-
1) Memorize the Continum Chart
- a) Stimulation – “+” sensation acuity (greater awareness of environment); “+” motor activity (restlessness)
- i) Death
- ii) Convulsions or seizures
- iii) Tremors & hallucinations
- iv) Anxiety, nerviousness
- v) Euphoria (feeling of well-being)
- b) Normal
- i) Neutral
- c) Depression – “-” sensation acuity (lack of perception, drowsy, not alert); “-” motor activity (lethargic)
- i) Sedation (drowsy)
- ii) Hypnosis (sleep)
- iii) General anesthesia (loss of consciousness)
- iv) Coma
- v) death
-
2) Understand the 2 types of tolerance
- a) –state where one must increase the dose of a drug in order to achieve or maintain the desired effect
- i) (all narcotics, barbiturates, alcohol, tobacco)
- b) May be “metabolic” or “receptor” based
- c) Tolerance always occurs in process of becoming physically addicted to a drug
- i) May get tolerance to drugs that are not addicting, but this is usually “metabolic” tolerance and does not deal w/ the CNS
- d) “Addiction” implies “compulsion” involving CNS drugs &/or endogenous CNS compounds
-
3) Factors contributing to drug dependence
- a) Addiction deals w/ “compulsion” to “self-administer” a drug
- i) Many agents that have strong psychological “hooks” are very addicting even though their degree of physical dependence is not that high
- b) Physical dependence
- i) –an adaptive physiological state that occurs after administration of a drug that manifests itself by physical disturbances when the drug is withdrawn (withdrawal syndrome)
- (1) Compulsion to take the drug to maintain well-being (no choice)
- ii) Characteristics
- (a) Also known if abstain = withdrawal symptoms
- (2) “receptor” tolerance always occurs, must increase dose to maintain effectiveness
- (3) Detrimental effects do occur
- (a) Preoccupation w/ obtaining & using drug
- (b) Harmful side effects
- (i) (Drowsiness, ulcers, high BP, etc.)
- (c) Chronic use of some drugs can cause permanent damage
- (i) Even tobacco does this – other drugs damage kidneys, liver, etc.
- iii) Note: Degree of physical dependence is NOT synonymous w/ degree of “addiction.
- c) Psychological dependence
- i) –a state of emotional reliance upon a drug in order to maintain a state of well-being
- (1) Tolerance, if it does occur, is of the “metabolic” type so there are no withdrawal symptoms
- (a) In reality, dependence causing drugs are usually both types at a same time
- (b) They are on a continuum between the 2 extremes w/ some features of both
- ii) Characteristics
- (1) Same compulsion but no withdrawal symptoms
- (2) Often, little or no tendency to increase dose
- (a) (may have “metabolic” tolerance)
- (3) Detrimental effects do occur
- (a) Preoccupation w/ obtaining & using drug
- (b) Harmful side effects
- (i) (Drowsiness, ulcers, high BP, etc.)
- (c) Chronic use of some drugs can cause permanent damage
- (i) Even tobacco does this – other drugs damage kidneys, liver, etc.
-
4) CNS Stimulants – how do they work? What are the main types we talked about in class the main indications for use. (amphetamines, xanthines, cocaine)
- a) General Stimulants: substances which generally increase the excitability of the CNS
- b) Amphetamines: d-amphetamine (Dexedrien®), methylphenidate (Ritalin®)
- i) - stimulates all area of the brain
- ii) Responses observed upon administration:
- (1) Increased alertness, wakefulness, decreased fatigue
- (2) Mood elevation or euphoria, increased initiative
- (3) Decreased appetite, but little effect in reducing food intake if eating for psychological reasons
- iii) MOA:
- (1) Increase the release of NE in the brain
- (a) (responsible for CNS stimulation)
- (2) BUT also, increases dopamine release
- (a) (causes side effects)
- iv) Therapeutic uses: Schedule II (high potential for abuse)
- (1) Narcolepsy- uncontrollable urge to sleep
- (2) Weight control (probably will not be approved by FDA in future)
- (a) –this is highly abused drug
- (b) Doesn’t control psychological eating
- (c) Tolerance occurs (must keep increasing dose) – too dangerous a drug
- (3) AD-HD “hyperkinetic” children
- (a) Methylphenidate or Ritalin ® used most often
- (i) Classroom improvement in 70-80%
- (ii) Active
- (iii) Learning and discipline problems
- (iv) Short attention span
- 1. Paradox- give stimulant to child who seems overstimulated
- (b) MOA in AD-HD:
- (i) + NE = + attention span
- (ii) Perhaps dopamine helps
- 1. (1996 study found abnormal D4 in 21% AD-HD)
- (c) Note: Strattera® approved Nov 2 is non-stimulant
- (i) (A selective NE Reuptake Inhibitor)
- (ii) 2005 “black box” warning: suicidal thoughts (similar to antidepressant)
- v) Side/Toxic Effects:
- (1) CNS- nervousness, anxiety, sleeplessness
- (a) High dose- schizophrenic behavior (+ dopamine), hallucinations, paranoia
- (2) Cardiovascular- + HR, BP, & possibly arrhythmias
- (3) Weight loss & malnutrition
- (4) In hyperkinetic child- sleeplessness, excessive crying, etc.
- (a) *Suppresses growth (reversibly if quit before bone closure)
- (b) Some experts recommend drug holiday’s
- (5) Possible (but rare) bone marrow suppression
- (a) (do periodic blood checks)
- vi) Contraindications:
- (1) Insomnia or psychological disorders (suicidal, schizophrenia, etc)
- (2) Hypertension, cardiac arrhythmias
- (3) Anorexia
- vii) Caution: potential for abuse
- (1) Drug interactions: All the ANTI
- (a) Anticholinergic, anticoagulants, anticonvulsants, tricyclic antidepressants
- (i) Usually requires a dosage adjustment
- c) Xanthines (more stimulants): caffeine, theobromine, theophylline
- i) From plants found all over the world:
- (1) Caffeine- coffee beans, tea leaves, kola nuts
- (2) Theophylline- tea leaves
- (3) Theobromine- cocoa
- (a) (Cocaine also in kola nuts –taken out of coke)
- (4) Common beverages
- (a) Coffee: 100-150 mg caffeine
- (b) Tea: 40-100 mg caffeine + theophylline
- (c) Coke: 35-55 mg caffeine
- ii) Responses observed:
- (1) CNS stimulation
- (a) + alertness, - fatigue
- (i) Caffeine > theophylline > theobromine
- (2) Cardiac stimulant (rate & force of contraction)
- (a) Theophylline > theobromine > caffeine
- (3) Constricts blood vessels in brain
- (a) Coffee may help headache (if cause – dilated blood vessels)
- (4) Diuresis
- (a) Theophylline > theobromine > caffeine
- (5) Bronchiorelaxation
- (a) Requires higher dose than CNS effects
- (i) Theophylline > theobromine > caffeine
- (ii) Aminophylline = a more water-soluble version of theophylline
- 1. –a drug used for asthma
- iii) MOA:
- (1) Inhibits breakdown of cyclic AMP
- (2) + CNS activity
- (3) Dilates bronchioles
- (4) Dilates pulmonary blood vessels, but constrict cerebral vessels
- (5) Note: Activates P450 enzymes after metabolism of many drugs
- iv) Therapeutic Uses:
- (1) Pain from headache
- (a) Caffeine often over the counter
- (i) Conflicting evidence over effectiveness
- (ii) No activity alone
- (iii) But is potentiator of other analgesics
- (2) Asthma, bronchitis, emphysema
- (a) Aminophylline
- (3) Counter drowsiness
- v) Side Effects:
- (1) + HR, cardiac arrhythmias
- (2) + gastric secretion
- (a) Caffeine worst culprit
- (3) Diuresis (not usually used as diuretics)
- (4) Excess CNS stimulation
- (a) Convulsion, insomnia
- (5) Withdrawal
- (a) Headache & irritability
- vi) Cautions:
- (1) Cardiac arrhythmia
- (2) Ulcers
- (3) Possibly pregnancy
- (a) Birth defects in small animals w/ large doses caffeine
- (4) So far no sign of birth defects in humans
- (a) No correlation w/ caffeine intake
- (b) A retrospective correlation study (Dec 1993 JAMA)
- (i) Links + caffeine consumption to an increased rate of miscarriages ( more than 321 mg/day = 2.62x risk of miscarriage).
- d) Cocaine: Schedule II drug- from cola leaves (Peru)
- i) Compared to amphetamines in:
- (1) Similarity
- (a) Responses observed
- (b) Mechanism of action in CNS
- (c) Many side or toxic effects
- (d) Cautions and contradictions
- (2) Differences
- (a) Cocaine not approved by FDA except as local anesthetic
- (b) Used only in hospital or clinic
- ii) Abuses:
- (1) Cocaine like amphetamine, but more INTENSE
- (2) If sniff cocaine, side effect may be: nosebleed
- iii) Uses:
- (1) Local Anesthetics- Cocaine or cocaine-like derivatives (Procaine, Benzocaine, Lidocaine, etc.)
- (2) There are not general depressants as are the general anesthetics
- iv) MOA:
- (1) Unknown but seem to elevate threshold for neuron excitement by decreasing permeability to all ions
- v) Side Effects:
- (1) CNS
- (a) Early signs of CNS stimulation (anxiety, restlessness, confusion, dizziness, tremors, convulsions)
- (b) Later may get depression, unconsciousness, and death
- (2) Cardiovascular
- (a) Early central stimulation
- (i) Like amphetamines, may begin w/ central stimulation causing + HR & BP
- (b) Later depressant action directly on heart (bradycardia, hypotension, cardiac arrest)
- (i) Different form amphetamines soon see depression
- (3) Allergic reactions
- (a) Not common but are possible
-
5) Treatment of ADHD & side effects of treatment
- a) AD-HD “hyperkinetic” children
- i) Methylphenidate or Ritalin ® used most often
- (1) Classroom improvement in 70-80%
- (2) Active
- (3) Learning and discipline problems
- (4) Short attention span
- (a) Paradox- give stimulant to child who seems overstimulated
- ii) MOA in AD-HD:
- (1) + NE = + attention span
- (2) Perhaps dopamine helps
- (a) (1996 study found abnormal D4 in 21% AD-HD)
- iii) Note: Strattera® approved Nov 2 is non-stimulant
- (1) (A selective NE Reuptake Inhibitor)
- (2) 2005 “black box” warning: suicidal thoughts (similar to antidepressant)
-
6) CNS depressants – how do they work? Differences between barbiturates and benzodiazepines. What are the main clinical uses we discussed for each type and main side effects.
- a) General Depressants:
- i) CNS depressant: agent which decreases excitability of tissue in CNS
- (1) Produces sedation, hypnosis, general anesthesia, coma, death
- (2) All drugs in this category can act as sedatives, hypnotics, or general anesthetics
- (a) – depends upon given
- ii) Sedatives: drugs to cause mild drowsiness or sedation or to reduce restlessness or anxiety
- (1) Ideally, shouldn’t interfere w/ person’s ability to function normally
- iii) Hypnotics: drug to induce sleep or allow an individual to stay asleep
- (1) Usually dosage range is 3-4 times that of sedative
- (2) By definition, a person can be aroused from a sleep
- iv) General anesthetics: drug to depress the CNS to degree that causes loss of consciousness (unarousable sleep), as well as analgesia
- (1) Person unarousable
- (2) Abolishes perception of and reaction to pain
- (3) Compare:
- (a) Analgesic: drug that relieves pain w/out loss of consciousness
- b) Sedative-hypnotics may be classified as:
- i) Useful Therapeutic Responses- for all: Note that these responses follow the continuum chart
- (1) As dose increases:
- (a) Reduced anxiety -> sedation (drowsiness) -> hypnosis (sleep) -> general anesthesia
- (2) Note: all activate P450 enzymes & so increase metabolism of many drugs
- ii) Barbiturates- about 15 kinds commonly available in the US (50 or so FDA approved)
- (1) Differ in:
- (a) Speed w/ which effect occur
- (b) Duration of action (absorbed in bloodstream at same rate, usually, but enter brain at different rates)
- (2) All barbiturates may be taken orally (Kinds not Tested)
- (a) Phenobarbital (Luminal®)
- (i) Slow onset, long acting (all day)
- (ii) Broadest spectrum of use medically (ex. Taken for epilepsy)
- (b) Secobarbital & pentobarbital (Nembutal®)
- (i) Intermediate acting (2-4 hours)
- (c) Thiopental (Pentothal®)
- (i) Short acting (onset in seconds, duration in minutes)
- (ii) Given IV
- (3) MOA- general depressant: mechanism unclear
- (a) Do depress all areas of brain
- (b) Seem to inhibit reticular activating system
- (i) Depress synapse activity in some way
- (ii) Probably enhance GABA receptor complex
- (iii) & enhance Cl- entrance to neurons and hyperpolarize cells
- iii) Non-barbiturates: “minor tranquilizers”- A CNS depressant that doesn’t have barbiturate structure
- (1) Benzodiazepines such as: flurazepam (Dalmane®), diazepam (Valium®), chloriazepoxide (Librium®)
- (a) MOA- all general depressants:
- (i) Bind to special receptor that decrease activity of brain
- (ii) Also increase activity of GABA (inhibitory transmitter)
- (2) Ethyl alcohol-
- (a) MOA- general depressant: unsure of mechanism-
- (i) Seems to increase GABA short term use
- 1. However, long term use (alcoholics) decreases GABA
- a. Decreases antianxiety effects of alcohol (Drinks to relieve anxiety)
- (ii) Large ingestion releases dopamine (“reward”)
- (iii) Avoid alcohol w/ head trauma (vasodilator)
- iv) Therapeutic uses: Generally true for all
- (1) Relieves anxiety (most common use) – 2 kinds of anxiety
- (a) Situational anxiety (exam, new job, dentist, etc.) – temporary
- (b) Neurotic anxiety- no rational reason – should use psychotherapy as well (drugs do not cure)
- (2) Sleep disorders – should only be used temporarily (highly abused drugs)
- (a) If trouble to sleep initially, use drug w/ quick onset (& short duration)
- (b) If trouble staying asleep, use slower onset but longer duration (try to avoid “hangover” effect)
- (i) Note: sleep promoting properties are lost in 3-14 days
- (ii) Few benzodiazepines are more long term – flurazepam (Dalmane®), temazepam (Restoril®), triazolam (Halcion®)
- (3) Anticonvulsant (e.g. epilepsy) – will discuss later
- (a) Note: Epilepsy is a major therapeutic reason to use barbiturates over benzodiazepines
- v) Side/Toxic Effects:
- (1) Drowsiness(if not primary use)
- (a) Perhaps less likely w/ benzodiazepines
- (2) Impaired performance/ or decreased perception or judgment
- (a) Incl. psychomotor activity (lethargic, walk slowly)
- (b) Often changes in EEG observed – long term use
- (3) Hangover effect – dizziness & fatigue, diarrhea and nausea
- (a) Slightly less true of benzodiazepines
- (i) Does not repress REM sleep
- (4) Hyperalgesia (increase sensitivity to pain)
- (a) Only true of barbiturates- barbiturates increase sensitivity to pain
- (i) Benzodiazepines are a better choice as sleep aid if patient can’t sleep because of pain (give analgesic like morphine or codeine first, however)
- vi) Overdose:
- (1) Depress respiratory (main cause of overdose death)
- (a) Benzodiazepines are less likely to be fatal in overdose, but only if no other depressant is involved (alcohol, barbiturates…)
- (2) Note: flumazenil (Romazicon®) a competitive antagonist for benzodiazepines may be used in overdose
- vii) Cautions:
- (1) Additive w/ others of sedative-hypnotics group
- (2) Drug abuse & habituation
- (a) Addiction occurs w/ daily use for 2 months
- (i) All sedative-hypnotics are additive.
- (ii) Non-barbiturates have no advantages over barbiturates
- (3) Withdrawal state – most severe symptoms possible
- (a) Mild- restless, insomnia
- (b) Severe – anorexia, nausea, vomiting, hypotension, hallucinations, seizures, convulsions, death
- (i) Take off drugs slowly – symptoms can last up to 6 weeks or longer
- 1. Usually only 2 weeks
- (4) Alcohol during pregnancy
- (a) Very serious!
- (b) As little as 2 ounces of alcohol daily during pregnancy increases chances of child having birth defects
- (c) Women who have 3+ drinks daily are at 2-3x risk of aborting fetus as women having <1 drink per day
- (d) Even drinking 2x/week increases risk of miscarriage
- (e) Fetal alcohol syndrome possible
- (i) Characteristics
- 1. CNS dysfunction (low IQ, microcephaly)
- 2. Slowness in growth
- 3. Facial abnormalities
- 4. Impaired immune system
- 5. Variable set of additional features
- (ii) Occurrence depends upon the population
- 1. In from 1 in 300 to 1 in 2k live births
- 2. 1 in 3 infants of alcoholic mothers
- a. Smallest amount reported w/ syndrome is 75 ml (2.5 oz) alcohol daily
- b. A glass of wine contains about 15 ml (0.5 oz) of alcohol
-
7) What is a general anesthetic?
- a) –drug causes loss of consciousness (unarousable sleep), as well as analgesia
- i) Person unarousable
- ii) Abolishes perception of and reaction to pain
- iii) Compare:
- (1) Analgesic: drug that relieves pain w/out loss of consciousness
- b) Goals:
- i) Analgesia (particularly upon emergence form anesthesia)
- (1) –narcotics, Ketamine used to supplement
- ii) Loss of consciousness and amnesia
- (1) –gases, nitrous oxide do quite well
- iii) Muscle relaxation
- (1) –curare used as an adjunct
- c) Inhalation Anesthetics – administered by inhalation (enflurane, halothane, methoxyflurane, isoflurane, -nitrous oxide)
- i) Responses upon administration:
- (1) Work too rapidly to see all stages –see:
- (a) Loss of consciousness
- (b) Amnesia
- ii) Toxic:
- (1) Depress respiration, lower BP, and decrease HR
- (2) Arrhythmias (especially w/ adrenergic agents)
- (3) Nausea & vomiting – postoperatively
- iii) Caution: malignant hyperthermia
- iv) Note: Nitrous oxide differs from other inhalation anesthetics
- (1) Adjunct only. Not potent enough to induce full anesthesia when alone
- (2) When used w/ others get less hypotension and respiratory depression for level
- d) Intravenous Anesthetics – liquids
- i) Thiopental (barbiturate)
- (1) Responses upon administration of thiopental
- (a) Loss of consciousness
- (b) Quick onset (works in seconds)
- (2) Toxic of thiopental
- (a) All of above except arrhythmia
- (i) i.e. depress vitals & some nausea (less)
- (b) Plus increased sensitivity to pain
- (i) Usually give analgesic (narcotic) as well
- ii) Ketamine – (not a depressant, related to PCP)
- (1) Responses upon administration
- (a) No depressed vitals
- (i) May even increase respiration and HR – acts as a stimulant
- (b) Causes analgesia without loss of consciousness at a low dose
- (c) Loss of consciousness at higher dose
- (d) No skeletal muscle relaxation
- (2) Toxic of ketamine
- (a) Upon emergence from loss of consciousness
- (i) Nightmares, hallucination, frightening experiences
- (b) Used in children (accept nightmares) and for minor manipulations (i.e. remove burn dressings)
- iii) Other IV Anesthetics
- (1) Considerably variety
- (2) Most similar characteristics to inhalation anesthetics because they are general depressants, though of different chemical structure than those discussed
- (a) Some more prominent examples include
- (i) Propofol or diprivan
-
8) What are the goals of anesthesia? (Note: no one drug meets all 3 goals)
- a) Analgesia (particularly upon emergence form anesthesia)
- i) –narcotics, Ketamine used to supplement
- b) Loss of consciousness and amnesia
- i) –gases, nitrous oxide do quite well
- c) Muscle relaxation
- i) –curare used as an adjunct
|
|
