CNS, pain, drug dependence and analgesics/anaesthetics Flashcards
What are the three main neurotransmitter classes?
- amino acid and derivatives (glutamic acid, GABA, aspartic acid, glycine)
- peptides: vasopressin, somatostatin, neurotensin
- monoamines: NA, DA, 5-HT
What is the nature of the CNS environment regarding synapses?
The CNS has a multi-synaptic environment where neurotransmitters affect multiple receptor targets with varying subunit conformations.
How do glial cells contribute to CNS function?
Glial cells, which outnumber neuronal cells by about 10:1, play major roles in supporting neuronal function through receptor expression, electrical coupling, and affecting neuronal activity.
What are secondary adaptive effects in the CNS?
Secondary adaptive effects may occur on receptors as a response to the presence of drugs, affecting the CNS response over time.
Why do individual experiences of drug effects in the CNS vary?
Individual experiences of drug effects vary due to the unique responses in the CNS, and this variation is often a key criterion for assessing drug effectiveness.
What types of changes occur in the CNS over time?
Changes occur via neurotransmitter, neuromodulator, and neurotrophic compounds, influencing CNS function over time.
What are neuromodulators?
- Cause complex responses/ modulation
- Alter sensitivities of synapses
- Modify post synaptic responses;
- Change pre-synaptic handling of NT
- Changes occur over minutes, hours or days; associated with slower events, e.g. growth, learning, protein synthesis
What is the blood brain barrier?
A system of tight junctions between the endothelial cells and surrounding astrocytes (glia) of the capillaries. You need to cross this to affect the CNS. It creates a challenge as it can prevent many therapeutic drugs from reaching the brain. It is tightly regulates the CNS and protects it from toxins, bacteria, etc.
What are the effects of agonist drugs
- bind to autoreceptors and blocks their inhibitory effect on neurotransmitter release
- binds to post-synaptic receptors and either activates them or increases the effect on them of neurotransmitter molecules
- blocks the deactivation of neurotransmitter molecules by blocking degradation of reuptake
What are the effects of antagonist drugs?
- activate autoreceptors and inhibits neurotransmitter release
- is a receptor blocker, it binds to the postsynaptic receptors and blocks the effect of neurotransmitter
What is glutamate?
Glutamate within the CNS usually comes from either glucose or glutamine; there is relatively little entering the CNS directly from the periphery after the first few weeks of life.
Describe the cycle of glutamate in the CNS.
Glutamine is converted by glutaminase to form glutamate.
Glutamate is then, using a pump, concentrated into a synaptic vesicle. This will require energy because we’re increasing concentration. If an action potential comes along that neuron, that vesicle will move to the end and fuse with the presynaptic membrane and release into the synaptic cleft.
Released Glu is captured partly by neurons and partly by astrocytes, which convert most of it to Gln.
Gln is tranported out of the astrocyte and taken up by neurons which use it to synthesis glutamate.
What is EEAT?
excitatory amino acid transporter
What is GlnT?
Glutamine transporter
What is VGluT?
Glutamate transporter
What is glycine?
Glycine is a positive allosteric modulator of NMDA receptor glutamate responses.
(glycine is not an agonist but can bind to the NMDA receptor and when it does it might change the affinity of that receptor)
It is manufactured premondinalty in spinal chord, packed into vesicles, released, have diversity of receptors post synaptically, chloride ion channel down central pore, no metabotropic forms (all ionotropic). Then cleared again using transporters located on nearby astrocytes
What are the issues with the glutamate receptor?
Penetration of BBB is a challenge
Difficult to selectively block function as glutamate is so generally used throughout CNS
only two drugs in current medicinal use and they are lipid soluble and can cross the BBB:
- ketamine (anaesthesia, depression)
- memantine (alzheimers)
What are PCP and ketamine?
Both are drugs which bind to the same site within the NDMA receptor pore, blocking ion movement down the concentration gradient.
This is a different site than where glutamate binds, so they are non-competitive antagonists of the NMDA receptor.
PCP used to be used as an anaesthetic but is now illegal.
Ketamine has an affect on opiod receptors.
What is memantine?
It is a non-competitive antagonist of the NMDA receptor and is clinically useful drug to treat alzheimers disease.
Describe the lifecycle of GABA
Glutamine can be converted enzymatically to glutamate.
Glutamate can then be converted to GABA via glutamic acid decarboxylase.
GABA is then pumped and concentrated into a synaptic vesicle and then exocytosis upon an action potential, you release GABA into that synaptic gap.
If there happens to be an astrocyte sitting nearby you have the enzymes to take that GABA, convert it to glutamate, convert it to glutamine and shuttle it across and start the whole cycle again.
If you’re presynaptic, you might take that GABA up through that transporter to repackage and recycle.
What are benzoadiapines?
They are positive allosteric modulators. When bnz binds it does not activate the receptor, it simply enables it to be more responsive when a GABA is present. Barbiturates have another positive allosteric binding site, and so do neurosteroids and alcohol.
What problems can arrive when some drugs are mixed?
If you mix BNZs and alcohol, they have different binding sites, and they are positive allosteric modulators so its not just a summative effect, the net hyperpolarisation possible is significantly greater. Mixing drugs that have a common action is potentially dangerous particularly if it’s inhibitory.
What are GABA a receptors?
Most GABAA receptors are post-synaptic, and activation
leads to hyperpolarization due to the inward movement of Cl- ions, making it less likely that an AP will occur.
What are GABA b receptors and what are some useful drugs?
Baclofen is a derivative of GABA and is an agonist of GABA b receptors. Like GABA it decreases neurotransmitter release in excitatory spinal pathways and increases inhibitory pathway activity by working presynaptically …
Are GABAB receptors drug targets?
Baclofen is a derivative of GABA and is an agonist of GABAB receptors.
Like GABA, it decreases neurotransmitter release in excitatory spinal pathways and increases inhibitory pathway activity by working presynaptically.
Spasticity, which leads to involuntarily tight or stiff muscles, can be treated with baclofen as it reinforces inhibitory input in the CNS.
What is γ-Hydroxybutyrate (GHB)?
GHB is also an agonist at GABAA receptors. GHB effects are similar to those of alcohol and ecstasy, such as euphoria, disinhibition, and enhanced sensuality. At higher doses, GHB may induce nausea, dizziness, drowsiness, agitation, visual disturbances, depressed breathing, amnesia, unconsciousness, and death.
What type of receptors are glycine receptors in the spinal cord?
Ionotropic receptors.
What is the structure of glycine receptors?
They are pentamers made of α and β monomers with an internal chloride ion channel.
How many known α subunits are there for glycine receptors, and are there any metabotropic forms?
There are 4 known α subunits, and no metabotropic forms.
How is glycine cleared from the synapse?
Via transporters: GlyT1 moves glycine into astrocytes, and GlyT2 moves glycine into presynaptic neurons.
Are glycine receptors pharmacological targets?
No therapeutic drugs currently being used on
these receptors, although there has been considerable interest in modulating NMDA-R function using glycine.
What is strychnine
A competitive antagonist for glycine receptors, blocking access of glycine to its receptors.
When blocking inhibitory receptors, the result is a greater excitatory response - normal stimulation leads to severe muscle spasms.
Define anaesthesia.
A state characterized by loss of sensation; the result of pharmacological depression of nerve function or of neurological disease.
What is local anaesthesia?
The ability to have anaesthesia (loss of sensation) in a defined region of the body. Produced by direct application of a drug into the operative site. The goal is a reversible block of sensory perception of pain, with the patient’s consciousness maintained.
What are the three structural requirements of local anaesthetics (LAs)?
1) Lipophilic groups (aromatic ring), 2) Intermediate bond (ester or amide linkage), 3) Hydrophilic group (basic amine side chain; either tertiary or quaternary amino group). Rule: if it has two “i”s in its name, it’s an amide; one “i” indicates an ester. Common LAs include procaine, lidocaine, bupivacaine, and tetracaine.
Describe Procaine (Novocaine).
One of the first synthetic LAs, procaine is less toxic and addictive than cocaine. It has a long onset time, wears off quickly, is less potent than cocaine, and causes vasodilation (which limits its local effect). It is an ester and has a high potential to cause allergic reactions.
Describe the properties of Lidocaine/lignocaine.
Lidocaine is an amide, hypoallergenic, has a quick onset of anaesthetic effect, but causes vasodilation at the injection site, leading to rapid absorption away from the area.
How do we address the vasodilation issue with non-cocaine local anaesthetics?
Cocaine blocks NA reuptake transporters, increasing NA and causing vasoconstriction. Synthetic LAs lack this NA effect, leading to vasodilation and increased absorption before the LA effect completes. Synthetic LAs are often mixed with low concentrations of adrenaline to cause vasoconstriction, slowing blood flow and prolonging numbness.
What are some toxicity issues with lidocaine?
Side effects include drowsiness, tinnitus, dysguesia, dizziness, and twitching. At higher doses, seizures, coma, respiratory depression, and arrest may occur. Signs of toxicity can be remembered by “SAMS”: Slurred or difficult speech, Altered cardiovascular system, Muscle twitching, and Seizures.
How and when are local anaesthetics used based on duration?
Ultra-short: 2% lignocaine (without vasoconstrictor)
Short: Procaine, lignocaine (1:100,000 epinephrine)
Intermediate: Articaine, mepivacaine, prilocaine, 2% lignocaine (1:200,000 epinephrine)
Long: Bupivacaine, etidocaine, 2% lignocaine (1:200,000 epinephrine)
What are examples of local anaesthetics (LAs) categorized by type?
Esters:
- Long action: tetracaine
- Short action: procaine
- Surface action: cocaine, benzocaine
Amides:
- Long action: bupivacaine, ropivacaine
- Medium action: lidocaine
Why is the pKa of a local anaesthetic important?
All LAs are weak bases that can exist as ionized (BH+) or unionized (B) forms. Acidic environments increase BH+ (ionized), while alkaline conditions increase B (unionized). LAs with a lower pKa are mostly unionized at pH 7.4, crossing membranes more easily for rapid onset. Higher pKa LAs are mostly charged and have a slower onset.
Why is membrane crossing important for local anaesthetics?
The binding site of LAs is on the inner surface of voltage-dependent Na+ channels, which can be in closed, open, or inactivated states. LAs bind to the inactivation gate, preventing channels from returning to the closed or open states.
Describe the Na+ channel block mechanism of LAs.
The block is concentration-dependent (effective in charged form), reversible, voltage-sensitive (greater with depolarization), and use-dependent (better access to inactivated channels).
How are local anaesthetics metabolized?
Amide LAs: Metabolized by cytochrome P450 enzymes in the liver, excreted in urine or stool. Caution needed in hepatic disease.
Ester LAs: Inactivated by plasma esterase enzymes.
Which nerve fibres are most affected by local anaesthetics?
LAs primarily affect small-diameter afferent neurons, especially myelinated (Aδ) and non-myelinated (C) fibres, making them effective for pain reduction. Larger motor neurons are less affected due to their larger diameter and surface area.
What are the adverse effects of local anaesthetics?
Temporary weakness or paralysis of the affected area. In high concentrations, CNS effects include tingling, visual disturbances, and tremors, followed by convulsions. Cardiovascular effects include reduced myocardial contractility and Na+ channel inhibition.
Describe bupivacaine’s binding affinity and cardiotoxicity.
Bupivacaine provides prolonged anaesthesia with sensory over motor block, making it ideal for labor or post-op analgesia. It is more cardiotoxic than lidocaine, causing severe ventricular arrhythmias at high systemic levels due to its slow dissociation from cardiac Na+ channels.
What factors influence the choice of local anaesthetics in dentistry and medicine?
Factors include procedure duration, vasoconstrictor use, cardiovascular health, infection presence, and potential for self-mutilation (e.g., in children). For post-op pain, long-acting LAs like bupivacaine are beneficial.
When would local or regional anaesthesia be preferred by anaesthetists?
Local anaesthesia avoids some risks (nausea, vomiting) of general anaesthesia, often lasts longer than the surgery for post-op relief, and may reduce blood loss.
In which cases might local anaesthesia not be suitable?
It may be unsuitable for major surgeries (e.g., abdominal), certain surgeons might prefer patients under general anaesthesia, and some patients cannot cope with being awake during surgery.
Define general anaesthesia and its components.
General anaesthesia is a state of loss of sensation, pain, and consciousness, usually achieved with intravenous or inhalation agents. It involves unconsciousness, analgesia, amnesia, muscle relaxation, and hemodynamic control.
What are the four stages of general anaesthesia?
Stage 1: Analgesia (loss of pain)
Stage 2: Excitement/delirium with heightened reflexes
Stage 3: Surgical anaesthesia with reflex loss
Stage 4: Medullary paralysis leading to respiratory failure (monitoring essential)
How is general anaesthesia typically induced and maintained clinically?
General anaesthesia (GA) is usually induced by an intravenous GA drug to achieve unconsciousness, followed by maintenance with an inhaled GA drug, often combined with opioids and neuromuscular blockers as needed.
What are the stages of general anaesthesia during clinical induction?
Analgesia: Preliminary introduction with sedatives or inhaled GA; preoxygenation.
Excitement (transition): Induction of GA with IV or inhaled agents, airway secured.
General Anaesthesia: Maintenance with adjusted IV or inhaled GA; avoiding under or overdosing.
Excitement (transition): Emergence from GA by stopping GA agents, reversing neuromuscular blockers, and managing potential issues like vomiting and shivering.
What is the mechanism of action (MOA) of general anaesthetics?
Early theories, like the “lipid theory,” suggested that GAs worked by dissolving into nerve membranes. Modern understanding indicates GAs have specific receptor targets and isomer-specific potency, disproving the theory of a purely nonspecific membrane mechanism.
List common modern anaesthetic drugs.
Intravenous (PET): Propofol, Etomidate, Thiopental
Volatile (SIN): Sevoflurane, Isoflurane, Nitrous Oxide
Note: Inhaled GAs like halogenated hydrocarbons are volatile at room temperature, affecting synaptic transmission and neuron hyperpolarization.
How do GABAA receptors serve as targets for general anaesthetics?
Most GAs, except cyclopropane, ketamine, and xenon, act as positive allosteric modulators of GABAA receptors. They prolong channel opening, increasing postsynaptic inhibition, often with affinities for α- and β-subunits.
What is the effect of GAs on GABAA receptor subunits?
GAs modulate GABAA receptors, with varying affinities for different subunits, particularly at α- and β-subunit interfaces, which influences their effects on the receptor.
How do GAs interact with glycine receptors?
Certain inhalation anaesthetics are positive allosteric modulators of glycine receptors, which modulate responses to noxious stimuli in the spinal cord and brainstem. However, this effect is not universal across GAs; propofol and barbiturates do, while etomidate and ketamine do not.
How do NMDA glutamate receptors act as targets for some GAs?
Xenon, nitrous oxide, and ketamine primarily affect NMDA receptors instead of GABAA or glycine receptors. Xenon competes with glycine at an allosteric site, while ketamine blocks the NMDA pore, resulting in inhibition of excitatory transmission.
What role do two-pore domain K+ channels play in GA mechanisms?
TREK and TASK K+ channels, activated by low GA concentrations, reduce neuron excitability by promoting hyperpolarization. They are found pre- and post-synaptically and are usually open at rest, though IV GAs do not affect this mechanism.
What brain regions are affected by general anaesthesia?
Anaesthesia mainly reduces cerebral metabolic rate and blood flow in the thalamus, a sensory input hub. This suppression facilitates the transition to anaesthesia and affects natural sleep pathways. GAs also reduce hippocampal activity, contributing to amnesia.
Describe the ADME process of inhaled general anaesthetics.
Inhaled GAs move according to partial pressure gradients. Less soluble drugs cross the blood-brain barrier faster, while the brain, a blood-rich organ, equilibrates quickly. Poorly perfused areas have minimal influence on GA diffusion in most surgeries.
What is the Minimum Alveolar Concentration (MAC) unit in inhalation anaesthesia?
One MAC is the drug concentration at which 50% of patients show no motor response to surgical incision. Lower MAC values indicate higher potency, unaffected by duration, gender, or size, but lower in the elderly and higher in infants.
Describe the properties and action of Isoflurane.
Isoflurane, a clear liquid at room temperature, is vaporized for use. It modulates GABAA receptors, inhibits glutamate, potentiates glycine receptors, reduces gap junction activity, and antagonizes certain acetylcholine receptors, impacting multiple CNS pathways.
What are the effects of Desflurane?
Desflurane, a rapid-onset, rapid-recovery GA used in outpatient surgery, modulates GABAA, glycine, and potassium channels, and antagonizes glutamate receptors. It irritates airways, causing coughing and bronchospasm, so induction is typically via IV.
Describe the properties of Nitrous Oxide (N2O).
N2O, or “laughing gas,” is a colourless, odourless gas with weak anaesthetic but strong analgesic effects. It modulates GABAA, glycine, and glutamate receptors and activates opioid receptors. It is insoluble in blood, enabling rapid induction and emergence.
What are the characteristics of Halothane?
Halothane is a non-explosive, pleasant-smelling anaesthetic with moderate induction speed. While potent, it is a poor analgesic, so it’s often combined with N2O or opioids. It can cause postoperative hepatitis and hyperthermic crisis in genetically susceptible patients.
How are inhaled GAs cleared from the body?
Inhaled GAs are eliminated through exhalation, allowing rapid drug removal from the body. Oxygen is administered to displace the GA, reversing its effects without needing metabolism for clearance.
Why are intravenous anaesthetics primarily used for induction?
Intravenous GAs, due to their lipophilicity and rapid distribution, cause quick onset and short duration with a single bolus. They’re generally unsuitable for maintenance due to slower elimination compared to inhaled agents.
What are the properties of Propofol?
Propofol modulates GABAA receptors and slightly antagonizes glutamate receptors. It has a narrow therapeutic window and can cause respiratory depression, hypotension, and bradycardia. It’s metabolized in the liver, with slower clearance in neonates and elderly.
Describe the concentration-response relationship of Propofol.
Propofol’s effect depth correlates directly with plasma concentration, necessitating careful patient monitoring. Overdosing can lead to severe metabolic issues, especially in ill patients, so careful dosing is critical.
What are the properties of Thiopental sodium?
Thiopental is a barbiturate, modulating GABAA receptors. It provides rapid, smooth onset and short action, making it less ideal for long procedures. It is slowly metabolized in the liver and excreted in urine.
What are the effects of Etomidate?
Etomidate, a non-barbiturate hypnotic, modulates GABAA receptors without providing analgesia. It induces unconsciousness rapidly with minimal respiratory depression, but common side effects include nausea and vomiting.
What does a steep concentration-response curve indicate in GA?
GA-induced loss of consciousness occurs over a narrow concentration range, with genetic variability, pharmacokinetics, and age broadening this range across populations. Older patients often require lower doses for effectiveness.
What are the risks of being conscious but paralyzed during surgery?
This rare event is usually prevented by monitoring vital signs. Drug and alcohol abusers may need higher doses due to cross-tolerance, but brain wave monitoring helps ensure adequate anaesthesia levels during surgery.
Describe the components of a pharmacological “symphony” in general anaesthesia.
- Sedative or anxiolytic premedication (e.g., benzodiazepine)
- IV anaesthetic for induction (e.g., propofol)
- Perioperative opioid analgesic (e.g., remifentanil)
- Inhaled anaesthetic for maintenance (e.g., nitrous oxide)
- Neuromuscular blocker for muscle relaxation (e.g., vecuronium)
- Antiemetic (e.g., ondansetron)
- Muscarinic antagonist for bradycardia and secretion reduction (e.g., atropine)
- At end of procedure: anticholinesterase (e.g., neostigmine) and analgesic for post-op pain (e.g., morphine).
