Lithium carbonate: 1st choice (controls mania in bipolar disorders); delay before onset of therapeutic benefit; no psychotropic effects in normal humans

i. Mechanism: blocks enzymes in inositol phosphate signaling pathway; no consistent effects of lithium on NE, 5-HT, and DA
ii. Side effects: severe CNS (ataxia, delirium, coma, convulsions) and CV (cardiac dysrhythmias)

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
 

Ibuprofen

used to relieve the symptoms of arthritis, primary dysmenorrhoea, fever; and as an analgesic, especially where there is an inflammatory component.

Indications

rheumatoid arthritis, osteoarthritis, juvenile rheumatoid arthritis, primary dysmenorrhoea

fever, relief of acute and/or chronic pain states in which there is an inflammatory component

MOA

inhibition of  cyclooxygenase (COX); thus inhibiting prostaglandin synthesis.

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.

Neuron Basic Structure (How brain cells communicate)

• Synapse:A junction between the terminal button of an axon and the membrane of another neuron
• Terminal button(orbouton):The bud at the end of a branch of an axon; forms synapses with another neuron; sends information to that neuron.
• Neurotransmitter:A chemical that is released by a terminal button; has an excitatory or inhibitory effect on another neuron.

Different types of Synapses
1-Axo-denrdritic 
2-Axo-axonal 
3-Axo-somatic

Chemical transmission in the CNS 

The CNS controls the main functions of the body through the action endogenous chemical substances known as “neurotransmitters”.
These neurotransmitters are stored in and secreted by neurons to “transmit”information to the postsynaptic sites producing either excitatoryor inhibitory responses.
Most centrally acting drugs exert their actions at the synaptic junctions by either affecting neurotransmitter synthesis, release, uptake, or by exerting direct agonistor antagonistaction on postsynaptic sites.

Macrolide

The macrolides are a group of  drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large  lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. The lactone ring can be either 14, 15 or 16-membered. Macrolides belong to the polyketide class of natural products.

The most commonly-prescribed macrolide antibiotics are:  

Erythromycin,  Clarithromycin, Azithromycin, roxithromycin,

Others are: spiramycin (used for treating  toxoplasmosis), ansamycin, oleandomycin, carbomycin and tylocine.

There is also a new class of antibiotics called ketolides that is structurally related to the macrolides. Ketolides such as telithromycin are used to fight respiratory tract infections caused by macrolide-resistant bacteria.

Non-antibiotic macrolides :The drug Tacrolimus, which is used as an

immunosuppressant, is also a macrolide. It has similar activity to  cyclosporine.

Uses : respiratory tract infections and soft tissue infections.

Beta-hemolytic  streptococci,  pneumococci, staphylococci and enterococci are usually susceptible to macrolides. Unlike penicillin, macrolides have shown effective against mycoplasma, mycobacteria, some rickettsia and chlamydia.

Mechanism of action: Inhibition of bacterial protein synthesis by binding reversibly to the subunit 50S of the bacterial ribosome, thereby inhibiting translocation of peptidyl-tRNA. This action is mainly bacteriostatic, but can also be bactericidal in high concentrations

Resistance : Bacterial resistance to macrolides occurs by alteration of the structure of the bacterial ribosome.