Pharmacology Flashcards
What is the sequence of dopamine synthesis?
- Tyrosine enters cell
- Converted into L-DOPA
- L-DOPA converted into dopamine
- Dopamine transported into vesicles
What drugs interfere with neuronal uptake of NA in the CNS?
Cocaine inhibits high affinity neuronal uptake
Amphetamine/ephedrine displaces NA from vesicles and causes non-exocytotic release of NA
What is the sequence for catecholamine biosynthesis?
- Tyrosine enters cell
- Converted to L-DOPA
- L-DOPA converted to dopamine
- Dopamine is transported into vesicle
- Dopamine converted into NA
- NA converted into Adr
How does cocaine act?
- Blocks uptake of NA, dopamine and serotonin
- Dopaminergic action linked to dependence
- NAergic and serotonergic actions related to euphoria and reward
- Blocks Na+ channels (anaesthetic drugs)
What type of ligand-gated ion channels are in the CNS?
Excitatory (nicotinic) - Na+ influx causes depolarisation
Inhibitory (GABA A) - Cl- influx causes hyperpolarisation
What is the effect of receptor location on neurons?
Receptors on post-synaptic cleft can generate APs
Receptors in pre-synaptic cleft can modulate neurotransmitter release
What neurotransmitters are implicated in movement disorders?
-Dopamine: degeneration of dopaminergic neurons in Parkinson’s disease (RX L-DOPA and Dopa decarboxylase inhibitor)
-GABA: GABA deficiency in Huntington’s disease (RX GABA agonist and dopamine antagonist)
(Concept: Multiple neurotransmitters can be involved in disease)
What pathways is dopamine involved in?
-Movement: basal ganglia
-Behaviour: schizophrenia
-Dependence and reward: nucleus accumbens and ventral tegmental area
-Pituitary function: prolactin secretion
(Concept: a single NT can be involved in multiple diseases)
What regulates nerve excitability?
Ion channels and receptors
What is the MOA of local anaesthetics?
- reversibly block conduction of nerve impulses at the axonal membrane
- Bind to transmembrane domain IV of Na+ channels
What are 3 classes of local anaesthetics?
- Aminoesters (e.g. procaine) - short acting (enzymatic hydrolysis)
- Aminoamides (e.g. lignocaine) - longer acting (hepatic metabolism)
- Benzocaine
What are the mechanisms of local anaesthetic binding to Na+ channels?
- Hydrophobic binding does not depend on activity of Na+ channels (e.g. MOA of benzocaine)
- Hydrophilic binding depends on the activity of Na+ channels (e.g. aminoester and aminoamides): hydrophilic drugs are charged and require Na+ channel to be open in order to bind to active site
What are the adverse effects of local anaesthetics?
Side effects that are proportional to blood concentration:
- hypotension (excl cocaine)
- myocardial depression
- inhibits inhibitory fibres: excitation, tremor, convulsion, resp arrest
Allergic reactions (independent of blood concentration):
What are the stages of general anaesthesia?
Stage 1: amnesia and euphoria
Stage 2: Excitement and delirium
Stage 3: Unconscious, regular resp, decreased eye movements
Stage 4: resp arrest, cardiac depression and arrest
What are some adverse effects of general anaesthetics?
- depression of resp centre
- obstruction of airways
- peripheral vasodilation
- cardiac arrythmias
- depress cardiac contractility
What are the MOA of general anaesthetics?
- Lipid theory: potency related to lipid solubility - accumulates in lipid space
- Receptor interaction: inhibit excitatory receptors and enhance the effects of inhibitory receptors
What are ways to modulate nerve excitability?
- enhance inhibitory inputs (e.g. enhance GABA receptor activity)
- limit excitatory nerve activation (e.g. inhibit Na+ channels)
- inhibit T-type Ca++ channels
- inhibit NMDA receptor
What is the scientific basis of benzodiazepines?
-enhance GABA A receptors (ligand gated ion channels) leading to decreased neuronal excitability and depressed CNS function which can reduce muscle contractions
therefore used in practice as a sedative, hypnotic and muscle relaxant
What is the MOA of benzodiazepines?
- Bind to specific binding site on GABA A receptor
- Increases receptor affinity for GABA (increased sensitivity)
- Increases the frequency of Cl- channel openings
- Allosteric modulator
What is potency?
Relative position of dose-effect curve along the dose axis
High potency not related to therapeutic effect
The higher the potency, the lower the dose administered
What is efficacy?
The ability of a drug to have a particular action
Pharmacological efficacy = strength of receptor activation
(full agonist has high efficacy and partial agonist has low efficacy)
Clinical efficacy = strength of the beneficial effect
How do benzodiazepines and barbituates compare?
Both potentiate the effect of GABA through GABA A receptor but
BDZs increase frequency of Cl- channel openings but does not change maximum response of the channel
BDZs increase the potency of GABA
Barb prolong Cl- channel openings and increase the maximum response of the channel
Barbs increase the efficacy of GABA
BDZs have wider therapeutic index than barb
What are actions of dopaminergic drugs?
- increase DA synthesis (L-DOPA and DCC inhibitor)
- increase DA release
- DA receptor agonists
- reduce DA metabolism (inhibit COMT to reduce metabolism of L-DOPA and inhibit MAO B to reduce metabolism of DA)
What are key transmitter systems in the brain reward pathway?
Dependence related to increased DA in nucleus accumbens
Transmitters which modulate DA transmission:
-ACh, serotonin, NA, GABA, glutamate, opioids
