PHAR 426 - Lecture 12: Depressants

types of depressants

sedatives, hypnotics

depressant MOA

GABA binds to receptors = hyperpolarization of cell = inhibition of post synaptic cell firing and release of neurotransmitter = reduced activity

barbiturates

sedative-hypnotics to treat seizures, neonatal withdrawal, insomnia, preoperative anxiety and induction of coma for increased intracranial pressure

phenobarbital

barbiturate, antiepileptic drug in neonatal and pediatrics

why are barbiturates used in neurosurgery

reduced cerebral metabolic rate of O2 consumption

Methohexital

barbiturate for sedition of short duration for cardioversion and pediatric outpatient surgery

butalbital

barbiturate for headache disorders

pentobarbital 

barbiturate pre anesthetic med and for status epilepticus

primidone

barbiturate for seizure disorders

amobarbital

barbiturate for insomnia

phenobarbital

long acting barbiturate for anticonvulsant 

intermediate and short acting barbiturates

faster onset = used as sedative hypnotics

ultrashort acting barbiturates

time of effect is minutes effects last for 30 mins, used for general anesthetics for short surgical procedures

barbiturates absorption

rapid abs (bcz its a salt), peak conc 2-4 hrs; 90% F in adults and less in neonatal; abs delayed by food

barbiturate metabolism and redistribution

high lipid sol = high redistribution; metabolized in liver to lipid sol. intermediate by oxidation, dealkylation and conjugation by CYP450

barbiturate excretion

25% excreted unchanged in urine rest is metabolic elimination (age dependent)

Barbiturate MOA

postsynaptic enhancement of GABA through interaction with a and b subunits of GABA_A

increases Cl ion flux = post synaptic hyperpolarization + CNS depression

Barbiturate adverse effects

excessive sedation, tolerance to sedative effects but not respiratory depression; reduced BP increased HR; histamine release; tissue necrosis hepatoxicity skin rashes; congenital defects in infants; addictive and dependency

benzodiazepines

anxiolytic sedative-hypnotic, anti convulsant; treats alcohol withdrawal and muscle relaxant

Benzodiazepine MOA

promotes binding of GABA to GABA_a through structural change of channel = increased ionic currents through ligand gated Cl channels = decreased neuronal excitability → increases CNS inhibitory tone/ decreased action potential

also increases activity of Da neurons

benzos act as

hypnotics in high dose

anxiolytics in moderate dose

sedative in low dose

benzo metabolisim

N-dealkylation

hydroxylation

conjugation

metabolized by CYPs

benzos as anxiolytic adverse effect

sedation, motor incoordination, impaired mental function, confusion

benzos as hypnotics adverse effects

daytime sedation, cognitive impairment, anxiety, rebound insomnia, early morning insomnia, memory impairment/amnesia

flumazenil

treats benzo OD

benzo abuse potential

relatively low on its own but high risk of dependency; increased risk of misuse when used with other depressants

Alcohol abs

variable but rapid absorption usually

peak blood alc conc. depends on

amount and conc, drinking pace, food consumption and composition, gastric emptying and metabolism, hepatic first pass

alcohol metabolism

alc → (alcohol dehydrogenase) → acetaldehyde (toxic) -(acetaldehyde dehydrogenase) → acetic acid -(oxidation) → carbon dioxide

alcohol MOA

enhanced dopamine release, enhanced GABA activity at GABA_A, blocks NMDA receptors = inhibit glu, inhibits voltage sensitive Ca channels

alc non specific effect on neuronal membrane

altered lipid comp, interacts with polar head of phospholipids, disturbs relationship between proteins and membrane

specific effects alc has on neuronal membrane

acts at neurotransmitter binding site, modifies gating mechanisms, interacts with channel protein directly, stimulates G protein?

alc positive reinforcing effects

gain in pleasure, altered consciousness, peer pressure?

alc negative reinforcing effects

relief of stress, negative emotions, withdrawal symptoms

2nd stage alc abuse

discomfort + desire for alc, habit of lies and new methods of use, tolerance progression

3rd stage alc abuse

visible symptoms of abuse, deteriorated relation, weight loss or gain, facial redness, sluggishness, stomach bloating

4th stage alc abuse

severe complications (ex. liver cirrhosis)

objective of withdrawal managment

prevent seizures, arrhythmias, delirium

balance K, Mg and phosphates

alc withdrawal treatments

thiamine therapy

wernicke-korskoff syndrome

damage to thalamus, ataxia, abnormal eye movement, impaired memory, loss of contact with reality, blurred and double vision, nystagmus

left untreated = death or Korsakoff psychosis

caused by thymine defficiency

FAS CNS anomolies

microcephaly, developmental delays, intellectual disabilities and neonatal problems

relation between alc, nicotine

positive correlation of use

nicotine enhances administration of OH