#Blog 11:

Name an example of each of the three phenothiazine sub-families and state how they differ from one another in terms of potency and side effects.

Phenothiazines are multi-potent competitive antagonists.

There are 3 sub-families based primarily on the side chain:

1. Aliphatic side-chain: Chlorpromazine (Largactil )
2. Piperidine side-chain: Periciazine (Neulactil ) & Thiordazine
3. Piperazine side-chain: Fluphenazine (Modecate ), Perphenazine, Trifluoperazine, Prochlorperazine.

Aliphatic and piperidine compounds:

• Low potency*, little EPS
• Severe sedation
• Strong anti-cholinergic effects,
• Strong α-lytic effects (postural hypotension), 
• Cardiotoxic

*These drugs do not bind very strongly to D₂ receptors (has a low affinity for D₂) thus need to administer large amounts to elicit strong therapeutic effects. 

Piperazine derivatives:

• High potency, more EPS,
• Weaker anti-cholinergic side effects  
• Weaker α-lytic effects,
• Less sedation
• Less cardiovascular (CVS) side effects

Which receptors in particular are blocked by the typical antipsychotic drugs?

Block mesolimbic Dopamine (more specifically D₂) receptors.

How does the mechanism of action of the atypical drugs differ from that of the typical drugs?

Atypical drugs:

• These drugs block 5-HT_2A receptors more than D₂ (has a higher affinity for 5-HT_2A receptors) . 
• MOA: D₂ blockade, strong M₁, H₁ and serotonin. Receptors.

Typical drugs:

These drugs block mesolimbic DA 2 receptors.

Which of the receptors blocked by the older drugs reduce the risk of extrapyramidal side effects?

Benzamides block both D₂ and D₃ receptors. The risk of extra pyramidal side effects is reduced due to the limbic localisation of the D₃ receptors.

Then also Aliphatic (Chlorpromazine) compounds because they are known to have a low potency and few extra pyramidal side effects.

Block of Muscarinic R's.

Which of the older drugs have a high incidence of extrapyramidal side effects? What is the reason for this?

Extra-pyramidal symptoms are also known as ‘drug-induced movement disorders’ and typical side effects include involuntary or uncontrolled movements, muscle tremors and contractions. The extrapyramidal system in the brain includes the basal ganglia – the nigrostriatal pathway. The nigrostriatal pathway consists of neurons that project from the substantia nigra to the striatum; it is involved in coordination of voluntary movement . Blockade of the D₂ receptors in t the nigrostriatal pathway is responsible for EPS. 

Piperazine derivatives has a high potency, therefore more extrapyramidal side effects. It very strongly blocks the D₂receptors causing extra-pyramidal side effects due to the dopamine content in the mesolimbic area being cut-off or significantly decreased.

Because of which receptor(s) blockade do the aliphatic group of drugs have a high incidence of autonomic side effects?

Autonomic effects are those drug blocking alpha receptors, cholinergic receptors in the parasympathetic systems & sympathetic nervous system. Blockade of Muscarinic receptors.