existing neurons are able to "repair" or "remodel" themselves

the brain is capable of making new neurons in the hippocampus and the frontal cortex 

stressful situations damage the hippocampus (stress is one of the most significant causes of depression) 

CREB (cAMP response-element inding protein) 

intracellular target of second-messenger system

amount of this protein increases in the hippocampus during chronic antidepressant treatment  (neurogenic hypothesis)

activates genes that produce BDNF

neurotrophin-important for the normal develpment and health of the nervous system 

prevents spontaneous death, protects poisoned neurons 

chronic stress decreases BDNF (cell death) 

levels increase with antidepressants 

block the presynaptic transporter protein receptors for norepinephrine and serotonin (therapeutic effects)

block postsynaptic receptors for histamine, acetylchoilne, and norepinephrine (drowsiness, cognitive probs, "dizzy") 

commonality in chemical structure (not mechanism of action) 

slow onset

CARDIOTOXIC

treatment of major depression 

first-generation antidepressants 

antidepressants 

bind to and block the enzyme monoamine oxidase 

metabolizes and regulates the amount of the biogenic amine transmitters in the presynaptic nerve terminal 

levels of neurotransmitters increase, more transmitter is available for release

first generation antidepressant

can be just as safe as SSRIs

work with those who respond poorly to TCA and SSRI

more favorable profile of toxicity/side effects than TCAs

block the reuptake of serotonin 

more 5-HT1 therapeutic effects

more 5-HT2 and 3 causes serotonin syndrome

serotonin syndrome, serotonin withdrawal, sexual dysfunction 

all three orally administered are irreversible 

form a chemical fond with the MAO enzyme that cannot be broken 

must observe dietary restrisctions for 10-14 days

tyramine

MAO-A inhibitor (moclobemide) did not bind as tightly to the enzyme and therefore when levels of tyramine increased, it was forced to detach from MAO (cardiotoxic risk minimized) 

MAO-B inhibitor? 

one of the two enzymes that regulate the amount of monoamine neurotransmitters in the body (norepinephrine, dopamine, and serotonin) 

MAO-A (dopamine, norepinephrine, seortonin, tyramin)

MAO-B (dopamine, tyramine) 

reversible MAO-A inhibitor 

did not bind as tightly to the enzyme as class MAOIs 

tyramine increases, eventually forced to detach and metabolize tyramine; cardiotoxic risk minimized

structurally a TCA but an SSRI

greater effect on serotonin reuptake 

also inhibits norepinephrine reuptake (mixed serotonin-norepinephrine reuptake inhibitor) 

used to treat OCD, panic disorders, phobic disorders

first for having efficacy in treatment of anxiety disorders

specific SSRIs 

block presynaptic transporter for serotonin reuptake 

make serotonin more available in the synaptic cleft activating all the postsynaptic receptors for serotonin 

structural derivative of fluoxetine

comparable to efficacy of imipramine 

effective in treatment of all anxiety disorders 

paroxetine 

specific SSRI 

more selective than fluoxetine in blocking esrotonin reuptake 

half-life 24 hours, 7 days steady-state

most associated with serotonin syndrome

no use during pregnancy (cleft lip/palate deformities)

Dopamine and norepinephrine reuptake inhibitor (DNRI)

ony available antidepressant that selectively inhibits the reuptake transporter for these two transmitters (no effect on serotonin neurons; no SSRI effects) 

Add-on to SSRI (sexual dysfunction fixer) 

nicotine replacement

first SSRI-type antidepressant and the first non-TCA to be a first-line antidepressant 

inhibit drug-metabolizing enzymes in the liver (increase the level of other drugs in the body)

drugs created to expand on the concept that actions at two different synaptic sites may imporve or maintain efficacy while limiting side effects 

most inhibit the active presynaptic reuptake of both serotonin and norepinephrine

specific norepinephrine reuptake blockade in the absence of dopamine or serotonin reuptake blockade 

reboxetine & atomoxetine (ADHD) 

Antidepressant of the future?

antidepressive effects produced by antagonizing presynaptic 5-HT1A autoreceptors (increasing serotonin release) 

stimulating postsynaptic 5-HT1A receptors (responsible for antidepressive/anxiolytic action) 

poor absorption

Warning on a medication that says  The medication can cause serious undesirable effects (such as a fatal, life-threatening or permanently disabling adverse reaction) compared to the potential benefit from the drug

Example would be a drug that leads to suicidal thoughts 

high doses of SSRI or combination of SSRI with other serotonigic drugs

cognitive disturbances, behavioral agitation, autonomic nervous system dysfunctions (fever, diarrhea, sweating) 

and neuromuscular impairment 

excess serotonin at 5-HT2 receptors 

the more specific the blockage of serotonin, the more serotonin syndrome 

glutocorticoid hormone secreted by the adrenal glands 

may increase the amount of available neurotrophins improving mood (delay cognitive decay of mind) 

androgen causes side effects acne, voice changes, male-pattern baldness, etc. 

breast/prostate cancer? 

produced in the liver from amino acid methionine (in diets)

donates methyl group to any wide range of molecules that are transformed to homocysteine 

less than 1% reaches the bloodstream

No formulation is regulated by the FDA 

overuse may predispose someone to coronary artery disease (elevated homocysteine levels) 

Anticholingeric effects

most widely used TCA

has higher sedative and antiholingeric effects

affects serotonin more than imipramine

often prescribed because it is cheaper 

but it does have toxic effect on the heart 

The Biogenic Amine Hypothesis states that depression is caused by a deficiency of monoamines, particularly noradrenaline and serotonin.

depression can be alleviated by drugs that increase the availability of noradrenaline and serotonin.

MAOIs and blocking reuptake 

MAOI 

more acceptable therapeutic index than other MAOIS

for major depressive disorder

last resort after conventional antidepressants have been tried without success

more effective in bipolar depression

the gold standard of bipolar treatment 

effective over long periods of time 

narrow therapeutic range 

closely resembles table salt, when a patient lowers salt intake, lithium blood levels rise (intoxication) 

No sedation, depression, or euphoria

inhibit GSK-3(neuroprotective effect) 

tremors, skin probs, weight gain

good for combination therapy 

may be better in rapid-cycling bipolar disorder

as effective as Lithium in preventing the recurrence of  mania 

blocks sodium channels and the ability of sodium to initiate action potentials

(reducing neuronal excitation) 

inhibits enzyme activity in intracellular second-messenger systems like Lithium 

Drug interactions bc of CYP-3A4 in the liver

Anticonvulsant 

Used since 1994 for treatment of bipolar illness

binds to/inhibits GABA transaminase (an enzyme that breaks down GABA)

increased brain concentrations of GABA 

blocks reuptake into glia and nerve endings

inhibits voltage-sensitive sodium channels 

treat lithium-resistant patients; combination therapy with lithium 

Side effects: hepatotoxicity; pancreatitis 

 Of, relating to, or causing malformations of an embryo or fetus.

These effects have been found with anticonvulsants (Carbamazepine and Valproate)  and Lithium i.e.: Valproate causes spina bifida, neural tube defects, and developmental deficits in the infant

alternative to Lithium

controversial

calcium-channel blocker 

controversial 

alternative to lithium

agonist at alpha 2 NE autoreceptors

presynaptic inhibition of NE

down regulated in depression

Block NMDA-receptor mediated Ca2+ excitotocitiy 

abnormally and persistenly elevated, expansive, or irritable mood

must last one week

part of bipolar II disorder

similar to mania except 

mood doesn't cause problems with working or socializing with others

no psychotic features 

 stressful situation leads to the first bipolar episode whether it be manic or depressive. 

like a fire kindling 

bipolar disorder theory 

fails to explain why people can go into remission for periods of time before their next episode or why people treated early go on to have severe episodes

episodic with alternating periods of mania and/or depression and intervening periods of at least some degree of remission 

onset generally occurs in the third decade or later (delay between appearance of symptoms and a correct diagnosis) 

Subtypes: BP-I (one episode of full-blown mania w/o depression)

BP-II "hypomanic" and major depression 

"Rapid cycler" four illness episodes occur in 12 month period 

highest category of any mental disorder

Generalized Anxiety Disorders

Panic disorder

Simple Phobia

Social phobia

PTSD

OCD

Acute Stress Disorder

Neurobiological connections: Frontal lobe function impaired, responds abnoramlly to feared stimuli

Increased Anterior cingulate activity

Caudate nucleus abnormal function 

part of the limbic lobe

highly influential in linking behavioral outcomes to motivation

increased activity with OCD

important to learning and memory

located in the basal ganglia

functions abnormally with OCD (affects the putamen)

Conscious levels: anxiolytic, behavioral disinhibition, sedation

Unconscious levels: Hypnagogic state, sleep, anaesthesia, coma 

structured way of observing and describing a patient's current state of mind

purpose is to obtain a comprehensive cross-sectional description of the patient's mental state

according to: general appearance, sensorium, behavior, stream of talk, cooperativeness, mood, expression, perception, logical thought, knowledge, intellect function, insight/judgment

associated with the production of behavioral responses to fearful stimuli and the central mediation of anxiety and panic 

along with amygdala, and insula 

located in prefrontal cortex in the frontal lobe of the brain

A family of over 2500 derivatives of barbituric acid of which 50 have been marketed

Can be ultra-short acting (short redistribution half-lives)

or short-to long-acting: long elimination half-lives

Low selectivity and low TI 

causes sleep abnormalities

not analgesic 

stimulate synthesis of enzymes in the liver (drug tolerance)

lethal in overdose

high potential for tolerance, dependence, and abuse

dangerous drug interactions

a state reached from drug withdrawal of barbituates

dreaming becomes vivid and excessive leading to insomnia 

glutethimide, ethchlorvynol, methyprylon 

initially introduced as anxiolytics, daytime sedatives, and hypnotics 

now are considered obselete for use in medicine but are occassionally drugs of abuse

marketing attempt to distinguish meprobamate from the barbiturates 

methaqualone episode little to justify its widespread use 
rivaled that of marijuana and alcohol for level of abuse

"date rape"  

1951: malaria treatment

1965: tranquillizer and panacea

1972: abuse epidemic

1973: Placed on Schedule II

1984: Withdrawn from market in US

Meprobamate, mebutamate, carisoprodol 

anti-anxiety agent/non-barbituates sedative-hypnotic drugs

drugs of abuse 

pure GABA agonists because they facilitate GABA binding at GABA receptors 

should not be used with elderly (dementia)

introduced in the 1960's the most widely used class of psychotherapeutic drugs (tranquilizer and anxiolytic)

not antidepressants 

cognitive impairments/dependency potential 

for short-term treatment of anxiety

treatment of insomnia 

muscle relaxants 

anterograde amnesia 

abuse of benzodiazepines

complicates flumazenial antagonistic effects

produce tolerance and dependence 

user combines different drugs to get desired effects

any drug that activates the BZ receptor

all benzodiazepines work by binding to BZ receptor and exert an agonist action to increase GABA activity 

include nonbenzodiazepine BZRA's hypnotic drugs for treatment of insomnia (zolpidem, zaleplon, eszopiclone)

partial BZRA to provide anxiolyics that are effective but without the side effects that limit use of benzodiazepines  

all manufactureres of sedative-ypnotic products must strengthen product labeling to include risks of "sleep driving and "sleep related activities" 

Sleep driving- driving while not fully awake and having no memory (drug induced amnestic state) 

includes zolpidem, zaleplon, and eszopiclone

weak agonist at 5-HT1A receptors

also antidepressant

no sedation; little amnesia 

slow development for effect 

Postsynaptic inhibitor of adenyl cyclase

Presynaptic inhibition of 5-HT synthesis

Grapefruit**

Illegal in US

produces amnesia 

synergistic with alcohol (toxicity and death) and "date rape drug" 

benzodiazepine

short-term hypnotic

GABAa enhancer

body as a whole or region of the body is deprived of adequate oxygen supply 

inhaled drugs (ether, nitrous oxide) are also drugs of abuse and this an additional risk 

melatonin agonist instead of GABA agonist

general anaesthetic 

used as a sleeping aid

new class of sleep agents 

anxiolytic and amnesiac effects

injectable anaesthetic 

rarely abused

similar to GABA 

not an analgesic

Established in 1994

Herbal medicines cannot make claims that they can treat a disease

They are allowed to claim to promote health even if it is not substantiated by research

Because of this, few herbal remedies have been adequately researched

blooms around the John the Baptist's feast day (June 24) 

Hypericin is its active ingredient (dosage based on its presumed hypericin content) 

dietary supplement to promote emotional balance (depression) 

contains flavonoids that inhibit the drug-metabolizing enzyme CYP-1A2 (drug interactions- caffeine increased, tricyclic antidepressants and antipsychotics increased; birth control and oxycodone reduced concentration b/c of increase of CYP-3A4 activity) 

the active ingredient in St. John's Wort

"to overcome an apparition" 

elimination half life of 25 hours, steady-state in 4-6 days

detectable in brain tissue 

mechanism of action is unclear 

found in St. John's Wort

one of which is quercitin 

inhibits drug-metabolizing enzyme CYP-1A2

interactions combined with other drugs (reduce effectiveness of codeine, and increase levels of caffeine and tricyclics and antipsychotics) 

CYP-3A4 activity increased, reduce levles of anti-inflammatory medicines 

also found in Gingko Bilboa 

extract (EGb-760) 

"mental sharpness" dementia and antioxidant protection 

active ingredients unkown, but contains flavonoids and terpenoids (antioxidants)

may inhibit blood clotting (terpenoid) 

induces relaxation, improves social interaction, promotes sleep

important role in the sociocultural life of South Pacific islanders

similar to effects of alcohol 

inhibits CYP-450 liver enzymes (increase blood concentrations and toxicity of other drugs)

GABA receptors or benzodiazepine-binding site (effects similar to those of benzodiazepines) 

acceptable for short-term use

releases the body's stores of NTs epinephrine (adrenaline), norepinephrine, and DA 

A drug NOT dietary supplement 

B/c increases blood pressure, heart rate etc. cardiac arrhythmias can be seious/potentially fatal 

drug interactions occur that can be fatal (caffeine increases cardiovascular toxicity)

Banned in US in 2004

EPA and DHA deficient in Western diets and pregnancy

found in wild ocean fish

help neural development (cognitive) in utero, prevent depression during pregnancy 

helpful in bipolar disorder (no harm in administering modest doses) 

beneficial effects on the cardiovascular system 

reduce incidence of dementia 

pain-sensing neurons

become sensitized with tissue injury or inflammation 

discharge spontaneously/produce ongoing pain 

located in the dorsal root ganglia, bidirectional axon relays pain impulses to a synapse in the dorsal horn of the spinal cord (then to the brain) 

the normal biological neurotransmitter at opioid or endorphin receptors 

opioid agonsts mimic the action of endogenous endorphins
all-inclusive term that applies to an endogenous substance that exhibits the pharmacological properties of morphine  

analgesic action exerted by acting presynaptically on nociceptive afferent sensory neurons to inhibit the release of pain-inducing transmitters (P) in dorsal horn of the spinal cord

enkephalins 

a family of endogenous opioid peptides

bind to body's opioid receptors

one type of opioid receptor

agonists of this receptor have the strongest analgesic actions + highest potential for abuse

Morphine = agonist at this receptor

opioid receptor agonists exhibit little addictive potential 

poor analgesics 

modulate the activity of mu receptors 

agonists at this opioid receptor exert modest analgesic effects, no respiratory depression, and barely any dependence. 

thought to antagonize mu-receptor-mediated actions in the brain 

have strong dysphoric responses accompanied with their use

have affinity for a receptor 

no change in cellular functions 

compete with mu agonist for the receptor (withdrawal, reversing analgesia) 

treatment for heroin addicts (naltrexone) because heroin taken after antagonists elicits no analgesic or euphoric effects

produces an agonistic effect at one receptor and antagonistic effect at another 

(kappa agonists, weak mu antagonists: bind to both but only kappa is activated) 

ceiling effect for analgesia (not so effective in treating severe pain) 

acute withdrawal syndrome because of antagonistic effect at mu receptor 

example: pentazocine 

binds to opioid receptors but has a low intrinsic activity 

ceiling at less than the maximal effect produced by a pure agonist 

buprenorphine (prototype for this opioid agonist) 

more potent than codeine 

no other drug found that exceeds this drug's effectiveness as an analgesic 

crosses BBB slowly 

Only 20% of administered morphine reaches CNS

analgesia, euphoria (contentment) 

dopaminergic and mu receptors 

acts on opioid receptors in PAG and raphe 

one of the most commonly prescribed opioids 

combined with aspirin or acetaminophen 

dependence/endogenous depression 

metabolied by CYP-2D6 to morphine (therefore, clinical efects result from the actions of morphine) 

SSRI's can block the conversion of codeine to morphine 

3 times more potent than morphine

produced from morphine

fast penetration of the BBB (intense rush) 

metabolized to morphine 

not legal in the United States 

euphoria intesified with crack cocaine and less depression and paranoia (multidrug addiction) 

synthetic mu agonist opioid 

blocks the effects of heroin withdrawal (prevention of abstinence symptoms) 

1) substitute for heroin in methadone maintenance treatment programs

2) long-acting analgesic for chronic pain syndromes

serious drug interactions*** requires multiple CYP hepatic enzymes 

synthetic opioid 

structurally different from morphine 

addictive* (substitute for morphine/heroin addicts) 

euphoria & dependence 

faster onset of withdrawal symptoms because shorter duration of action

excitatory effects (tremors, delirium, hyperreflexia)

clinical management of opioid dependence in heroin addicts

related to methadone

serious cardiac complications therefore N/A

slow onset/long duration***

semisynthetic opioid similar in action to morphine

treatment of acute pain 

Percodan, OxyContin 

abuse and drug dependence, deaths from overdosag 

long-acting for treatment of chronic/long-lasting pain 

drug tolerance develops, high doses

"poor man's heroin, hillbilly heroin, oxy, OC, killer) 

Abuse: crush pills to destroy time-release mechanisms

abusers are true abusers 

pure opioid antagonists

naloxone- short duration (15 to 30 minutes) of action

injected not oral absorption 

reverse respiratory depression that follows acute overdoses of opioids (and in infants) 

naltrexone- first orally absorbed pure opioid antagonist approved for treatment of heroin dependence 

long duration of action 

also used for treatment of alcoholism 

the combination of buprenorphine and neltrexone

combining an opioid with an antagonist 

both are effective when crushed and injected, naltrexone precipitates withdrawal therefore making it unattractive for abuse 

analgesic that blocks NMDA receptors on the spinal cord

synthetic opiate

do not take with MAOI or SSRI

facilitates morphine analgesia

non-opioid opioid

member of the mint family

recreational hallucinogen in Mexico

opium in Scripture? 

Matthew 27:34 

bad taste, very bitter like dandelions 

release triggered by nociceptive neurons

releases in the spinal cord

opioids inhibit the release of substance P (pain) 

when it is inhibited this is called analgesia 

inventor of aspirin

added acetyl group to get heroin (heroin=morphine + two acetyl groups) 

1803

isolated morphine from opium 

similar to codeine and morphine 

stimulatory effects

converted into oxycodone 

sap of papaver somniferum 

used by Greeks and Romans to produce constipation and sleep

eye disease use recommended in Persia

traded from India to China

ineffective legal controls (Harrison Narcotic Act, banned in US in 1924)

can be used to counter barbiturate poisoning, that can occur during general anesthesia or during a large intake outside of the hospital

channel blocker rather than receptor antagonist

stimulant and convulsant effects

competitive antagonist of GABA_A receptors

mimics epilepsy

identified in plant alkaloid extracts

highly addictive drugs causes a manifold increase in dopamine levels in the nucleus accumbens

dopaminergic reward system

was a United States federal law that regulated and taxed the production, importation, and distribution of opiates

1914 established

narcotics could be prescribed for therapeutic treatment, but not for treatment of addiction

block the opiate receptors, which in turn leads to a blocking of the drugs’ effects, drug no longer attractive for abuse (no euphoria) 

naltrexone, nalexone 

treatment of heroin addiction (or in other cases Suboxone)

A chemical produced inside the body that binds to opiate receptors in the brain, mimicking the analgesic effects of morphine.

enkephalins, dynoprhine, beta endorphins 

naturally formed in the body 

compare to: semisynthetic opiods and synthetic opioids

metabolite of caffeine but does not behave similarly to caffeine

found in chocolate 

fresh leaves contain 4% caffeine

small tree trimmed when cultivated for its leaves for tea

native to East, South, and Southeast Asia 

small evergreen tree found in the tropical region of  America

seeds are used to make cacao powder and chocolate

most active constituent is theobromine a metabolite of caffeine

native to tropical rainforests in Africa

contains caffeine 

sometimes used as flavoring ingredient in beverages

containe theobromine

therefore large amounts elevated pulse rate, dizziness, low blood pressure, nausea because of stimulant of CNS

Holly

used to make caffeine-rich herbal teas