PHAR 3 Section 1

what do sedative-hypnotic agents due to CNS

they are CNS depressants 

different magnitudes of CNS depression low to high dose

In order from low to high

1. anti-anxiety

2. setation

3. hypnosis

4. general anesthesia

what is the major excitatory neurotransmitter in the brain?

Glutamate

What is the role of excitatory neurons?

Excitatory neurons release the neurotransmitter glutamate. Neurons “fire” when the excitatory inputs exceed inhibitory inputs.

effect of GABA nuerons in glutamate nerve firing 

inhibitory signals from GABA neurons increase the most sedative-hynpotics, resulting in decreased glutamate nerve firing.

What is GABA?

the primary inhibitory neurotransmitter in the CNS

what does GABA cause

it causes inhibition by binding to and selectively opening chloride channels

what are GABA channels built of

built of multiple subunits that span the neuronal cell membrane, allowing chloride ions to flow into the cell when signalled to open 

What happens when GABA bind to and opens the chloride channel

when gaba binds to and opens the chloride hannel, chloride ions flow into the postsynaptic neuron.

how is CNS neuronal signalling depressed.

The influx of chloride ions makes it harder for the postsynaptic neuron to transmit incoming messages to other neurons, thereby depressing CNS neuronal signalling

most sedative-hypnotics module what?

modulate the chloride ion channel in the brain and spinal cord, but each bind to a different site on the chloride channel, as indicated in the diagram.

what is the result of sedative hypnotics that bind to the chloride channel 

an increase in synaptic inhibition and thus a dampening of neuronal responses.

In essence, they enhance the inhibitory effect of GABA 

what is a fun fact about benzodiazepines

benzodiazepines are among the most widely prescribed drugs in the world, with 5-10% of Canadians being prescribed this class of drugs.

Many benzodiazepines exist, what differs and what remains the same?

• therapeutic effects and duration of ation differ

• mechanism of action is the same

what is the route of administration of benzodiazepines

usually taken as a capsule or tablet, but some are available for intravenous or intranasal use

mechanism of action of benzodiazepines

activation of benzodiazepine receptor increases the frequency of the opening of the chloride channel

what are the therapeutic effets of benzodiazepines

• the therapeutic of desirable effects of benzodiazepines are relaxation, calmness (i.e., they can decrease aggression,) and relief from anxiety or tension.

• They also produce skeletal muscle relaxation and have anticonvulsant effects.

• some benzodiazepines are effective hypnotics

• have mininmal supression of REM-type sleep

what is the lethality of benzodiazepines (fun fact)

they are among the drugs most commonly involved in overdose

Talk about the therapeutic index and margin of safey of benzodiazepines

Fortunately, they have a very high therapeutic index, and therefore, a wide margin of safety which means that deaths from overdose are very rare.

when has death from benzodiazepines occurred

death has occured following ingestion of enormous doses, rapid intravenous injection of a large dose, or when taken in combination with other sedating drugs (e.g., alcohol)

is there an antidote for benzodiazepine

yes

what is the antidote called for benzodiazepines 

flumazenil 

how does the antidote for benzodiazepine work?

its a benzodiazepine receptor antagonist that blocks the effects of benzodiazepines

adverse effects of short-term benzodiazepine use on the CNS

• drowsiness, lethargy, fatigue, and impairment of thinking and memory

adverse effects of short-term benzodiazepine use on the lungs

respiratory depression has been observed following rapid intravenous administration of benzodiazepines

adverse effects of short-term benzodiazepine use on motor coordination

moderate doses of all benzodiazepines can impair motor coordination and driving

loing term adverse effects of benzodiazepine use 

• chronic sedative-hypnotic intoxication 

  • impaired thinking

  • poor memory and judgment

  • disorientation

  • incoordination

  • slurred speech

how does benzodiazepines affect pregnant/chestfeeding people

benzodiazepines cross the placenta and distribute into the fetus. If they are administered in the first trimester, they result in a small but signiicant risk for fetal abnormatlities. benzodiazepines are secreted into the milk, exposing nursing infants to therapeutic or toxic doses of the drug and can result in sedation or death.

how does benzodiazepines affect older people

can produce cognitive dysfunction in older adults 

• they metabolize more slowly in older adults than in young adults, often leading to over-sedataion, falls, and injury 

benzodiazepines: potential for misues and SUD… what can it result in

• tolerance

• withdrawal

• addiction

what is the inherent harmfullness of benzodiazepines

inherently low

• does not depress respiration at therapeutic doses

• does not often lead to death on its own

benzodiazepines tolerance 

a high degree of cross-tolerance occurs among benzodiazepines and other sedative-hypnotic drugs 

the magnitude of tolerance that develops to benzodiazepines does not produce clinical concerns 

benzodiazepine withdrawal

• a mild but distinct withdrawal can occur

  • anxiety

  • headache

  • insomnia

• Following chronic use (1 year or more)

  • agitation

  • paranoia

  • seizures

  • delirium

addiction to benzodiazepines 

• may develop in some individuals but not all 

• depends on genetics and environment 

How do benzodiazepines reduce and atheletes anxiety?

it increases CNS depression in a dose-dependent mannter. therefore at lower doses, they act as anti-anxiety agents

what class of drugs are barbiturates apart of

another class of sedative-hypnotics 

how are barbiturates classified

according to their duration of action

• long acting (1-2days)

• short acting (3-8 hours)

• ultra short acting (20 min)

Barbiturates routes of administration

administered in different ways depending on what they are being used to treat

• for epilepsy, barbiturates are administered orally.

• For anesthesia, they are administered intravenously

Barbiturates mechanism of action

activation of the barbiturate receptor increases the duration of the opening of the chloride channel

• they demonstrate the full spectrum of dose-dependent CNS depression

  • anti-anxeity → sedation → hypnosis → general anesthesia → death

Therapeutic use of barbiturates

in low doses, barbiturates usually result in the beneficial effects of tranquility and relaxation

• they willl also induce sleep if the dose is sufficient 

ultra-short acting and short-acting can be used to induce anesthesia 

long lasting can be used as antiepileptics 

lethality of barbiturates

barbiturates have been replaced for the mot part by newer and safer drugs, because of their low therapeutic index and potential for lethality

• death can occur during barbiturate withdrawal

what is usually the common cuase of lethality from barbiturates

lethality due to depression of respiration is common, especially when combined with alcohol

adverse effects of barbiturate use 

• they supress REM-type sleep 

adverse effects of short term barbiturate use

• in low doses, usually result in mild euphoria and reduced interest in ones surroundings

• may cause dizziness and mild impairment of motor coordination

• may cause a pleasurable state of intoxication and euphoria as the dose of drug is increased

• in high doses, depress the cardiovascular system, slowing the heart and lowering blood pressure

the long term adverse effects of barbiturate use

chronic inebriation.

Memory, judment, and thinking are all impaired

individuals often exhibit hostility and mood swings, including depression

Barbiturates potential for misuse 

potential for misuse is equal to or greater than alcohol 

• the pleasurable effects of some barbiturates give a significant degree of reinforcement 

Barbiturate tolerance

tolerance can develop

• a high degree of cross-tolerance occurs between barbiturates and other sedatives

barbiturate withdrawal

withdrawal occurs after discountinuation of chronic use. symptoms usually appear as tremors, anxiety, weakness, and insomnia, as well as postural hypotension.

• these symptoms may progress to include seizures, delirium, visual hallucinations, and a high body temperature

Addiction of barbiturates

• addictian can result from regular use, irrespective of the dose. 

• those with addiction will crave the drug and a feeling of panic may occcur if they cannot get adequate supplu 

mechanism of action of barbiturates

increases the duration of the opening of the chloride channel

therapeutic use of barbiturates

• tonic-clonic seizures

• partial seizures

pharmacology of barbiturates

• low therapeutic index 

• supress REM sleep 

• cause dose-dependent respiratory and cardiovascular depression 

• lethality common, espeically with alcohol 

• no antidote 

barbiturate misuse

misuse potential equal to or greater then alcohol

• tolerance yes

• withdrawal yes

• addiciton yes

what class are benzodiazepine-like drugs apart of

benzodiazepine-like drugs are another lass of sedative-hypnotics used to treat problems like anxiety or difficulty sleeping

2 examples of beznodiazepine-like drugs 

• zopiclone 

• zolpidem 

how does benzodizepine-like drugs act on GABA receptors

they bind to a subset of the GABA receptors and cause sedation

Benzodiazepine-like drugs vs benzodiazepine 

• acts similarily to benzodiazepine

• has an advantage over the benzodiazpeines as a hypnotic as they disturb REM sleep even less than the benzodiazepines 

• appear to have more sedative effects 

• like benozdiazepine, they should be used with caution in older adults 

Therapeteutic use of barbiturates, benzodiazepines, benzodiazepine-like drugs, flumazenil 

barbiturates: anti-epileptic 

Benzodiazepines: anti-anxiety 

benzodiazepine-like drugs: hypnotic 

flumazenil: antidote for benzodiazepine overdose 

what is Buspirone and what receptor does it act on

an interesting anxiolytic, as it is not a sedative. It does not act on the GABA receptor, but rather at the serotonin receptor

when is buspirone used

used in generalized anxiety states and may have an advantage over the sedatives in that it does not appear to have additive effects with other sedative-hypnotic drugs