Midazolam -Intravenous Anesthetics
 Midazolam is a benzodiazepine used for preoperative sedation, induction of anesthesia, or maintenance of anesthesia in short procedures.

Barbiturates (BARBS): 

were used for antianxiety, sedation but now replaced by BZs; for IV sedation & oral surgery

Advantages: effective and relatively inexpensive (common in third world countries), extensively studied so have lots of information about side effects/toxicity

Peripheral effects: respiratory depression (with ↑ dose), CV effects (↓ BP and HR at sedative-hypnotic doses), liver effects (bind CYP450 → induction of drug metabolism and other enzymes → ↑ metabolism of steroids, vitamins K/D, cholesterol, and bile salts)

General mechanisms: potently depress neuron activity in the reticular formation (pons, medulla) and cortex 
o    Bind barbiturate site on GABAA receptor → enhanced inhibitory effect and ↑ Cl influx; → ↓ frequency of Cl channel opening but ↑ open time of Cl channels (in presense of GABA) so more Cl enters channel (at high [ ] they directly ↑ Cl conductance in absence of GABA- act as GABA mimetics)

Metabolism: liver microsomal drug metabolizing enzymes; most are dealkylated, conjugated by glucoronidation; renal excretion

Uses: anticonvulsant, preoperative sedation, anesthesia

Side effects: sedation, confusion, weight gain, N/V, skin rash

Contraindications: pain (can ↑ sensitivity to painful situations → restlessness, excitement, and delirium) and pulmonary insufficiency (since BARBS → respiratory depression)

Drug interactions: have additive depressant affects when taken with other CNS depressants, enhance depressive effects (of antipsychotics, antihistamines, antiHTNs, ethanol, and TCAs), and accelerates metabolism (of β blockers, Ca-channel blockers, corticosteroids, estrogens, phenothiazines, valproic acid, and theophylline; occurs with chronic BARB ingestion)

Acute toxicity: lower therapeutic index; can be fatal if OD; BARB poisoning a major problem (serious toxicity at only 10x hypnotic dose; → respiratory depression, circulatory collapse, renal failure, pulmonary complications which can be life-threatening)

Symptoms: severe respiratory depression, coma, severe hypotension, hypothermia

Treatment: support respiration and BP, gastric lavage (if recent ingestion)

Tolerance: metabolic (induce hepatic metabolic enzymes, occurs within a few days), pharmacodynamic (↓ CNS response with chronic exposure occurs over several weeks; unknown mechanism), and cross tolerance (tolerance to other general CNS depressants)

Physical dependence: develops with continued use; manifest by withdrawal symptoms (mild = anxiety, insomnia, dizziness, nausea; severe = vomiting, hyperthermia, tremors, delirium, convulsions, death)

Other similar agents: meprobamate (Equanil; pharmacological properties like BZs and barbiturates but mechanism unknown) and chloral hydrate (common sedative in pediatric dentistry for diagnostic imaging; few adverse effects but low therapeutic index)

Other drugs for antianxiety: β-adrenoceptor blockers (e.g., propranolol; block autonomic effects- palpitations, sweating, shaking; used for disabling situational anxiety like stage fright), buspirone (partial agonist at serotonin 1A receptor, produces only anxiolytic effects so no CNS depression, dependence, or additive depression with ethanol but onset of action is 1-3 weeks), lodipem (not a BZ but does act at BZ receptors)

Dental implications of these drugs: 

1.    Adverse effects: gingival hyperplasia (phenytoin), osteomalacia (phenytoin, Phenobarbital), blood dyscrasias (all but rare)
2.    Drug interactions: additive CNS depression (anesthetics, anxiolytics, opioid analgesics), induction of hepatic microsomal enzymes (phenytoin, Phenobarbital, carbamazepine), plasma protein binding (phenytoin and valproic acid)
3.    Seizure susceptibility: stress can → seizures

Operator position

For the right-handed operator, the 8 and 10 o’clock position and for left-handed operators, the corresponding 2 and 4 o’clock position almost always allows for optimal visualization of the injection field.

Oxycodone  
About equal potency to morphine. Very effective orally.

It is combined with aspirin or acetaminophen for the treatment of moderate pain and is available orally

Oxycodone is a semisynthetic compound derived from thebaine, with agonist activity primarily at mu receptors.

Distribution

Three major controlling factors:  

Blood Flow to Tissues:  rarely a limiting factor, except in cases of abscesses and tumors.
Exiting the Vascular System:  Occurs at capillary beds.
- Typical Capillary Beds - drugs pass between cells 
- The Blood-Brain Barrier-  Tight junctions here, so drugs must pass through cells.  Must then be lipid soluble, or have transport system.
- Placenta - Does not constitute an absolute barrier to passage of drugs.  Lipid soluble, nonionized compounds readily pass.  
- Protein Binding:  Albumin is most important plasma protein in this respect.  It always remains in the blood stream, so drugs that are highly protein bound are not free to leave the bloodstream.  Restricts the distribution of drugs, and can be source of drug interactions.

Entering Cells:  some drugs must enter cells to reach sites of action.