PHAR 100 - Module 03

sedative hypnotic agent

CNS depressants with different effects depending on dose

Purpose of sedative hypnotic agents

1. anti-anxiety
2. sedation
3. hypnosis
4. general anesthesia

Mechanism of Action of Sedative Hypnotics

therapies aim to depress brain activity by decreasing glutamate-induced nerve firing → increases inhibitory brain signalling 

without sedative hypnotics

* Excitatory neurons release neurotransmitter glutamate 
* Neurons fire when excitatory inputs exceed inhibitory inputs

with sedative hypnotics

Inhibitory signals from GABA neurons increase sedative hypnotics → decreased glutamate nerve firing

GABA

primary inhibitory neurotransmitter in CNS causing inhibition by binding to chloride channels

GABA Signalling

* Chloride channels allow chloride ions to flow into cell when signalled 
* GABA binds to and opens chloride channel, chloride ions makes it harder for postsynaptic neuron to transmit incoming messages to other neurons (depressing CNS neuronal signalling)

Sedative Hypnotics and Chloride Channel

* Sedative hypnotics modulate chloride ion channel in brain and spinal cord but bind to different site on chloride channel 
* Increases synaptic inhibition

Benzodiazepines

1. Routes of Administration 

* Capsule, intravenous, intranasal 


2. Mechanism of Action 

* Activation of benzodiazepine receptor increases frequency of opening of chloride channel 


3. Therapeutic Effects 

* Relaxation, calmness, relieving anxiety/tension, hypnotics 
* Minimal suppression of REM sleep

Lethality of Benzodiazepines

* High therapeutic index → wide margin of safety 
* Antidote (flumazenil) used to reverse effects if overdose 
* Benzodiazepine receptor antagonist blocks effects of benzodiazepines

Short-Term Effects of Benzodiazepine

* CNS: drowsiness, lethargy, fatigue, impairments of thinking and memory 
* Breathing: observed following rapid intravenous administration of benzodiazepines 
* Motor Coordination: impairment

Long-Term Effects of Benzodiazepine

Symptoms of chronic sedative hypnotic intoxication → impaired thinking, poor memory and judgement, disorientation, incoordination, slurred speech

Impact on special populations

* Pregnant/Chestfeeding 
* Crosses placenta and distributes into fetus 
* Secreted into milk exposing nursing infants to therapeutic or toxic doses of drug 
* Older Adults 
* Cognitive dysfunction 

Benzodiazepine Misuse Potential

* Weaker reinforcing properties than other drugs 
* Low Inherent harmfulness

Benzodiazepine Tolerance

* Develop to sedative effects and impairment of coordination → Anxiolytic effects or euphoric effects 
* High degree of cross tolerance modulate chloride channel in CNS

Benzodiazepine Withdrawal

* Anxiety, headache, insomnia 
* Discontinuation to more pronounced withdrawal symptoms: agitation, paranoia, seizures, delirium (extreme symptoms less frequent)

Benzodiazepine Addiction

Rare depending on genetics and environment

How do benzodiazepines reduce an athlete’s anxiety?

increase CNS depression in a dose-dependent manner and act as anti-anxiety agents

Barbiturates (sedative-hypnotics)

* Classified according to duration of action: long acting, short acting, ultra-short acting 
* Replaced by safer, more effective sedative-hypnotics 

Barbiturates Routes of Administration

* Epilepsy: administered orally 
* Anesthesia: administered intravenously

Barbiturates Mechanism of Action

* Increase duration of opening of chloride channel 
* Dosage spectrum: anti-anxiety, sedation, hypnosis, general anesthesia, death

Barbiturates Therapeutic Use

* Low doses: tranquilitiy, relaxation, sleep 
* Higher doses: antiepileptics, induce anesthesia

Barbiturates Lethality

* Low therapeutic index (now replaced by safer drugs) 
* Lethality → caused by depression of respiration when combined with alcohol 
* Lethal dose varies by person

Adverse Effects of Barbiturate

Generally used to suppress REM type sleep → feeling of not having slept/hangover

Short Term Effects of Barbiturate

* Low doses: mild euphoria, reduced interest
* Dizziness, mild impairment of motor coordination 
* Pleasurable state of intoxication and euphoria as dosage increases

Long Term Effects of Barbiturate

* Chronic inebriation → impairment of memory, judgment, thinking 
* Mood swings, hostility, depression 

barbiturates potential for misuse

* Higher than alcohol because pleasurable effects higher 
* Injected to obtain rush effect 
* Harmful due to risk of death from respiratory depression/withdrawal

barbiturates tolerance

* Develops over time 
* Cross tolerance with sedatives

barbiturates withdrawal

* Discontinuation of chronic use causes withdrawal 
* Initial symptoms: Tremors, anxiety, weakness, insomnia, postural hypotension (low blood pressure when suddenly standing up) 
* Progress to: seizures, delirium, visual hallucination, fevers

barbiturates addiction

Caused by regular use → leads to craving and feeling of panic without supply

Zopiclone and zolpidem

* (benzodiazepine-like drugs): bind to subset of GABA receptors causing sedation 
* Beneficial due to limited disturbances to sleep → more sedative effects

Buspirone

Acts on serotonin receptor used for anxiety without additive effects while simultaneously taking sedative-hypnotic drugs

Alcohol

CNS depressent that slows down brain functioning and neural activity (ethanol is the only safely consumable alcohol)

Alcohol Absorption

* 20% absorbed in stomach and 80% absorbed in small intestines 
* Absorption rate affected by: 
* Stomach-emptying time: time required for alcohol to reach small intestine 
* Ethanol concentration in GI tract and presence of food 
* Time from last drink to maximal blood alcohol concentration ranges from 30-90 minutes

Alcohol Distribution

* Throughout total body water and gains access to brain 
* Across placenta and distributes throughout fetus 

Alcohol Metabolism

1. Alcohol dehydrogenase
2. Microsomal Ethanol Oxidizing System (MEOS)
3. Aldehyde Dehydrogenase
4. Acetate

alcohol dehydrogenase

* Ethanol converted to acetaldehyde by enzyme alcohol dehydrogenase (ADH) 
* Speed of conversion sets pace for metabolism

MEOS (microsomal ethanol oxidizing system)

part of PP450 system 

* Breaks down to acetaldehyde

Aldehyde Dehydrogenase

Acetaldehyde converted to acetate by enzyme aldehyde dehydrogenase (ALDH)

Acetate

Metabolized by tissues into CO2 and water

Excretion

* 95% eliminated by biotransformation → liver 
* 5% breathe, urine, sweat

Medical Uses of Ethanol

* Alcohol sponge applied topically to treat fever 
* Skin disinfectant 
* Antidote in treatment of methanol poisoning 
* Hand sanitizer

CNS Effects of Ethanol

Effect proportional to blood alcohol concentration

* Risk of driving accident increases exponentially

Mechanism of Action of Alcohol

* Alcohol works by binding to chloride ion channel and augmenting GABA-mediated neuronal inhibition 
* Interaction of alcohol with chloride ion channels on dopaminergic neurons in reward areas explains addiction tendency

Effects of Low dose Short-Term Use of Alcohol

1. Vasodilation
2. increased gastric secretion

effects of high dose short term use of alcohol

1. alteration in normal heart rythm
2. inflammation and gastritis


1. inhibits glucose production, hypoglycemia

Adverse Effects of Short-Term High Dose Alcohol Use

1. Memory Loss
2. Psychiatric Effects


1. Overdose

Adverse Effects of Chronic High Dose Alcohol Use

1. alcohol dementia
2. cardiomyopathy, hypertension, stroke


1. liver damage

effects of alcohol use during pregnancy

fetal alcohol spectrum disorder

* recommended alcohol abstinence during pregnancy

alcohol use during drug therapy

* Additive or synergistic effect of CNS depression 
* Inhibition of metabolism of certain drugs

chronic alcohol use before drug therapy

Increases activity of metabolizing enzymes in liver → increased metabolism of drug

alcohol and SUD

1. moderate misuse potential
2. tolerance to chronic consumption
3. cross tolerance
4. withdrawal
5. addiction

cross tolerance

sedative hypnotics: higher dose needed for therapeutic effect

general anesthetics: higher dose required for those with alcohol tolerance

alcohol withdrawal

Produces compensatory excitation of CNS → delirium tremens, convulsions, coma, death

alcohol addiction

Compulsive desire to seek, obtain, and drink leading to SUD

Treatment of Alcohol Withdrawal

* Initial treatment: maintain fluid and electrolyte balance to present seizure 
* More severe: use oral administration of diazepam (benzodiazepine)

What is the pharmacological basis for using benzodiazepines to treat alcohol withdrawal symptoms?

* Suppressed by administration of second drug of similar mechanism action 
* After successful withdrawal, dose of diazepam decreased gradually

Drugs Used to Treat Alcohol Use Disorder

* Naltrexone (opiod antagonist): effective treatment of alcohol addiction 
* Diminishes craving for ethanol, blocks activation of dopaminergic reward pathways

cannabis

drug-containing forms of herbaceous annual (cannabis sativa)

Cannabinoids (CB)

60 chemical compounds

* I-trans-delta-9-tetrahydrocannabinol (THC): potent psychoactive agent in cannabis accounting for psychoactive effects

Classification of Cannabis

1. Pharmacological: CNS depressant, euphoriant, hallucinogen 
2. Legal: cannabis legalized in Canada (2018)

Administration of Cannabis

* Smoked or inhaled 
* Extracts with cannabinoids in oil administered by vaping or oral consumption 

Mechanism of Action of Cannabis

* THC binds to cannabinoid receptors (CB1) 
* CB receptor activated by anadamide/THC: inhibits release of excitatory neurotransmitters → causing reduction in cognitive function

anadamide

endogenous ligand for CB receptors involved in learning and memory process

Cannabinoid Receptors

1. CB1 Receptors


1. CB2 Receptors

CB1 Receptors

* Receptors in the cerebral cortex mediate distortions of time, colour, sound, taste → mediate decrease in cognitive function and concentration 
* Receptors in hippocampus cause changes in memory and learning
* No receptors in brain stem → do not depress respiration (non-lethal drug)

CB2 Receptors

* Found outside CNS → involved in inflammation 
* Binding THC to CB2 receptors on lymphocytes causes immunosuppressive properties of THC

Absorption of THC

* Inhaled: rapid and onset of action immediate → 3-4 hours 
* Ingested: THC absorbed after oral administration, absorption is slow and incomplete → less effect

Distribution of THC

* THC distributes to tissues with high blood perfusion → lung, heart, brain, liver, placenta 
* THC stored in adipose tissue

Metabolism of THC

metabolized slowly

Excretion of THC

* THC half life: 30 hours 
* Elimination of THC from adipose tissue takes longer

Effects of Short-Term Cannabis Use

1. CNS 

* Relaxation, drowsiness, euphoria, impaired motor coordination, increased appetite 
* Higher dosage = pseudo-hallucinations (impaired judgement and coordination) 


2. Cardiovascular System 

* Increased heart rate, increased blood flow to extremities, postural hypotension 


3. GI Tract 

* Increased appetite, dryness of mouth and throat 


4. Other 

* Reduction in sex drive, disruption in ovarian cycle, hangover

Psychological Effects of Long-Term Cannabis Use

* Occasional low-dose: not associated with harmful psychological effects 
* High doses: short-term memory loss, lack of concentration, loss of ability in abstract thinking, lack of motivation 
* Permanent effects: unknown → memory impairment and learning

Cardiovascular Effects of Long-Term Cannabis Use

* Reversible effects 
* Increase in heart rate may cause problems for those with heart disease

Respiratory Effects of Long-Term Cannabis Use

Bronchitis, asthma, sore throat, chronic irritation to respiratory tract

Fertility Effect of long term cannabis use

* Males: decreased sperm count 
* Females: cycles occur without ovulation 
* Pregnancy: developmental delays leading to cognitive deficits, impulsiveness, inattention, hyperactivity

Medical Uses of Cannabis

* Currently not used due to more effective anti-nausea medications 
* Challenge for pharmacological use due to difficulty in separating beneficial effects from psychotropic effects

cannabis concerns

* Misuse potential: low to moderate 
* Inherent harmfulness: low 
* Main concern: car accidents, exposure to children, lung effects

cannabis tolerance

* Psychoactive properties of THC 
* Effects of cardiovascular system 
* Impairment of performance and cognitive function

cannabis withdrawal

Mild withdrawal syndrome occurs: sleep disturbances, irritability, loss of appetite, nervousness, mild agitation, upset stomach, sweating

cannabis addiction

* Develops as persistent craving for drug 
* Risk of addiction higher

Opioids

natural or synthetic substance which exerts action on body through binding to opioid receptors

* Class of drugs naturally found within opium poppyy plant (Papaver somniferum) 
* Opiods used for morphine and codeine
* Useful drug but can cause opioid use disorder (OUD)

Classes of opioids

1. endogenous opioids
2. natural opioids
3. semi-synthetic opioids
4. synthetic opioids

Endogenous Opioids

* Not administered drugs → made in body that bind to opiod receptors and relieve pain 
* 3 families: enkephalins, dynorphins, beta-endorphins 
* Affect perception of pain and emotional respoonse to pain influencing mood and reward pathways

natural opioids

derived from plants

* Morphine: binds directly to opioid receptors used to treat severe pain, causes euphoria (10x more powerful than codeine) 
* Codeine: converted to morphine by liver enzymes → commonly Tylenol 3

semi-synthetic opioids

altered versions of morphine chemically changed to different pharmacological properties

* Hydromorphone: clinically used for analgesia (inability to feel pain) → 5x stronger than morphine 
* Diacetylmorphine: injectable opioid against therapy to manage OUD 
* Ilicit use → 2-5x more potent than morphine

synthetic opioids

chemically synthesized to bind to opioid receptor


1. Fentanyl and Related Compounds
2. Loperamide
3. Methadone

Fentanyl and Related Compounds

100x stronger than morphine and designed for treatment of severe acute chronic pain → contribute to OUD crisis

Loperamide

* Stays in intestines and quickly metabolized 
* Prevents illicit use, does not cause substantial analgesia(inability to feel pain)/euphoria

Methadone

* Used for analgesia and used in treatment of OUD 
* Prevents withdrawal symptoms, does not cause euphoria

Opioid Receptors

Located in central and peripheral nervous systems, and GI tract


1. Mu
2. KAPPA
3. DELTA

Mu (μ) receptors

brain and spinal cord

* Mediate analgesia and responsible for morphine-mediated depression of respiration in brrain stem 
* Involved in misuse of opioids

KAPPA (k)

involved in analgesia, dysphoria (dissatisfaction), miosis (pinpoint pupils)

DELTA (δ)

analgesia at spinal cord and brain → modulate emotional response

Mechanism of action of opioids

Block pain pathways in spinal cord and brain → exerted through activation of mu receptors

Reduce Neurotransmitter Release

Reduces neurotransmitter release from presynaptic neurons and reduces effect on postsynaptic neurons → preventing pain signals

Reduce Emotional Reaction

Reduce emotional reaction to pain → modulating limbic system

Short Term Effects of Opioids

1. Analgesia
2. Sedation and Hypnosis
3. Suppression of cough center
4. Respiratory Depression
5. Endocrine Effects
6. Miosis
7. Heart Rate and Thermoregulation
8. Decreased Intestinal Motility

Therapeutic Uses of Opioids

1. relieves severe pain
2. treatment of diarrhea
3. cough suppression

Opioid Potential for Misuse

1. Misuse Potential 

* Powerful euphoric effects → large risk for misuse 
* Low-moderate dose: low inherent harmfulness for morphine 
* High doses: high risk if lethal dose 


2. Risks of Injections

* High risk of developing abscesses at site of administration and infections


3. Overdose 

* Medical emergency → respiratory depression and death 
* Treatment: opiod antagonist (naloxone, naltrexone) and support of respiration