Pharmacological Principles of General Anesthetics, Sedatives, etc. (Week 3, Mod 8)

What are the psychotropic drug classifications based on increasing unresponsiveness?

1) Tranquilizer

2) Neuroleptic

3) Sedative

4) Hypnotic

What are the 2 amino acid pathway receptors that are targets for consciousness-altering drugs, and what kind of drug targets each receptor?

1) Glutamate ‘NMDA’ receptor

• Ketamine (General Anaesthetic/Analgesic)

2) GABA_A receptor 

• Benzodiazepines (sedative, antiepileptic, anxiolytic)

• Several general anaesthetics

What are the 3 Monoamine pathway receptors that are targets for consciousness-altering drugs, and what kind of drug targets each receptor?

1) Alpha₂-adrenoceptor

• Sedative/analgesic

2) Noradrenaline/5-HT (Serotonin) degradation/reuptake

• Monoamine Oxidase Inhibitors

• Tricyclic antidepressants

• Selective serotonin reuptake inhibitors  (SSRIs)

3) Dopamine D₂ receptors

• Sedative/tranquilizers

• Antiemetic drugs

What is one thing in particular about the pharmacokinetics of these drugs that you need to keep in mind?

THEY CAN CROSS THE BLOOD BRAIN BARRIER

• Are either small, non-polar molecules or they get through via transporters

Describe the NMDA receptor… what neurotransmitter usually binds to it? What is its function normally?

Glutamate receptor = NMDA receptor 

• Excitatory receptor 

• Ion channel with many binding sites 

• Glutamate binds to binding site, opening the channel and resulting in an influx of sodium -> action potential 

Describe the mechanism of action of ketamine on the NMDA receptor…

Inhibits the excitatory action of the receptor by being either a competitive receptor antagonist, or as a physical channel blocker 

What are the 5 features of ketamine as an anesthetic? What will you see in the patient?  

• Sensory loss with analgesia

• Increased muscle tone

• Eyes open ± slow nystagmus

• Active reflexes incl. laryngeal/pharyngeal reflexes

• Less profound CVS & respiratory depression

Describe the GABA a receptor… what neurotransmitter usually binds to it? What is its function normally?

• GABA binds to the GABA receptor 

  • Is the MAIN INHIBITORY transmitter / channel in the CNS

• GABA receptor is a ligand-gated Cl- channel; when GABA binds, opens to allow Cl- to flood into the cell, resulting in a hyper polarization 

• Responsible for mediating fast inhibitory synaptic responses 

What receptor is the MOST important target for general anesthetic drugs?

GABA is the MOST important target for GA drugs

Describe the mechanism of action of general anesthetics on the GABA a receptor…

• Work by ENHANCING the inhibitory function of the receptor 

• Bind to an allosteric site on the receptor, which allows for a larger, more frequent current of Cl- to enter the cell

What are the pharmacodynamics of general anesthetics that target the GABA receptor?  What do they cause (both good, and bad)?

Cause sedation at the CNS

BUT cause significant depression of the CVS / RESP 

Describe the mechanism of action of benzodiazepines (BZPs) on the GABA a receptor?

• Has a SPECIFIC binding site on the receptor that it binds to (BZP binding site)

• Has agonists, antagonists, and inverse agonists

  • What we usually use when using BZPs is the agonist… enhances the function of the GABA receptor 

• Uses as a sedative / premedicant (also an anticonvulsant)

What are the pharmacodynamics of BZP’s? (both desired and side effects)

• CNS: primarily anxiolytic action

• muscle relaxation

• CVS/RESP: minimal depression

Describe the function of the alpha-2 adrenoceptor… what is its function normally?

• Inhibits the release of neurotransmitters presynaptically when stimulated; activated by endogenous norepinephrine and epinephrine, but are a typical target for sedatives and analgesic agents

• ALSO causes post-synaptic inhibition of smooth muscle relaxation

  • Results in vasoconstriction

Describe the mechanism by which noradrenaline induces a contraction on smooth muscle via alpha 1 and alpha 2 adrenoceptors…

Alpha-1 mediated pathway…

• Induces a contraction in smooth muscle when noradrenaline binds

• Is the PRIMARY pathway to induce a contraction

Alpha-2 mediated pathway…

• When noradrenaline binds, inhibits adenylate cyclase (enzyme that produces cAMP)

  • cAMP INHIBITS CONTRACTION, causing relaxation of smooth muscle

• Since cAMP is inhibited, contraction isn’t inhibited; instead, enhances contraction of muscle by secondary means

Describe the specificity exhibited by alpha-2 AGONISTS for their alpha-2 adrenoceptor… what does this mean in terms of its effects and/or side effects?

Alpha-2 agonists are PREFERENTIAL for alpha 2 receptors, but CAN stimulate alpha 1 receptors at smooth muscle

• Essentially, we use alpha 2 agonists for sedation at the CNS.  Its primary target is the alpha 2 adrenoreceptors at the pre-synaptic level to inhibit neurotransmitter release, inhibiting signals for wakefulness / pain

• HOWEVER, still have a 1620:1 (or 260:1 or 160:1) chance of those agonists acting on the ALPHA 1 RECEPTORS of smooth muscle within the autonomic nervous system

  • Causes peripheral nervous system side effects

Describe the pharmacodynamic actions (the sedative / analgesic effects) of alpha 2 agonists…

PRIMARILY used as a sedative, but has the added benefit of analgesic effects (potent, but shorter lived than sedation)

Sedation

• dose-dependent (not at higher serum concentrations)

• mild sedation to deep sedation

Analgesia

• potent analgesic action, dose dependent and shorter than sedation

• central action: spinal & supraspinal

  • spinal: receptors are located densely in laminae I & II of dorsal horn of spinal cord

  • supraspinal: receptors located in PAG, LC, NRM - associated with pain information processing 

What are the effects that alpha 2 agonists can have on the CVS?  Respiratory system?  GIT?

CVS

• hypertension (bp increase) -> hypotension / normotension

• marked bradycardia

Respiratory

• mild to moderate depression: cat, dog, horse

• ruminants - arterial hypoxaemia 

GIT

• vomiting in some species, generally GIT motility is depressed (not as extreme compared to opioids)

What are 2 medicines that are considered to be dopamine antagonists? What is their general mechanism of action?

Dopamine antagonists:

• Phenothiazines (acepromazine)

• Butyrophenones (azaperone and fluanisone)

Mechanism of action:

• Dopamine transmission is EXCITATORY in the CNS, especially in movement and behavior 

• Antagonists are NON-SELECTIVE; cause a REDUCTION in activity at the basal ganglia, limbic system, etc.

Most phenothiazines affect other receptor systems, causing a wide range of peripheral effects (effects the ANS)

Describe the pharmacodynamics of phenothiazines… both the desired effect, and the side effects in the periphery

DESIRED:

CNS – tranquilliser

SIDE EFFECTS: come from anti-adrenergic or anti-cholinergic effects

CVS - Arterial hypotension (10-20% decrease ABP) *** can be problematic in hypovolemic patients

• Peripheral vasodilatation (α adrenergic blockade)

• Central actions, medulla (decreased sympathetic outflow)

• Mild tachycardia

• Anti-arrhythmic action

Respiratory - generally minimal

GIT (anti-emetic)

• Decrease gastrointestinal smooth muscle activity (anti-muscarinic action)

• Delayed gastric emptying

• Decrease gastro-oesophageal sphincter tone

What are the 2 main targets for inhibiting adrenergic (noradrenaline) transmission at the synapse?

1) Monoamine oxidase

• Breaks down noradrenaline within the synapse; stopped by MAO inhibitors

2) Neuronal epinephrin transporter (NET)

• Takes transmitted noradrenaline in the synaptic cleft and transfers it back into the synapse; stopped by tricyclic antidepressants 

What 2 monoamine pathways are involved in depression?

NORADRENALINE

SEROTONIN 

What 3 classes of mood-altering drugs act on adrenergic transmission?  Describe their mechanisms of action 

Tricyclic antidepressants

• block noradrenaline and 5HT (serotonin) reuptake into the synapse

  • Increases the availability of noradrenaline and serotonin

Monoamine oxidase inhibitors (MOAI) 

• increase stores of noradrenaline and 5HT in the synapse

Selective serotonin reuptake inhibitors (SSRIs)

• block 5HT reuptake SELECTIVELY