS
Attenuation of drug effect due to learning to cope with intoxication
Cross tolerance with other sedative-hypnotics
Chronic EtOH dependence
Ethanol withdrawal syndrome
Craving and desire to avoid withdrawal
EtOH withdrawal syndrome
Amount, rate and duration of alcohol consumption can affect severity
Repeated withdrawals - increase probability of more severe withdrawal
Sx: hyperexcitability, convulsions, toxic psychosis, delirium tremens
Delirium Tremens
Relatively rare, but life threatening
Mental confusion with fluctating levels of consciousness
Tremor
Agitation
Autonomic over-activity (increase BP/P/R)
Management of EtOH Withdrawal
Thiamine Glucose Prevent seizures - diazepam/BZD K, Mg, Phos Psychosocial therapy, pharm
BZD substitute for EtOH with tapering (long acting BZD like diazepam, but use oxazepam/lorazepam for liver dz)
When DT’s occur can you give BZD?
Little impact
Wernicke-Korsakoff
Wernicke’s: confusional state associated with alcoholic thiamine deficiency - tx with thiamine
Korsakoff’s: long lasting memory impairment (confabulations)
Fetal Alcohol Syndrome
Epicanthal folds at corner of eye Low nasal bridge Short nose Indistinct philtrum Small head Small eye opening Small midface Thin upper lip Retarded body growth Poor coordination Minor joint anomalies Heart/kidney defects Greatest preventable form of MR
Best treatment of alcoholism
AA
Genetics of alcoholism
higher concordance for monozygotic
four fold increase risk in children of alcoholics
Alcoholic Labs
Increase MCB
Increase liver enzymes (GGT and CDT)
Naltrexone
Opioid antagonist (mu)
Reduces CRAVINGS
Can’t use in impaired liver or opioid pts
Acamprosate
Treating abstinent alcoholics
Reduces CRAVING
Blocks NMDA and activates GABAa
Combo with naltrexone or conseling/psychosocial
Disulfiram
Aversion therapy
Blocks aldehyde dehydrogenase
Acetaldehyde syndrome - N/V, flushing, HA, sweating, confusion
EtOH as a therapeutic in what?
MeOH and Ethylene Glycol poisoning
Used with hemodialysis, emesis, gastric lavage, correction of acidosis, supportive care
Higher affinity for alcohol dehydrogenase - inhibit formation of toxic aldehydes
Fomepizole
Inhibit the action of alcohol dehydrogenase to reduce synthesis and accumlation of toxic aldehydes
MeOH and ethylene glycol poisoning
Psychostimulants
Cocaine
Amphetamines
Nicotine
Hallucinogens
LSD, LSD-like
Phencyclidine
Ketamine
MDMA
Most drugs of abuse increase ____ in ____
DA in nucleus accumbens
Targets of drug abuse in the brain
Reward pathway
VTA, nucleus accumbens, prefrontal cortex
VTA connected to both - VTA release DA to NA and prefrontal cortex –> rewarding stimulus
Differences in route of admin
Oral - slow absorption for most, ethanol is rapid
Sublingual: more rapid than oral, bittera alkaloid taste deters
Nasal: readily absorbed
Inhaled: allows drug to reach large absorbing surface - high concentration to brain quickly
IV: most direct route
Termination of reinforcing effect is associated with
declining plasma concentration
abused drugs tend to have short t1/2 lives
continued drug taking to achieve reinforcing may lead to accum in plasma at toxic level
Pharmacokinetic Tolerance
Changes in distribution or metabolism of a drug after repeated admin –> diminished concentration of drug at site of action
Pharmacodynamic Tolerance
Adaptive changes in target tissue occur with repeated use so diminished reponse to the same concentration of drug (reduced receptor density, uncoupling of receptors to signal transduction, compensatory changes in systems mediating opposing effects)
Learned Tolerance
Behavioral: skills developed through experience with drug
Conditioned tolerance: pairing of drug admin with a specific environmental cues related to drug taking
Acute tolerance
rapid tolerance developing w/ repeated use on single occasion (cocaine)
Cross tolerance
Tolerance conferred upon one or more other drugs as a result of repeated use of a given drug (drugs in same structural/mechanistic category)
Sensitization
increase in response to a drug after repeated admin
Cocaine
MOA
Reinforcing correlated with blocking DA transporter; also binds NE and 5HT transporters
Also local anesthetic action - convulsion effect in OD
Cocaine
Targets
Reward pathway: VTA - NA (mesolimbic/cortical DA pathway)
Arousal: NE - Locus Ceruleus, dorsal bundle
Autonomic: NE in periphery (BP, arrhythmia)
Cocaine
Sources
Forms
Coca plant Erythroxylon coca (peru, bolivia, coloumbia, argentina, brazil, ecuador)
Chewing leaf or powder (snorting, oral, IV, smoked = crack - less effect)
Cocaine
Pharmocokinetics
1/2 life = 50 min
Toxicity by local anesthetic action
Fatality related to plasma concentration from binge abuse to maintain high
Cocaine
Effects
Acute
Euphoria Arousal Sense of psychic/physical well being Self confidence Improved vigilance/alertness Increase HR/BP Decrease appetite Delays ejaculation
Cocaine
Effects
Chronic
Dysphoria Stereotyped behavior Anxiety Sexual dysfxn: impotence Hallucination: objects in periphery, voices, sensations of bugs crawling under skin Paranoia Hyperreflexia Convulsions, coma, CV collapse
Cocaine
Withdrawal
Dysphoria, depressed mood
Fatigue
Craving
Bradycardia
Cocaine
Toxicity
Fatality MC with IV or smoking
Arrhythmias (NE/E at heart), seizures, coma, CV collapse
MC due to binge usage over several hours (toxic plasma levels)
Cocaine
Interactions
Opioids
Alcohol - cocaethylene –> long 1/2 life, blocks DA transporter
Cocaine
Tolerance
Occurs to euphoria during a run of use but not much carryover tolerance
Don’t really escalate dose across sessions
Amphetamine
MOA
Reinforcing effects correlates best with presynaptic release of DA (reuptake transporter in reverse)
Amphetamine
Neural Targets
Reward pathway: VTA –> NA (mesolimbic/cortical DA pathway)
Arousal systems (NE pathway –> Locus ceruleus/dorsal bundle)
Autonomic: not as profound as cocaine
Amphetamine
Effects
Acute
Alertness/anti-fatigue Euphoria Anorexia Emotionality Toxic psychosis with chronic use
Amphetamine
Toxicity
Low acute toxicity
Paranoid psychosis and violence in high dose/prolonged used
Sympathetic arousal
Amphetamine
Drugs
d-Amphetamine
methamphetamine - ice is smoked
methylphendiate - ritalin
phenmetrazine
Military uses what for anti-fatigue?
Amphetamine
Tx for Narcolepsy
Amphetamine but low abuse potential ones - modafanil and armodafanil
Nicotine MOA/targets
Agonist at CNS/peripheral nicotinic sites
Activate VTA –> NA with DA pathway (less so than amphet/cocaine)
Onset with 7 seconds –> 10 puffs/cig
Stim and depressant –> more alert and less tension
Indoleamien like hallucinogen
LSD (lysergic acid diethylamide)
DMT (dimethyltryptamine)
Psilocybin (mushrooms)
Phenethylamine like hallucinogen
DOM (dimethoxymethylamphetamine)
MDMA derivatives
Mescaline
MDA/MDMA
Methamphetamine analog
Modest stimulant/hallucinogen
Initial sedative/dysphoria
Phencyclidine
MOA
PCP, angel dust, ozone, rocket fuel
Non-competitive blocker of NMDA receptors
Smoking, snorting, oral
Psychotomimetic effects with profound tolerance
12-24 hr 1/2 life
Phencyclidine
Effects
Euphoria
Staggering
Disorientation
Paresthesia
Nystagmus
Slurred speech
Distortion of body image
Strength/power/invulernability/anger/rage
Depression/paranoia/hostility
Moderate dose - tachy, increase BP, mydriasis, xerostomia
High dose - analgesia, anesthsia, decreased BP/R, horizontal/vertical nystagmus
Phencyclidine
OD
Anxiety, agitation, aggression, hallucination
Dysphoria, catatonia, muscle rigidity, convulsion
Tachy, sweating, salivation, lacrimation, HTN crisis
Ketamine
MOA
Special K, vitamine K, cat valium
Dissociative anesthetic, non-competitive blocker of NMDA receptor
Power/liquid - snorted, smoked
Ketamine
Effects
Disorientation
Sensory illusions
Hallucinations
Marijuana
MOA
Dope, pot, grass, reefer, herb, ganja
Binding to cannabinoid receptors
Smoked, food, tea
Marijuana
Uses
delta-9-THC and dronabinol for Glaucoma Reduce N/V in chemo Anorexia - weight loss in AIDS Recreational
Marijuana
Pharmacokinetics
Rapid absorption following inhalation Euphoria after 10-30 min for 3-4 hours Accum in fatty tissue Active and inactive metabolites 10-15% urinary excretion - up to 30 days
Marijuana
Acute Effects
Increased pulse Decrease exercise tolerance Reddening on conjunctiva Euphoria/relaxation Impaired memory/motor coord Distorted time sense, hunger, dizzy
Marijuana
Chronic Effects
Bronchial - irritation, impaired fxn, cancer Aggravation of angia Ortho hypoTN Decrease testosterone Diminished intellect Amotivational
Marijuana
Dependence
Tolerance reported
Withdrawal: anorexia, N/V, diarrhea, irritability, restlessness, insomnia (after sudden stopping of prolonged use)
Marijuana
Overdose
Euphoria, time space distortion, tachycardia, fever
Psychosis (hallucinations, depersonalization)
tx with haldol/diazepam for agitation and propranolol for CV
Inhalants
glue, gasoline, nail polish
damage to neurons, kidney, liver
excitation followed by drowsiness, disinhibition, staggering, agitation
Nitrates/Nitrites
Systemic vasodilators (amyl nitrate, butyl nitrite)
Abuse associated with enhancedment of sexual sensations
Toxicity: HA, peripheral pooling of blood, decrease myocardial flow
GHB
alcohol like effects, anabolic steroid like effects, aphrodisiac
synergistic interaction with alcohol - coma like sedation (date rape)
Flunitrazepam
Rapid onset BZD
Sedative-hypnotic
Amnestic effect - date rape
