IC4 Neuropharmacology Flashcards
What do the pre-synaptic autoreceptors do wrt NTM?
Presynaptic autoreceptors (eg, m2 muscarinic receptors) are activated together with postsynaptic receptors and inhibit further transmitter release via feedback inhibition
How is the signal propagated and terminated?
Propragation:
- Neurotransmitters in the synaptic cleft activates postsynaptic receptors (GPCRs and ion channels and the signal has reached the receiving neuron)
- GCPR –> Second messenger activation
-
Ion channels –> Depolarization; propagation of action potential
- Then the post-synaptic neuron will conduct the electrical signal until it reaches its own terminal button
Termination:
- Signal termination by catalytic enzymes (AChE) and / or reuptake transporters (SDHACU)
What are the potential drug targets and MOA?
Agonistic Drug effects
- ↑Synthesis of NTM
- Block/destroy degrading enzymes
- ↑Exocytosis / NTM release
- Blocks auto-receptors –> prevent inhibition of NTM release
- Activates receptor on post-synaptic membrane
- Block reuptake of NTM
Antagonistic Drug Effects
- Synthesis of NTM
- ↑Degradation by enzymes (cause NTM to leak from vesicle)
- ↓ Exocytosis / NTM release
- Activates auto-receptors –> allow inhibition of NTM release
- Deactivates receptor on post-synaptic membrane
What are the factors to be considered for non-saturable transmembrane movement?
- Non-saturable: Transmembrane diffusion (passive diffusion)
a. Increase amt of particular substance, increase rate that crosses BBB
b. Mechanism for most drugs with low molecular weight (easy to pass through) and high lipid solubility (so don’t repel).
c. However, when lipid solubility too high
→sequestered in capillary bed (stuck there, high affinity for the membrane)
→uptake by peripheral tissues
d. Molecular weight, inversely related to BBB penetration (< 500 Da, re: Lipinski’s Rule of Five)
e. Charge, tertiary structure, and degree of protein binding
f. Pharmacogenomics → “Overexpressors” vs. “under-expressors” of P- glycoprotein → limit the rate of uptake by BBB (see next)
i. Especially for saturable systems
What are the factors to be considered for saturable transmembrane movement?
- Saturable: Transporter systems (e.g. facilitated diffusion)
a. Rate depends on how many transporters present
b. Rate of uptake across BBB around 10x > transmembrane diffusion
c. Rate of uptake across BBB is regulated by cerebral bloodflow, co-factors, hormones / peptide modulators
d. Specific regions of brain express transporters for regulatory molecules, eg, L-dopa, vitamin B12
e. Efflux transporters work in opposite → decrease uptake of drugs, e.g., P-glycoprotein
i. Removes poisons out of the cell, sometimes see drugs as “poisons”
Uncoupling between BBB functions and CNS needs is accompanied by disease states
Neuroinflammed –> easier for drugs to get through
Causes changes in BBB that allows a disease to be treated
What are the possible causes of a single seizure?
- Possible causes of a single seizure
1. Alcohol
2. Hypoglycemia
3. Pyrexia
4. Sleep deprivation
What is the MOA, place in therapy, notable PK of phenytoin?
Phenytoin
- MOA:
- Blockade of voltage-dependent Na+ channels prevents Na+ influx and AP
- Type of seizures:
- all types of seizures except absence seizures.
- Characteristics:
- A relative narrow therapeutic range (plasma concentration 40-100 μM), saturation kinetics and consequent non-linear relationship between dose and plasma concentration necessitates titration and monitoring.
- Needs close monitoring
- Teratogenic
Phenytoin: Saturation kinetics
Non-linear relationship between daily dose of phenytoin and steady-state plasma concentration in five individual human subjects.
- Very different between individuals –> great interindividual variability
What is the MOA, place in therapy, notable PK of carbamazepine?
Carbamazepine
- MOA:
- Blockade of voltage-dependent Na+ channels (like phenytoin).
- Types of seizures:
- all types of seizures except absence seizures. (like phenytoin).
- Hepatic enzyme (CYP450) inducer (enhance metabolism), T1⁄2 shortens with repeated doses (auto-induction, IC7) → accelerates elimination of other drugs.
- Pharmacogenomics effects in Stevens-John Syndrome / Toxic Epidermal Necrolysis:
SJS / TEN and Carbamazepine
❑ In Caucasians: up to 0.06% (6 in 10000)
❑ In Asians: up to 0.6% (6 in 1000)
❑ In Asians with confirmed human leukocyte antigen (HLA)-B*1502 allele: up to 5%
* Not good risk, HSA want phenotyping to be done before starting CBZ
❑ Rationale for genetic screening prior to commencing carbamazepine regimen
What is the MOA, place in therapy, notable PK of valproate?
Valproate
- MOA: (ion channels + degradation enzyme)
- Blockade of voltage-dependent Na+ and Ca2+ channels
- Also inhibits GABA transaminase (enzyme that breaks down GABA) –> increased GABA
- Types of seizures:
- all types of seizures, including absence seizures
- Strongly bound to plasma proteins, displaces other antiepileptics
- Actual F of other drugs will increase (increase free drugs)
What are the ADR of phenytoin, CBZ, and valproate?
For phenytoin, CBZ, valproate
Dose Related Side Effects:
(Altered state of consciousness)
- drowsiness, confusion, nystagmus, ataxia, slurred speech, nausea, unusual behavior, mental changes, coma
Non-Dose Related:
- sometimes even when very low dose can get these
- hirsutism, acne, gingival hyperplasia, folate deficiency, osteomalacia (softening of bones), hypersensitivity reactions (including SJS/TEN)
What is the MOA of benzodiazepines?
Benzodiazepines:
MOA
- used for people with anxiety disorders but certain types of Benzodiazepines can work as antiepileptics
- Enhance effects of inhibitory GABA neurotransmitters
- GABA—inhibitory transmitter in brain regions: acts via GABA receptors Cl- channels
o Cl- channels have many binding sites
o Have a specific site for BZDs
o So specific that can be blocked by a medicine –> Flumazenil (reversal agent), a BZDs site inhibitor, in case of overdose on BZDs - Potentiates influx of Cl- ions leading to hyperpolarization → neurons not firing (reduce neuronal excitability)
What type of BZD is the best for anti-seizure effects?
- Want sth that is not dosed frequently since need to take for life
- Short acting not used for epilepsy since epilepsy is for life, can’t really cure
- BZDs are not preferred AED since addictive and easily get overdosed, but sometimes no 1st lines or need sth that works very fast but long acting (Diazepam) e.g. for status epilepticus (fast onset: 0.5hrs; long acting: 42hrs)
What are the ADRs of BZD?
Benzodiazepines: Unwanted effects
1. Acute toxicity / overdose:
a. Can cause severe respiratory depression (lung collapse), especially used concurrently with alcohol.
b. Treatment is by flumazenil, a benzodiazepine antagonist.
2. Side effects during use:
a. Drowsiness, confusion, amnesia.
b. Impaired muscle co-ordination (impairs manual skills, can’t operate heavy machinery)
3. Tolerance and dependence (Addiction):
a. Depends on frequency of use. Therefore, tolerance develops faster for epilepsy than for use to induce sleep.
b. Dependence can develop. Withdrawal effects include disturbed sleep, rebound anxiety, tremor and convulsions.
c. Important to withdraw gradually.
d. Has abuse potential.
What is the MOA of Phenobarbital?
Phenobarbital as Barbiturate AED
Limited use, think about all the things said about BZDs but worse :”)
Barbiturates:
- Also potentiate GABAA mediated Cl- currents (increase Cl- influx), but at a site distinct from benzodiazepines, thus flumazenil won’t work
- Use as a sedative-hypnotic has largely been replaced by benzodiazepines due to barbiturates’ tendency to develop tolerance and dependence
- Use as AED mainly for pediatric or neonatal patients (emergency) (IV loading dose followed by IV or oral maintenance doses)
o Since they are less likely to abuse drugs:) - **Severe withdrawal symptoms **
What type of barbiturates would we like to use for anti-seizure effects if we do have to use it?
long acting (1-2d) e.g. phenobarbital
