Miconazole

Miconazole is an  imidazole antifungal agent commonly used in topical sprays, creams and ointments applied to the  skin to cure fungal infections such as Athlete's foot and Jock itch. It may also be used internally to treat vaginal  yeast infection.

When used by a person taking the anticoagulant medication warfarin, Miconazole may cause an adverse reaction which can lead to excessive bleeding or bruising.

Ethosuximide (Zarontin): use in absence seizures (may exacerbate tonic-clonic seizures)

Mechanism: ↓ T-type Ca currents in thalamic neurons, inhibits bursts of APs, ↓ synchronous neuronal firing
i.    Thalamo-cortical reverberating circuits: during absence type seizures, have reverberating circuits between cerebral cortex and thalamus at 3 Hz maintained by T-type Ca channels (since blocking these channels blocks the reverberating circuit)

Side effects: quite non-toxic; common= N/V and anorexia; less common = headache, sedation, photophobia

Neurophysiology

Nerve fibers exhibit wide range of sensitivity to nerve blockade-in order of increasing resistance to block are the sensations of pain, cold, warmth, touch, pressure, proprioception and motor function

Nerve Fibers:

Myelinated = faster conducting

Unmyelinated = slower conducting

- Small non-myelinated fibers (C- pain fibers) and smaller myelinated pre-ganglionic B fibers are more readily blocked than are larger myelinated fibers responsible for muscle activity and touch [A-alpha and A-beta].

- Clinically, a person would notice complete lack of sensation to a pinprick, while at the same time still be able to move their fingers.

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
 

Gastric acid neutralizers (antacids)

Antacids act primarily in the stomach and are used to prevent and treat peptic ulcer. They are also used in the treatment of Reflux esophagitis and Gastritis.

Mechanism of action: 

Antacids are alkaline substances (weak bases) that neutralize gastric acid (hydrochloric acid) they react with hydrochloric acid in the stomach to produce neutral or less acidic or poorly absorbed products and raise the pH of stomach secretion.

Antacids are divided into systemic and non-systemic.

• Systemic antacids (e.g. sodium bicarbonate) are highly absorbed into systemic circulation and enter body fluids. Therefore, they may alter acid–base balance. They can be used in the treatment of metabolic acidosis. 

Non-systemic: they do not alter acid–base balance significantly, because they are not well-absorbed into the systemic circulation. They are used as gastric antacids; and include:

• Magnesium compounds such as magnesium hydroxide and magnesium sulphate MgS2O3. They have relatively high neutralizing capacity, rapid onset of action, however, they may cause diarrhoea and hypermagnesemia.

• Aluminium compounds such as aluminium hydroxide. Generally, these have low neutralizing capacity, slow onset of action but long duration of action. They may cause constipation.

• Calcium compounds such as. These are highly effective and have a rapid onset of action but may cause hypersecretion of acid (acid - rebound) and milk-alkali syndrome (hence rarely used in peptic ulcer disease). 

Therefore, the most commonly used antacids are mixtures of aluminium hydroxide and magnesium hydroxide . 

PSEUDOEPHEDRINE

Pseudoephedrine appears to have less pressor activity and weaker central nervous system effects than ephedrine. It has agonist activity at both β1  and β2 adrenoceptors, leading to increased cardiac output and relaxation of bronchial smooth muscle.

Pseudoephedrine is rapidly absorbed throughout the body. It is eliminated largely unchanged in urine by N-demethylation.

It is indicated in symptomatic relief from stuffed nose, respiratory tract congestion, bronchospasm associated with asthma, bronchitis and other similar disorders.