Final Flashcards
How are new chemicals identified and characterized for pharmacological activity? (4 EPPC)
- Extraction
- Purification
- Predictions
- Characterization
What series of experiments should psychoactive chemicals pass? (3)
- Animal behaviour
- Physiological measures
- Biochemical assays
In coffee Primary actives are
methylxanthines
Coffee:
_ (-rgic)→base nucleus
purine
Metabolism: Caffeine→ (3)
theophylline, theobromine and paraxanthine
Additional chemicals and sources of coffee:
Chlorogenic acids- induce (phase II _ , like _ ) _ enzymes
* Dihydrocaffeic acid- anti- _ with vascular benefits (promotes _ production)
* Kahweol and cafestol- di_ , increase phase _ enzymes, induce anti- _ genes, but elevate _
(phase II transferases, like GST) liver enzymes
inflammatory, NO
terpenes, II, stress, cholesterol
- Coffee and tea are the most common anti- _ sources
oxidant
Medical indications for caffeine
Respiratory stimulation in _ infants
* 2nd most commonly prescribed NICU drug (after _ )
* PDE4 stimulation/inhibition increases [cAMP] in _ _ _
* Asthma → bronchoconstrictor/dilator
* Migraines→increase/reduces cranial blood flow
premature
antibiotics
inhibition, rhythmogenic preBötC complex
dilator
reduces
t/f: Caffeine is the most commonly consumed psychoactive substance on the planet
t
Caffeine distribution - 3
Amphipathic
* Rapid
* Widely distributed
Caffeine absorption - 3
- Ingestion
- Small intestine
- 45 min to peak
Caffeine metabolism
Limited or no first-pass
* CYP1A2 → demethylation
* Paraxanthine (84%) → increases blood glycerol/fatty acids via
lipolysis
* Theobromine (12%) → dilates vessels, increases urine volume
* Theophylline (4%) → inhibits PDE, increases [cAMP], relaxes
smooth muscle
Caffeine excretion
Kidney
Methyl]xanthine cellular drug actions
* Non-selective _ and _ antagonists
* Additional targets→ _ release, _ receptors
* _ and _ are ubiquitous
adenosine receptor (AR), phosphodiesterase (PDE)
Ca, GABA
ARs and PDE
Adenosine receptor signaling
* _ of all 3 major types
* 4 main sub-types are
* _ and _ play primary roles in caffeine effects
* Mostly _ -synaptic receptors that limit neurotransmitter _
Antagonist
A1, A2a, A2b, A3
A1 and A2a
pre, release
Adenosine Receptors form _ _
* At rest or to form a signaling complex
* 3 pair complexes
extensive pairs
A1-D1
* 2 A2a + 2 D2 * A1+A2a
Acute caffeine effects:
General _ effects
* Similar, _ compared to _, _
* Increased _ mobilization,
stimulant
milder, cocaine, amphetamines
fat
Caffeine physl mechanisms:
Increases _, _, _ release
* Long-term drinkers more/less likely to experience elevated heart rates/BP
* Constriction in _ vessels can treat _
* Diuretic- 300+ mg, increases _ blood flow, promotes _, prevents _ re-absorption by kidneys
NE, Glu, DA
less
cranial, headaches
Diuretic- 300+ mg, increases kidney blood flow, promotes micturition, prevents water/salt re-absorption by kidneys
Caffeine heart rate, bp, endurance mech:
Heart effects are complicated by peripheral and central mechanisms *
Inhibits _ enzymes which metabolize _
producing high cAMP levels
* Results in relaxation of _ but _ vasoconstricting effect
* Increases intracellular concentration of _ by increasing activation of calcium _
* Thought to increase _ _ of muscle
phosphodiesterase (PDE), cAMP
smooth muscle (vasodilation), central
calcium, channels
work capacity
Reinforcing mechanism of caffeine
* Good _ release in the _
* Likely due to blocking _
* Pre-synaptic A1 signal via _
* Also increases _ release in the NAc
dopamine, NAc
pre- synaptic A1 on DA-ergic VTA→NAc neurons
Gi/o
Glu
Caffeine facilitates wakefulness by disrupting adenosine signaling
* Extracellular _ increases during waking until a point is reached that triggers sleep
* Adenosine thought to come from metabolism of _ in _
* Stimulation of _ receptors by adenosine in the _ triggers _ release
* GABA release _ arousal systems
* Caffeine prevents _ this process
* This prevents _ release, preventing _
adenosine,
ATP in neurons
A2a, hypothalamus, GABA, inhibits
adenosine binding to A2a receptors and interrupts
GABA, inhibition of arousal systems→wakefulness
Coffee intake may reduce risk of _ disease
* Strong _ relationship between caffeine
Parkinson’s
inverse
Caffeine + heart attack risk
_ polymorphisms confer _ and _ metabolism rates
* _ copies of *1A = fast; At least _ copy of *1F = slow
* _ metabolizers show increased _
CYP1A2
fast (1A) and slow (1F)
2, 1
slow, dose-dependent risk
Caffeine chronic effects - TOLERANCE
Develops quickly/slowly
Tolerance to _, _, _, but not effects on _
quickly
cardiovascular, respiratory, sleep effects, mood
Caffeine chronic effects - withdrawal 6
THE DIF
Headache, fatigue, decreased
energy, irritability, thirst
Caffeine chronic effects - dependence Develops quickly/slowly
quickly
Long term health risks of caffeine
Osteoporosis- due to
* Increased risk of _ due to stimulant effects
* Adenosine receptor antagonists may be _ due to regulating synaptic neurotransmitter levels
Use during pregnancy
* Many women drink caffeine
during pregnancy; Effects on the fetus are _
increased calcium elimination and reduced dietary Ca absorption
panic attacks
anti- depressants
inconclusive
Nootropic:
cognitive enhancers
Does caffeine improve memory
- Acute doses increase _ _activation in the _
- _ is linked to LTP
- Remembering objects was better if learning while on caffeine
Yes, , seems to positively affect learning and memory
BDNF and TrkB , hippocampus
BDNF
Taurine – Monster, Red bull
* Anxiolytic→may be due to glycine receptor activation and increased IPSPs
What types of drugs are these
L-theanine, Herbs – TCM herbs Ginkgo biloba & Panax ginseng, Ayurvedic herb Bacopa monnieri
Nootropics
Nicotine, amphetamines, Ritalin, afinil family are examples of
Nootropics
Eg of amphetamine nootropic
Adderall
Afinil family drug eg
Modafinil, Adrafinil, Armodafinil
Forms of tobacco product - 7
- Cigarettes
- E-cigarettes
- Cigars, cigarillos
- Shisha
- Smokeless
- Patches
- Gum
e-cig
* Vaporize e-juice containing nicotine; usually glycerin or PG-based
* No burning of plant material, no tar
* Major marketing angle → cleaner smoke is healthier!
* Flavours and additives caused severe adverse effects:
* Diacetyl – butter flavour, obliterates lung tissue (bronchiolitis obliterans),
‘popcorn’ lung in factory workers
* Vitamin E acetate – allergic reactions
* Vapour damages immune system via ROS same as cigarettes, macrophages
infiltrate lung tissue over time
* Cause ‘throat catch’ → otherwise smooth, similar to cigarettes
* Delivers higher nicotine dose per puff
* 5-8x more than cigarette
Early electronic cigarette additives
caused severe adverse effects, Vitamin E
Hookahs are better and worse than other forms
Water cools smoke, less irritating, fewer
particulates, but much longer sessions
* Shisha is the most processed, flavoured tobacco
form
* Hot air vaporizes chemicals, produces 11x the
CO by weight compared to cigarettes
* Increased heart rate may be due to elevated CO
in blood
* Increased lung disease,
oral/lung cancer risk
What is smoke?
* Particulates → nicotine, water, tar, PAHs, benzo[a]pyrene, metals
* Gases → nicotine, CO, CO2
, NO, nitrosamines, ammonia, nitrites,
sulfur, alcohols, ketones, aldehydes, hydrocarbons
* Particulates + gases = aerosol
* First-hand → inhalation of smoke
directly from burning tobacco
* Second-hand → smoke that has
already been inhaled by others
* Third-hand → 1
st and 2nd
-hand fumes
from fingers, clothes, fabric, etc.
nicotine:
Alkaloid, causes addiction
* Competitive acetylcholine receptor (AChR) agonist
* Both Ns pick up a hydrogen at low pH
* Uncharged = free base
* Protects the plant from pests
Nicotine has mono- and di-protonated
forms governed by pH
Pharmacokinetics of nicotine
absorption 1. Inhalation
* Controlling pH in cigarettes optimizes lung absorption (free base)
* Burning generates up to 4000 new chemicals
* 1 cigarette = contains ~8 mg nicotine, delivers 0.5-2 mg, 60 mg is lethal
* Pyrolysis, filter, side-stream smoke lower bioavailability
* Art of the dose → 1-2 puffs/min, 2 sec long, 1-2 μg nicotine/kg body
weight is delivered to the brain, one pack/day is optimal for brain
stimulation
2. Oral (smokeless forms)
* 3-4x greater nicotine absorption, area under the plasma vs time curve
* Much slower rate of absorption
Absorption of different tobacco forms
Distribution of nicotine
* Blood pH is 7.4 → 70%
monoprotonated, 30%
unprotonated
* <5% is bound to plasma protein
* Liver, kidney, spleen, lung get
largest amounts
* Adipose gets least amount
80% of binding sites in the brain are
occupied after 1 cigarette
Most nicotine is converted to cotinine in
the liver
* Half life = 2 hrs
* Aldehyde oxidases CYP2A6 and CYP2B6 are main
enzymes
* Monooxygenases process small amount
* CYP2A6 mutation that slows metabolism
results in lower tobacco use
nic distribution summary - 2
Brain, lungs, liver,
spleen, kidney
* Crosses placenta
nic metabolism - 4
Liver:
* CYP2A6
* monooxygenases
* 2 hr half-life
nic abs summary - 2
- Inhalation (11-20%
bioavailable) - Oral (50-80%
bioavailable)
nic excretion - 2
- Kidneys
- Breast milk
Plasma [nicotine] peaks
in the evening
* Receptors re-sensitize
over night
* First daily cigarette is
most pleasant
Acute effects of nicotine
Mostly
sympathomimetic
effects
mechanisms of tobacco and nicotine
Affects ACh, DA, GABA, Glu NTs
* Binds and depolarizes cells via nAChR
* High affinity leads to inactivation of receptor → biphasic
mechanism at high doses
* Affects heart rate, BP, GI movement, motor commands, focus
and mood
* Acetaldehyde (from burning) may inhibit
monoamine oxidases and boost NT levels,
e.g. DA
mechanisms of tobacco and nicotine
CNS receptors are located in:
* Cortex, hippocampus,
midbrain
* Pre-synaptic receptors cause:
* Increased glutamate release
* Increased GABA release →
quickly desensitize
* Increased DA release
Reinforcing mechanism of nicotine via DA, Glu,
GABA modulation in the VTA & NAc
Acute adverse effects
* “Safe” additives turn bad after burning
* Stimulation of the vomiting centre → common in first-time
users
* Headaches, nausea, disrupted autonomic nervous system
functioning
* Alternating tachycardia and bradycardia
* Severe intoxication → seizures, hypotension, respiratory
depression
Nicotinic acetylcholine receptors
(nAChRs) in the brain
* Heteropentameric receptors, alpha and beta subunits
* Conduct cation (Na+
, Ca2+) influx to
depolarize neurons
* Pre- and post-synaptic
* Trigger neuromuscular activity
Nicotinic acetylcholine receptors
(nAChRs) in the brain
Pre-synaptic increase NT release
* Post-synaptic will depolarize the cell
* Receptors inactivate if continuously exposed to agonist →
nicotine has high affinity
* Receptor subunit composition affects reinforcement and reward
(alpha4, alpha6, alpha7, beta2)
* α6 modulate locomotor responses
* α7 facilitate glutamate release
* β2 subunit knockout in mice prevents DA release, selfadministration stops
* α4β2 receptor antagonists block reward
α4β2 nAChRs are most important for DA
reinforcement
Alpha6-beta2 nAChR mainly on DA-ergic terminals in NAc
* α6β2 do not release DA after systemic nicotine administration
α4β2 are main functional nAChRs on VTA DA-ergic soma
Activating α4β2 on soma
drive DA release and
reinforcement
Inactivation rates depend on subunit
composition
α4β2 sub-type govern GABA
release and inactivate quickly
(after 30-60 seconds) and for a
long time (1 hour)
* α7 sub-types govern Glu release
and are not inactivated
* A single dose of nicotine injected
into NAc elevates DA levels for
80 min
Tolerance to nicotine
First uses are unpleasant → brain regions/circuits for dizziness, nausea, sweat
* Little or no decrease in heart effects, tremor and
peripheral vasoconstriction
* Metabolic → increased enzyme activity, first cig
is the best
* Cellular → receptor inactivation, affects reward
* Behavioural → mindset stages experience, ritual
of smoking
Tolerance to nicotine
nAChR expression increases, mostly α4β2 subtype
* Enhances sensitivity to nicotine effects
nic withdrawal
Physiological symptoms → headache,
drowsiness, insomnia, increased appetite
and weight gain, GI upset
* Psychological → Craving, mood
changes, irritability, anxiety,
restlessness, depression, difficulty
concentrating, poor judgement and
psychomotor performance
Nicotine dependence
If you must smoke within 30 min of
waking up, chances are you’re addicted
* Starts to occur within days of habit
* Both physical and psychological
dependence
* Quick metabolism leads to withdrawal,
seek another dose to avoid symptoms
* Intensely cue-driven habit; after eating,
while drinking, out with friends, after
sex
Long-term adverse effects of tobacco
Cancer → lung, liver, colorectal
* Benzo(a)pyrene initiates cancer → intercalating agent
* Nicotine enhances growth/metastasis, not initiation
* Inhibits apoptotic signaling by binding α7 nAChRs on
mitochondria → allows cells with damaged DNA to
replicate
Nicotine promotes cancer growth and
metastasis
* Nicotine enhances
cancer cell growth in
vitro
* Nicotine
injections/patches on
mice injected with
cancerous cells
display enhanced
cancer growth
* Does NOT initiate cancer formation
Nicotine promotes cancer growth and
metastasis
* Experimental design:
* Mice given cancer
* Treated with nicotine or saline for
two weeks
* Tumours were removed
* Treatment continued
* Re-examined lungs after two weeks
* Nicotine treated mice re-grew
tumours and developed new tumours
Long-term adverse effects of tobacco
Accelerate skin aging due
to peripheral
vasoconstriction
* Sexual dysfunction →
impaired NO signaling
prevents erections
* Type 2 diabetes → stressed
vasculature is insensitive to
insulin
Long-term adverse effects of tobacco
* Cataracts, macular degeneration
* Tooth decay, periodontitis, IBS, Crohn’s
* Infection
* Rheumatoid arthritis, osteoporosis
* Cardiovascular disease, like coronary heart disease
(CHD), MI, ischemic stroke
* COPD includes chronic bronchitis and emphysema2
* Caused by inflammation of airways covered in tar
and ash deposits
* Cilia function is impaired by PAH and ketones in
smoke
* ‘Smokers cough’ when quitting indicates
recovery of cilial function
Long-term adverse effects of tobacco
* Second-hand smoke, nonsmokers that live with
smokers have higher rates
of lung cancer, heart
disease
Pregnancy and smoking
Constriction of umbilical arteries, reduced oxygen
May affect reward system leading to increased addiction
risk
Higher risk of stillbirth, premature
or miscarriage, low birth weight
* Cleft palate and lip risk goes up
Smoking cessation
* Like safe injection sites, the goal is to provide safe nicotine to ease
withdrawal and cravings
* Very difficult; 74% of American smokers want to quit and 78% make
a serious attempt → success rate is 6%
* 3 day hump correlates with nicotine clearance
* Is it harder to quit smoking or smokeless forms? Smokeless, higher
doses
Smoking cessation
* Earlier the better: at 30 years old reduce risk by 90%, at 45 years old
reduce risk by 87%, at 50 years old reduce risk by 50%
* Within 8 hours, blood [CO] normalizes
* Within a week, heart, BP, circulation, breathing improve
* Within 9 months, respiratory cilia recover
* Within 1 year, CHD risk drops 50%
* Within 5-10 years, risk of stroke matches non-smokers
* Within 15 years, CHD risk matches non-smokers while lung cancer
risk is 50% lower than smokers
Smoking cessation is big business
Nicotine withdrawal must be overcome so cessation therapies offer nicotine without the
hazards of smoking
* Several forms include patches, gum, nasal spray, inhalers, lozenges and e-cigarettes
* Gum can cause bad taste, irritate throat, induce nausea
* Patches/spray can cause irritation
* E-cigarettes might be effective, risk of reverting might by high
Pharmacological cessation aids
Bupropion → antidepressant
* nAChR antagonist, blocks the channel
even when nicotine is present
* DAT and NET inhibition
* Helps reduce cravings
* Varenicline → partial nAChR agonist,
reduces reward and cravings
* Methoxsalen and NicVAX are in
development
Behavioural and psychosocial cessation
aids
* Counseling, stress management
* Behaviour modification → identify and avoid
risky situations
* Combine with pharmacological treatments
Large-scale awareness campaigns in N. America
have lead to increased attempts to quit
difference between a sedative and a hypnotic?
Sedatives
* Relieve anxiety, cause relaxation,
mild CNS depressants
* Hypnotics
* Cause drowsiness and sleep
* Z-drugs (Ambien), orexin antagonists,
melatonin agonists, anti-histamines
difference between sedative and hypnotic
Anxiety
* benzos → ‘aze’-pams (Valium diazepam, Klonopin clonazepam)
* Anti-convulsants
* Longer-acting drugs treat seizure disorder → Phenobarbital
* Anesthesia
* Short-acting drugs → Thiopental, midazolam, triazolam
* Sedatives for calming
* Hypnotics for sleeping e.g. zopiclone (Lunesta), zolpidem
(Ambien)
Sedatives in the clinic
* Progressively greater depression of electrical activity