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
What issues are associated with amphetamine use?
What are the adverse effects?
Dependence related to DAnergic actions in the nucleus accumbens
Ecstasy: releases DA and serotonin
psychological dependence, sympathomemetic, disrupted thermoregulation, potential degeneration of neurons caused by toxic metabolites (possible effects on mood, memory, sleep and appetite), psychosis
What is MOA of TCA?
- inhibits neuronal uptake of NA and 5-HT
- poorly selective
- takes weeks for clinical effects to develop
- narrow therapeutic window (limited efficacy)
What is MOA of MAOIs?
- inhibit metabolism of 5-HT, NA, and DA
- serotonin syndrome (tyramine-containing foods can precipitate hypertensive crisis)
- weight gain
- liver toxicity
MOA of SSRIs?
- inhibit uptake of 5-HT selectively
- high therapeutic index
- increased anxiety and suicidal tendencies in adolescents
- sexual dysfunction
What are the components of noradrenergic transmission?
- Influx of Ca++ causes release of NA in vesicles
- NA can activate alpha and beta receptors on postjunctional folds
- NA can also activate alpha receptors on prejunctional folds
- NA can be inactivated via neuronal uptake (high affinity) and degradation by MAO as well as via extraneuronal uptake (low affinity) and degradation by MAO and COMT
What are the components of chemical neurotransmission that can be used as targets for drug action?
- Synthsis/storage of neurotransmitter
- Release of vesicles containing neurotransmitter (Ca++ influx)
- Inactivation of neurotransmitter (uptake or metabolism)
- Receptors (pre and postjunctional folds)
