Heroin (diacetyl morphine)

Heroin is synthetically derived from the natural opioid alkaloid morphine

Largely owing to its very rapid onset of action and very short half-life, heroin is a popular drug of abuse

It is most effective when used intravenously

Heroin is rapidly deacetylated to 6-monoacetyl morphine and morphine, both of which are active at the mu opioid receptor

More lipid soluble than morphine and about 2½ times more potent.  It enters the CNS more readily.

Seizure classification:

based on degree of CNS involvement, involves simple ( Jacksonian; sensory or motor cortex) or complex symptoms (involves temporal lobe)

1.    Generalized (whole brain involved): 

a.    Tonic-clonic:

Grand Mal; ~30% incidence; unconsiousness, tonic contractions (sustained contraction of muscle groups) followed by clonic contractions (alternating contraction/relaxation); happens for ~ 2-3 minutes and people don’t breathe during this time

Drugs: phenytoin, carbamazepine, Phenobarbital, lamotrigine, valproic acid

Status epilepticus: continuous seizures; use diazepam (short duration) or diazepam + phenytoin

b.    Absence:

Petit Mal; common in children; frequent, brief lapses of consciousness with or without clonic motor activity; see spike and wave EEg at 3 Hz (probably relates to thalamocorticoreverburating circuit)

Drugs: ethosuximide, lamotrigine, valproic acid

c.    Myoclonic: uncommon; isolated clinic jerks associated with bursts of EEG spikes; 

Drugs: lamotrigine, valproic acid

d.    Atonic/akinetic: drop seizures; uncommon; sudden, brief loss of postural muscle tone
Drugs: valproic acid and lamotrigine

2.    Partial:  focal

a.    Simple:  Jacksonian; remain conscious; involves motor or sensory seizures (hot, cold, tingling common)

Drugs: carbamazepine, phenytoin, Phenobarbital, lamotrigine, valproic acid, gabapentin

b.    Complex: temporal lobe or psychomotor; produced by abnormal electrical activity in temporal lobe (involves emotional functions)

Symptoms: abnormal psychic, cognitive, and behavioral function; seizures consist of confused/altered behavior with impaired consciousness (may be confused with psychoses like schizophrenia or dementia)

Drugs: carbamazepine, phenytoin, laotrigine, valproic acid, gabapentin

Generalizations: most seizures can’t be cured but can be controlled by regular administration of anticonvulsants (many types require treatment for years to decades); drug treatment can effectively control seizures in ~ 80% of patients

Griseofulvin

• Griseofulvin is an antifungal drug. It is used both in animals and in humans, to treat ringworm infections of the skin and nails. It is derived from the mold Penicillium griseofulvum.
• It is administered orally.

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

Benzodiazepines (BZ): 

newer; depress CNS, selective anxiolytic effect (no sedative effect); are not general anesthetics (but does produce sedation, stupor) or analgesics 

BZ effects: 

1.  Central: BZs bind GABA_A receptors in limbic system (amygdala, septum, hippocampus; involved in emotions) and enhance inhibition of neurons in limbic system (this may produce anxiolytic effects of BZs)

a. GABA receptor: pentameric (α, β, δ, γ subunits)
i.  Binding sites: GABA (↑ conductance (G) of Cl-, hyperpolarization, inhibition), barbiturate (↑ GABA effect), benzodiazepine (↑ GABA effect), picrotoxin (block Cl channel)

b. GABA agonists: GABA (binds GABA → Cl influx; have ↑ frequency of Cl channel opening; BZs alone- without GABA don’t affect Cl channel function)

c.  Antagonists: bicuculline (competitively blocks GABA binding; ↓ inhibition,→ convulsions; no clinical use), picrotoxin (non-competitively blocks GABA actions,  Cl channel → ↓ inhibition → convulsions)

2.  Other agents at BZ receptor: 

a.    Agonists: zolpidem (acts at BZ receptor to produce pharmacological actions)

b.    Inverse agonists: β-carbolines (produce opposite effects at BZ binding site-- ↓ Cl conductance; no therapeutic uses since → anxiety, irritability, agitation, delirium, convulsions)

3. Antagonists: flumazenil (block agonists and inverse agonists, have no biological effects themselves; can precipitate withdrawal in dependent people)

Metabolism: many BZs have very long action (since metabolism is slow); drugs have active metabolites

2 major reactions: demethylation and hydroxylation (both very slow reactions)

Fast reaction: glucuronidation and urinary excretion

Plasma half life: long (for treating anxiety, withdrawal, muscle relaxants), intermediate (insomnia, anxiety), short (insomnia), ultra-short (<2hrs; pre-anesthetic medication)

Acute toxicity: very high therapeutic index and OD usually not life threatening (rarely see coma or death)

Treatment: support respiration, BP, gastric lavage, give antagonist (e.g., glumazenil; quickly reverses BD-induced respiratory depression)

Tolerance: types include pharmacodynamic (down-regulation of CNS response due to presence of drug; this is probably the mechanism by which tolerance develops), cross-tolerance (with other BZ and CNS depressants like EtOH and BARBS), acquisition of tolerance (tolerance develops fastest in anticonvulsant > sedation >> muscle relaxant > antianxiety; means people can take BZs for long time for antianxiety without → tolerance)

Physical dependence: low abuse potential (no buz) but physical/psychological dependence may occur; physical dependence present when withdrawal symptoms occur (mild = anxiety, insomnia, irritability, bad dreams, tremors, anorexia; severe = agitation, depression, panic, paranoia, muscle twitches, convulsions)

Drug interactions: minimally induce liver enzymes so few interactions; see additive CNS depressant effects (can be severe and → coma and death if BZs taken with other CNS depressants like ethanol)

PHARMACOLOGY OF LOCAL ANESTHETICS

 Characteristics

1. Block axon conduction (nerve impulse) when applied locally in appropriate concentrations.

2. Local anesthetic action must be completely reversible; however, the duration of the anesthetic block should be of sufficient length to allow completion of the planned treatment.

3. Produce minimal local toxic effects such as nerve and muscle damage as well as minimal systemic toxic effects of organ systems such as the cardiovascular and central nervous system.