What must drugs do in order to access the CNS?
Cross the blood brain barrier
What effect do drugs that cross the blood brain barrier have?
Interfere with chemical neurotransmission within CNS
Which processes of chemical neurotransmission can drugs that enter the CNS affect?
Inactivation (reuptake and metabolism)
Describe the effects of cocaine and amphetamine on noradrenergic nerves?
Both increase NA in synaptic cleft
How can excitatory input be reduced to treat epilepsy?
Limits excitatory nerve activation
Describe the action of phenytoin?
Decreases excitatory fibre activity (glutamate) by inhibiting Na channels
Only binds Na channel while it is open
How can inhibitory input be enhanced to treat epilepsy?
Enhance GABA receptor activity
Which neurotransmitters are implicated in the use of sedative, hypnotic and anxiolytic agents?
GABA (sedation and anxiety)
Serotonin (sedation and anxiety)
What are the clinical applications of benzodiazepines?
Premedication (sedation for procedures)
Acute alcohol withdrawal
Why can beta-andrenoceptor antagonists be useful in the treatment of anxiety?
Can block the physical symptoms
(sweating, tremor, tachycardia)
Which drug class is now obsolete as hypntoic/anxiolytics?
What are barbiturates?
Produce all levels of CNS depression
Why are barbiturates no longer used?
Why are benzodiazepines more favourable than barbiturates?
Wider therapeutic index
Less depression of resp and cardio centres
Safe in overdose
Describe the effects of benzodiazepines?
Elicit sedation and induction of sleep
Reduce anxiety and aggression
Reduce muscle tone
How do benzodiazepines exert their effect?
Interact with GABA A receptor and interfere with GABAergic transmission
GABA A receptors are ligand-gated ion channels that let Cl into cell
Where do benzodiazepines bind to the GABA A receptor?
What do benzodiazepines modulate on the GABA A receptor?
Orthosteric ligand affinity
Orthosteric ligand efficacy
Receptor activation level
Describe the effect that benzodiazepines have when they bind the GABA A receptor?
Bind > increase in receptor affinity for GABA > increases frequency of Cl channel opening > increased sensitivity, no change in maximum response
Describe the effect that barbiturates have when they bind the GABA A receptor?
Bind receptor > prolong opening of Cl channel > increased sensitivity and maximum response
Why are benzodiazepines considered safe in overdose, whereas barbiturates are not?
Benzodiazepines increase the frequency of Cl channel opening, and do not change the maximum response. Therefore, they have a celing effetc.
Barbiturates prolong the opening of Cl channels, and increase the maximum response. Therefore, there is no ceiling effect.
Describe the advantages of allosteric modulators?
Celing effect of inhibitors
Positive modulation of endogenous agonist effect, rather than continuous effect of exogenous agonist
Great receptor subtype selectivity possible
Describe some of the disadvantages of usinjg benzodiazepines?
Unwanted effects: drowsiness, confusion, impaired coordination
Interaction with alcohol, antihistamines and barbiturates
Long lasting hangover effects
Describe the tolerance effect of benzodiazepines?
Gradual escalation of dose needed
Describe the dependence effect of benzodiazepines?
Signs of physical and psychological withdrawal
What determines the route of administration of benzodiazepines?
Active orally, but differ in duration
Describe the differences in characterisitcs and usage between short and medium/long acting benzodiazepines?
Short: no daytime anxiety, can be used by elderly and drivers
Medium/long: 3-4 daily doses needed, fast onset, muscle tension
Is low potency a disadvantage in drugs?
Only if the dose is so large that it is awkward to administer
Describe the difference between pharmacological efficacy and clinical efficacy?
Pharmacological efficacy: strength of receptor activation
Clinical efficacy: strength of beneficial effect