1 - Pharmacology Flashcards
What is the mechanism of action of benzodiazepines? What are their major advantages and disadvantages?
- bind between alpha(1-3,5) and gamma(2) subunits of GABA r. resulting in allosteric enhancement of GAGA binding
- increases the FREQUENCY of Cl- channel opening
- can NOT cause direct activation of channel -> no affect w/o GABA
- Metabolized: mostly distributed to high perfusion tissue first (brain); met in liver (CYP3A4); many metabolites are active!! thus increasing effective t1/2 of drug (ex: diazepam, flurazepam)
- Advantages: CNS depression with higher therapeutic index, broad uses(anxiety, hypnotic, seizures, alcohol withdrawal, muscle relaxation)
- Disadvantages: altered sleep patterns, impaired mental/motor function, additive with other CNS depressants (ALCOHOL), withdrawal symptoms, no anesthesia
What is the mechanism of action of barbiturates? What are their major advantages and disadvantages?
- bind to the Beta subunit of the GABA receptor and allosterically enhances GABA action; this increases DURATION of Cl- channel opening
- HIGH doses: 1) direct activation of GABA r.(w/o GABA); 2) inhibit AMPA r.; 3) inhibit nACh r.
- metabolized by liver (CPY450) and excreted in urine; short-acting are redistributed into tissue
- Advantaged: general CNS depression is dose dependent; used for HYPNOTICS and ANTI-SEIZURE, anesthesia
- Disadvantages: low therapeutic index, does NOT induce physiologic sleep, LOTS of interactions, susceptible to abuse/addition/tolerance/withdrawal,
- Overdose: direct action at GABA r. can lead to DEATH via respiratory depression
What is the mechanism of action of non-benzodiazapines? What are their major advantages and disadvantages?
- bind to the BZ1 site of GABA r. resulting in allosteric enhancement with no direct stimulation
- similar to BZ, but only activates alpha1 subtype (not alpha2) producing only sedation and anterograde amnesia (vice anxiolytic and muscle relaxant)
- Advantages: more specific action, maintains normal sleep, less rebound insomnia, less tolerance/abuse/dependence
- Disadvantages: headaches, additive with other CNS depressents (ALCOHOL), reports of sleep walking/eating (zolpidem), habit forming with chronic use
What is the mechanism of action of melatonin receptor agonists? What are their major advantages and disadvantages?
- melatonin is a serotonin derivative secreted by the pineal gland
- thought to play a role in sleep/wake cycle, is known to suppress ovarian function and lighten skin
- Melatonin(synthetic): dietary supplement that has NOT been shown to be clinically effective
- Ramelteon: MT1/MT2 receptor agonist in the Suprachiasmic Nucleus (SCN) which regulates sleepiness and circadian rhythm
- Metabolized: in liver (CYP450)
- Advantages: not operating through CNS depression->no cognitive/motor impairment, not controlled, long term use
- Disadvantages: increased serum prolactin (chronic=hypogonadism, infertility, less libido, osteoporosis), lower testosterone
What is the mechanism of action of GHB/Sodium Oxybate? What are their major advantages and disadvantages?
- gamma-hydroxybutyrate/sodium oxybate is a precursor and metabolite of GABA which can cause direct and indirect CNS depression
- Direct: binding to GHB r. can stimulate pre and post-synaptic neuron; can also allosterically enhance GABAb
- Indirect(high doses): by metabolizing to GABA, can cause increased depression via both pre and post-synaptic activation
- Uses: GHB is Schedule I drug seen primarily as flunitrazepam (Rohypnol)
- Sodium Oxybate(Xyrem) is Schedule III used in cataplexy and EDS in narcolepsy
- SEVERE potential for abuse/overdose
What are the classes of spasmolytics? What are their mechanisms? What are their main adverse effects?
Centrally Acting: block muscle reflex arc, enhance descending inhibitory (GABA) and inhibit descending excitatory (Glutamate)
1) Benzodiazepines(diazepam): allosteric enhancement of GABA receptors (alpha 1/2)
2) Baclofen: bind to GABAb r. causing more K+ outflow, less Ca++ inflow -> hyperpolarize both pre and post-synaptic neuron
- adverse: weakness, increased seizures/CNS depression via intrathecal
3) Tizanidine: alpha2 andrenergic r. antagonist, leading to less Glu release and blocking of excitatory pathway
-adverse: drowsiness, weakness, hypotension
Direct Acting:
1) Dantrolene: blocks skeletal muscle release of Ca++ from SR, leading to uncoupling of excitation-contraction-> used in Malignant Hyperthermia
-adverse: general muscle weakness (contra in ALS), sedation
What are major examples of barbiturates? What are their uses?
- phenobarbital: Long acting-> anti-seizure
- pentobarbital: intermediate acting-> hypnotic, preoperative sedation, emergency tx of seizures
- thiopental: short acting-> induction/maintenance of anesthesia
What is MAC?
- Minimal Alveolar Concentration-> steady state alveolar concentration of inhaled anesthetic req’d for immobility in 50% of individuals exposed to surgical incision
- 0.5 MAC-> MAC awake: 50% can be awakened
- 1MAC-> MAC: 50% immobile at incision
- 1.3MAC-> ED95: 95% immobile at incision
- 1.5-2.0MAC -> MAC-BAR: 50% have Blocked Autonomic Response
What are the stages of anesthesia?
1) Analgesia: no pain w/o amnesion, impaired judgement, vertigo/ataxia, increased HR/RR/BP
2) Excitement: delirious, excited, amnestic, irregular respirations
3) Surgical Anesthetic: recurrance of regular respiration to cessation of spontaneous breathing, loss of corneal reflexes, swallowing, eyelid reflex
4) Medullary Depression: cessation of spontaneous respiration, results in death w/o artificial support (circulation, ventilation, ect)
What are the factors that affect the rate of establishing a desired inhaled anesthetic concentration?
Delivery
1) Gas concentration-> HIGHER the FI (inhaled fraction), faster induction
2) Alveolar Ventilation-> HIGHER respiration rate causes faster induction
Uptake:
3) Solubility-> the higher the solubility, the more will be “stored” in the blood before being passed to the brain; LOWER solubility causes faster induction
4) Pulmonary Blood Flow (Cardiac Output)-> more cardiac output increases the volume of blood that needs to be saturated prior to passing to brain, it also leads to more perfusion of tissue vs brain; LOWER blood flow causes faster induction
5) Arterio-venous concentration gradient-> a larger gradient leads to more efficient transfer; HIGHER gradient causes faster induction
What is the partition coefficient?
This is an assessment of the solubility of the inhaled gas. It is the ratio between 2 phases at steady state.
Blood:Gas partition coefficient-> low means there is a low solubility, so there less total gas is needed to achieve a desired gas concentration
What is the affect of inhaled agents on:
1) cardiovascular
2) respiratory
3) CNS
4) Renal/Hepatic
1) Cardio-> dose-dependent decrease in MAP; most decrease SVR, while halothane are myocardial depressents-> ALL reduce myocardial O2 consumption; N2O can mask some of the affects
2) Lung-> all decrease minute ventilation (decrease TV, increase RR), decrease sensitivity to PCO2 and PO2
3) CNS-> decrease metabolic rate and increase blood flow; may lead to increase in ICP; enflurane implicated in causing seizures
4) kidney/Liver-> decreased perfusion, decreased renal autoregulation and possible hepatotoxicity
What is malignant hyperthermia? How is it related to inhaled anesthetics?
- rare, inherited, potentially lethal hypermetabolic syndrome resulting in elevated CO2, altered muscle tone, and metabolic acidosis
- can be triggered in susceptible individuals by potent inhaled anesthetics and succinylcholine
- Tx: dantrolene(local muscle relaxant)-> Ca++ release blocker
