Psychopharmatology (2) Flashcards
Antagonists
Block the effects of endogenous neurotransmitters
and oppose normal synaptic transmission, although in some
cases if they act predominantly on presynaptic receptors they
may increase neuronal firing and so increase neurotransmitter
release.
Haloperidol
Receptors
Dopamine D2 - neuroleptics
Benzodiazepine - flumazenil
Opiate - naltrexone
5-HT2 - clozapine
Enzyme
Noradrenaline - MAOIs
Acetylcholinesterase - donepezil
GABA transaminase - vigabatrin
Uptake sites
SSRIs - paroxetine
TCAs - imipramine
NARIs - reboxetine
GABA - tiagabine
Ion channels
Most anticonvulsants
Partial agonists
Act somewhat like agonists in that they directly
act on receptors, but if used in the presence of an agonist they
compete for the receptor and so can have partial blocking properties;
hence they are sometimes called agonist–antagonists.
Receptors
Dopamine - Aripiprazole
5-HT1A - buspirone
Opiate - buprenorphine
Agonists
Act to mimic the action of an endogenous neurotransmitter, though their net action is not necessarily to promote synaptic transmission because of the effect that presynaptic autoreceptors may have.
Site: receptors
Dopamine, apomorphine, noradrenaline, opiate, clonidine.
Receptors
Proteins expressed on the surface of neurons that have specialized peptide conformations which allow the binding of neurotransmitters or hormones = pharmacophore. They convey the exquisite selectivity of receptors for substances such as neurotransmitters and drugs.
Affinity
The stickiness with which a neurotransmitter or drug binds to a receptor is called its infinity. Usually measured in nanomolar concentrations (nM).
Receptor classification
(1) Site or location, (2) way in which they transmit information across the cell membrane.
postsynaptic receptors
Typical receptors that mediate the actions of the released neurotransmitter. They can be excitatory (produce depolarization of the target postsynaptic neuron - action potential - neurosignal transmitted) or inhibitory (switching of the target neuron). It is the receptor not the neurotransmitter which determines whether excitation or inhibition occurs. Neurotransmitters can be excitatory or inhibitory depending on the receptor subtype it acts on.
Receptors classification according to location
Postsynaptic
- Stimulatory or inhibitory
- Ropinirole - D2 dopamine –> Parkinson’s
- Bezodiazepines - GABA-A –> anxiety, insomnia
Presynaptic autoreceptor
- Usually inhibitory
- Clonidine/lofexidine - A2 adrenoreceptor –> opiate withdrawal
- Low dose amisulpride - dopamine D2/3 –> improve cognition
Presynaptic heteroreceptors
- Clonidine - 5TH neurons –? may lead to depression
Presynaptic autoreceptors
Are located both on the cell bodies/
dendrites of neurons and on the terminal axonal processes. They detect neurotransmitter released from the parent neuron (hence the term ‘auto’) and, because in general they are inhibitory,
they act as a ‘brake’ on further release of the neurotransmitter. They represent important regulating mechanisms to limit excessive release of neurotransmitter into the synapse and have critical
roles in the action of many psychotropic drugs such as the antidepressants and antipsychotics.
Presynaptic heteroreceptors
Are located on neurons that release different neurotransmitters from those that act on the receptor, hence the term ‘hetero’. Again, they are generally inhibitory in nature.
Receptor subtypes
Receptors are grouped into families based on several different features, most usually the neurotransmitter that binds to them and the way in which they pass information into the target cell – the second-messenger system they are coupled to. Molecular genetic
studies have shown that there are at least 15 different genes that can produce proteins that look like known 5-HT receptor proteins, and these are now considered the class of 5-HT receptor subtypes. As they all bind 5-HT (though with quite different affinities) it is assumed that 5-HT is the endogenous neurotransmitter for them all. They are classified into families based on their linkage to second-messenger
systems.
Different receptor families act through different second messenger systems because the proteins that make up the binding site or receptor also act to transmit a signal into the cell after the transmitter binds to the receptor. This transmission of signal can
be in the form of a change in second messengers, such as cAMP or phospholipids catalysed by enzymes that the receptor protein activates: these are metabotropic receptors. Alternatively, receptor
activation by a ligand can result in a change in the conductance of an ion channel that alters ion flux across the cell membrane; these are ionotropic receptors. Each of these processes can either stimulate or inhibit the target cell, depending on whether the metabotropic or ionotropic processes that are initiated are excitatory or inhibitory.
Receptor activation + 5 HT receptors
Zie tabel 3 +4
Repeated drug administration
Tolerance: is a state of reduced drug action following repeated use. It is generally found with agonist drugs only and reflects homeostatic compensatory mechanisms that can occur in the target neuron or can be due to adaptive changes in neural circuitry.
Tolerance is often associated with a reduction in the number or density of the target receptors (down-regulation). Tolerance results in the loss of action of an agonist and is revealed by the need for higher doses to produce the same effect.
Sensitization: describes the increase in function of a drug when it is used repeatedly. This is rarely seen in psychiatry but has been put forward as an explanation of why repeated stimulant use (e.g. cocaine) may lead to psychotic phenomena. Following chronic use of antagonists, a form of supersensitivity to agonist
drugs may be seen when they are stopped. This is thought to be due to an increase in receptor density (up-regulation) and may explain some of the phenomena seen in drug withdrawal.
Drug treatment is stopped
Withdrawal
(1) Rebound: is the worsening of the original condition for which the drug was used, manifested by an increase in symptoms that were originally a reason for the prescription of the drug. It can be considered as the reappearance of the underlying disorder and, if severe enough, may equate to a relapse. In some cases, rebound can result in worse symptoms than those at the outset of drug therapy; this is considered as rebound with overshoot (or recoil). Rebound can happen without discontinuation phenomena
(e.g. in the case of lithium). Rebound can continue even when blood levels of the drug are undetectable, so presumably it indicates adaptive changes in brain function that are a consequence of drug use directly, or the physiological changes produced by the drug, rather than being simply the removal of the drug from
its binding site.
(2) Discontinuation symptoms: is a term that has been used in recent years in an attempt to clarify the phenomenon of selective serotonin reuptake inhibitors (SSRI) withdrawal symptoms. The key feature of a discontinuation syndrome is that it is a reaction
occurring during drug withdrawal (i.e. as plasma/brain levels of the drug are falling) whose symptoms are not features of the underlying disorder. Thus discontinuation syndromes can be distinguished
from rebound, and frequently (but not exclusively)
the symptoms do not bear any relation to the known pharmacology of the drug. They can be seen in people who have not had a therapeutic response to the drug, and have been seen in volunteers.
