OXYMETAZOLINE
 

It is a directly acting sympathomimetic amine used in symptomatic relief in nasal congestion which increases mucosal secretion.

It is used:
- As a nasal decongestant in allergic rhinitis, with or without the addition of antazoline or sodium chromoglycate. 
- As an ocular decongestant in allergic conjunctivitis.

Compounds like naphazoline and xylometazoline are relatively selective α2 agonists, which on topical application produce local vasoconstriction.

Antipsychotic Drugs

A.    Neuroleptics: antipsychotics; refers to ability of drugs to suppress motor activity and emotional expression (e.g., chlorpromazine shuffle)
Uses: primarily to treat symptoms of schizophrenia (thought disorder); also for psychoses (include drug-induced from amphetamine and cocaine), agitated states

Psychosis: variety of mental disorders (e.g., impaired perceptions, cognition, inappropriate or ↓ affect or mood)

Examples: dementias (Alzheimer’s), bipolar affective disorder (manic-depressive)

B.    Schizophrenia: 1% world-wide incidence (independent of time, culture, geography, politics); early onset (adolescence/young adulthood), life-long and progressive; treatment effective in ~ 50% (relieve symptoms but don’t cure)

Symptoms: antipsychotics control positive symptoms better than negative

a.    Positive: exaggerated/distorted normal function; commonly have hallucinations (auditory) and delusions (grandeur; paranoid delusions particularly prevalent; the most prevalent delusion is that thoughts are broadcast to world or thoughts/feelings are imposed by an external force)

b.    Negative: loss of normal function; see social withdrawal, blunted affect (emotions), ↓ speech and thought, loss of energy, inability to experience pleasure

Etiology: pathogenesis unkown but see biochemical (↑ dopamine receptors), structural (enlarged cerebral ventricles, cortical atrophy, ↓ volume of basal ganglia), functional (↓ cerebral blood flow, ↓ glucose utilization in prefrontal cortex), and genetic abnormalities (genetic predisposition, may involve multiple genes; important)

 Dopamine hypothesis: schizo symptoms due to abnormal ↑ in dopamine receptor activity; evidenced by 

i.    Correlation between potency and dopamine receptor antagonist binding: high correlation between therapeutic potency and their affinity for binding to D2 receptor, low correlation between potency and binding to D1 receptor)

ii.    Drugs that ↑ dopamine transmission can enhance schizophrenia or produce schizophrenic symptoms:

A)    L-DOPA: ↑ dopamine synthesis
B)    Chronic amphetamine use: releases dopamine
C)    Apomorphine: dopamine agonist

iii.    Dopamine receptors ↑ in brains of schizophrenics: postmortem brains, positron emission tomography

Dopamine pathways: don’t need to know details below; know that overactivity of dopamine neurons in mesolimbic and mesolimbocortical pathways → schizo symptoms

i.    Dorsal mesostriatal (nigrostriatal): substantia nigra to striatum; controls motor function
ii.    Ventral mesostriatal (mesolimbic): ventral tegmentum to nucleus accumbens; controls behavior/emotion; abnormally active in schizophrenia
iii.    Mesolimbocortical: ventral tegmentum to cortex and limbic structures; controls behavior and emotion; activity may be ↑ in schizophrenia
iv.    Tuberohypophyseal: hypothalamus to pituitary; inhibits prolactin secretion; important pathway to understand side effects

 Antipsychotic drugs: non-compliance is major reason for therapeutic failure

1.    Goals: prevent symptoms, improve quality of life, minimize side effects
2.    Prototypical drugs: chlorpromazine (phenothiazine derivative) and haloperidol (butyrophenone derivative)
a.    Provide symptomatic relief in 70%; delayed onset of action (4-8 weeks) and don’t know why (maybe from ↓ firing of dopamine neurons that project to meso-limbic and cortical regions)
3.    Older drugs: equally efficacious in treating schizophrenia; no abuse potential, little physical dependence; dysphoria in normal individuals; high therapeutic indexes (20-1000)

Classification: 

i.    Phenothiazines: 1st effective antipsychotics; chlorpromazine and thioridazine
ii.    Thioxanthines: less potent; thithixene
iii.    Butyrophenones: most widely used; haloperidol

 Side effects: many (so known as dirty drugs); block several NT receptors (adrenergic, cholindergic, histamine, dopamine, serotonin)  and D2 receptors in other pathways

i.    Autonomic: block muscarinic receptor (dry mouth, urinary retention, memory impairment), α-adrenoceptor (postural hypotension, reflex tachycardia)
Neuroleptic malignant syndrome: collapse of ANS; fever, diaphoresis, CV instability; incidence 1-2% of patients (fatal in 10%); need immediate treatment (bromocriptine- dopamine agonist)

ii.    Central: block DA receptor (striatum; have parkinsonian effects like bradykinesia/tremor/muscle rigidity, dystonias like neck/facial spasms, and akathisia—subject to motor restlessness), dopamine receptor (pituitary; have ↑ prolactin release, breast enlargement, galactorrhea, amenorrhea), histamine receptor (sedation)

DA receptor upregulation (supersensitivity): occurs after several months/years; see tardive dyskinesias (involuntary orofacial movements)

Drug interactions: induces hepatic metabolizing enzymes (↑ drug metabolism), potentiate CNS depressant effects (analgesics, general anesthetics, CNS depressants), D2 antagonists block therapeutic effects of L-DOPA used to treat Parkinson’s

Toxicity: high therapeutic indexes; acute toxicity seen only at very high doses (hypotension, hyper/hypothermia, seizures, coma, ventricular tachycardia)

Mechanism of action: D2 receptor antagonists, efficacy ↑ with ↑ potency at D2 receptor

Newer drugs: include clozapine (dibenzodiazepine; has preferential affinity for D4 receptors, low affinity for D2 receptors), risperidone (benzisoxazole), olanzapine (thienobenzodiazepine)

Advantages over older drugs: low incidence of agranulocytosis (leucopenia; exception is clozapine), very low incidence of motor disturbances (extrapyramidal signs; may be due to low affinity for D2 receptors), no prolactin elevation

Side effects: DA receptor upregulation (supersensitivity) occurs after several months/years; may → tardive diskinesias
 

Different Systems of the CNS & their functions

These systems are pathways formed of specific parts of the brain and the neurons connecting them. 

They include:
1.The pyramidal system 
2.The extrapyramidal system 
3.The limbic system 
4.The reticular formation 
5.The tuberohypophyseal system

The pyramidal system: 

It originates from the motor area of the cerebral cortex and passes through the spinal cord, therefore it is also known as the “corticospinaltract”. 
It is responsible for the regulation of the fine voluntary movements.

The extrapyramidal system: 

It also controls the motor functionbut involves areas other than the corticospinal tract. 
It is involved in the regulation of gross voluntary movements, thus it complements the function of the pyramidal system. 

The “basal ganglia” constitute an essential part of this system. 

Degenerative changes in the pathway running from the “substantianigra”to the “corpus striatum”(or nigrostriatal pathway) may cause tremors and muscle rigidity characteristic of “Parkinson’s disease”.

The limbic system: 

The major parts of this system are: the hypothalamus, the basal ganglia, the hippocampus(responsible for short term memory), and some cortical areas. 

The limbic system is involved in the control of “behavior”& “emotions”.

The reticular formation:

It is composed of interlacing fibers and nerve cells that run in all directions beginning from the upper part of the spinal cord and extending upwards. 
It is important in the control of “consciousness” and “wakefulness”.

The tuberohypophyseal system: 

It is a group of short neurons running from the hypothalamusto the hypophysis(pituitary gland) regulating its secretions.
 

FUNDAMENTALS OF INJECTION TECHNIQUE

There are 6 basic techniques for achieving local anesthesia of the structures of the oral cavity:

 1. Nerve block

 2. Field block

 3. Infiltration/Supraperiosteal

 4. Topical

 5. Periodontal ligament (PDL)

 6. Intraosseous

 Nerve block- Nerve block anesthesia requires local anesthetic to be deposited in close proximity to a nerve trunk. This results in the blockade of nerve impulses distal to this point. It is also important to note that arteries and veins accompany these nerves and can be damaged. To be effective, the local anesthetic needs to pass only through the nerve membrane to block nerve conduction Field block/Infiltration/Supraperiosteal - Field block, infiltration and supraperiosteal injection techniques, rely on the ability of local anesthetics to diffuse through numerous structures to reach the nerve or nerves to be anesthetized:

  - Periosteum

 - Cortical bone

 - Cancellous bone

 - Nerve membrane

Topical - Topical anesthetic to be effective requires diffusion through mucous membranes and nerve membrane of the nerve endings near the tissue surface

PDL/Intraosseous - The PDL and intraosseous injection techniques require diffusion of local anesthetic solution through the cancellous bone (spongy) to reach the dental plexus of nerves innervating the tooth or teeth in the immediate area of the injection. The local anesthetic then diffuses through the nerve membrane

Carbonic anhydrase inhibitors

Acetazolamide, Dichlorphenamide, Methazolamide, Ethoxzolamide

Mechanism of Action

1.    Carbonic anhydrase (CA) facilitates excretion of H+ and recovery of bicarbonate by the proximal renal tubule and ciliary epithelium of the eye. Sodium is recovered in exchange for H+. 
2.    Inhibitors block CA block sodium recovery. A very mild diuresis is produced (this is really a side effect of their use in glaucoma) because relatively unimportant mechanism for Na recovery and because proximal tubule site means that other sodium recovery mechansims continue to process their normal fraction of the sodium load.
 

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.