Class 2-Pharmacodynamics Flashcards
PHARMACODYNAMCS
« WHAT THE DRUG DOES TO THE BODY »
• Relationship between drug concentration and response
• Drug activity at the receptor
RECEPTOR
o Mainly made up of proteins
o Specific conformation
Ø Receptor only interacts with ligands that have a compatible structure
LIGAND
o Any substance capable of binding to a receptor
Ø Neurotransmitters
Ø Hormones (natural ligands)
Ø Drugs
« RECEPTOR BINDING » CHARACTERIZED BY 4 CRITERIA
- Affinity
- Saturability
- Reversibility
- Specificity
Affinity
Probability of a drug occupying a receptor at any given time. how much the drug loves to bind to the receptor
Expressed by a constant : Ki
- Ki = dose of a drug needed to occupy 50 % of receptors
- Ki is inversely proportional to affinity
high number = low affinity
Saturability
« Receptor binding » is sometimes limited by the number of receptors
available
Reversibility
« Receptor binding » can be reversible or irreversible
Specificity
- Specific = binds only to its receptor
- Non specific = binds to other receptors
EC50
Concentration needed to achieve 50% of the maximum effect
POSSIBLE EFFECTS OF A DRUG / SUBSTANCE ON A RECEPTOR
o Complete agonist o Partial Agonist o Antagonist Ø Competitive Ø Non competitive
INTRINSIC ACTIVITY
The ability of a substance to initiate a response after binding to a receptor
COMPLETE AGONIST
o Generates intrinsic activity
o May be endogenous (e.g. neurotransmitter) or exogenous (e.g. medication)
PARTIAL AGONIST
o Generates lower intrinsic activity than agonist
ü 0 to 99,9 % of response (Vs an agonists)
o Good affinity for the receptor, just like the agonist
ANTAGONIST
o No intrinsic activity
o Binds to the receiver, but does not activate it
o Prevents an agonist from binding to the same receiver
ANTAGONIST-COMPETITIVE
o Antagonist effect is surmountable if we increase concentration of the agonist
o If simultaneous administration of an agonist + competitive antagonist : affinity to the receptor and drug concentrations will determine the winner
ANTAGONIST-NON COMPETITIVE
o Inhibits an agonist’s response regardless of concentration
o Antagonist effect is insurmountable even if concentrations of the agonist are increased
PHARMACODYNAMIC INTERACTIONS
o Additive effect
o Synergistic effect
o Antagonistic effect
Additive effect
Drug 1 + Drug 2
- 1 + 1 = 2
- Total effect = sum of the effects of
the two drugs used separately
Synergistic effect
Drug 1 + Drug 2
- 1 + 1 > 2
- Total effect > sum of the effects of the two drugs used separately
- Generally when drugs have different mechanisms of action
Antagonistic effect
Drug 1 + Drug 2
- 1 + 1 < 2
- Administration of drugs with opposite effects
- Measured effect is less for at least 1 of the drugs
DENDRITES
• Extension of the cell body
• Present receptors to detect chemical signals
(neurotransmitters)
AXONE
Transmet un signal électrique
CELL BODY
- Includes core
* Protein synthesis and maintaining cellular integrity
AXONAL TERMINATION
• The main site of the synthesis and release of neurotransmitters
SYNAPSE
- Area between two neurons that ensures the transmission of information
- Interesting target for many psychotropic drugs
NEUROTRANSMISSION
RECEPTION INTEGRATION / CHEMICAL ENCODING ELECTRICAL ENCODING SIGNAL PROPAGATION SIGNAL TRANSDUCTION
RECEPTION
STIMULATION OF A PRESYNAPTIC NEURON VIA : o Hormone o Neurotransmitter o Drug o Nerve impulse
ENCODING
o Chemical signal converted to electrical signal
SIGNAL PROPAGATION
o Electrical signal spreads to the terminal axon
SIGNAL TRANSDUCTION
o Reconversion to a chemical signal
o Release of a neurotransmitter
o Stimulation of the post-synaptic receptor
Communication between neurons is chemical (not electrical)
NEUROTRANSMITTERS
SYNTHESIS BY
By the neuron
NEUROTRANSMITTERS
RELEASE By
the axonal termination
NEUROTRANSMITTERS
EFFECT
Produce an effect on the post-synaptic neuron
Ø The same effect as that generated by stimulation
of the pre-synaptic neuron
Ø Interact with the post-synaptic receptor in a specific way
NEUROTRANSMITTERS
ACTION ARE TERMINATED BY :
- Recapture by receptors
2. Degradation by an enzyme
SEROTONIN (5-HT)
SYNTHESIS
- By the neuron
* Tryptophan is the precursor to 5-HT
SEROTONIN (5-HT)
RECEPTORS
• 5-HT1 to 5-HT7
Ø Many have subtypes (e.g. 5-HT1A)
SEROTONIN (5-HT)
ACTION ARE TERMINATED BY :
- Recapture by SERT receptors
- Degradation by an enzyme, monoamime oxidase
(MAO)
SEROTONIN (5-HT)
IMPLICATIONS
o Mood o Sleep o Appetite o Pain o Temperature o Cognition o Psychomotor agitation / retardation
NOREPINEPHRINE (NE)
SYNTHESIS
- By the neuron
* Tyrosine is the precursor to NE
NOREPINEPHRINE (NE)
RECEPTORS
• Alpha or beta receptors
NOREPINEPHRINE (NE)
ACTION ARE TERMINATED BY :
- Recapture by NET receptors
- Degradation by an enzyme, monoamime oxidase
(MAO)
NOREPINEPHRINE (NE)
IMPLICATIONS
o Awakening/sleep o Mood o Agitation/ psychomotor delay o Attention o Heart rate o Blood circulation
DOPAMINE (DA)
SYNTHESIS
- By the neuron
* Tyrosine is the precursor to DA
DOPAMINE (DA)
RECEPTORS
• D1 to D5
DOPAMINE (DA)
ACTION ARE TERMINATED BY :
- Recaptured by DAT receptors
- Degradation by an enzyme, monoamime oxidase
(MAO)
DOPAMINE (DA)
IMPLICATIONS
o Movement o Posture o Pleasure o Emotional response o Pain
GLUTAMATE, receptors, implications
• Excitatory neurotransmitter
• Receptors (examples):
Ø NMDA, AMPA
• Implications : memory, energy
GABA, receptors, implications
- Inhibitory neurotransmitter
- Receptor : GABA
- Implications : stress, anxiety
ACETYLCHOLINE (ACH)
SYNTHESIS
- By the neuron
* Choline and acetyl coenzyme A are the precursors of ACh
ACETYLCHOLINE (ACH)
RECEPTORS
- Muscarinic (M1 to M5)
* Nicotinic
ACETYLCHOLINE (ACH)
ACTION ARE TERMINATED BY :
- Degradation by acetylcholinesera (AChE)
2. Degradation by butyrylcholineseterase (BuChE)
ACETYLCHOLINE (ACH)
IMPLICATIONS
o Memory o Learning o Cognition o Awakening o Muscle contraction
MAIN TARGETS FOR PSYCHOTROPIC DRUGS
TRANSPORTERS
G PROTEIN-COUPLED RECEPTORS
ENZYMES
ION CHANNELS
MONOAMINES TRANSPORTERS
PRE-SYNAPTIC REUPTAKE OF NEUROTRANSMITTERS
o Prevents the neurotransmitter from accumulating in the
synapse
o Interesting target to increase the activity of these neurotransmitters
DRUGS THAT TARGET MONOAMINE TRANSPORTERS
o Antidepressant
Ø Selective serotonin reuptake inhibitors (SSRIs; e.g. citalopram): • Selective inhibition of 5-HT recapture via SERT receptor inhibition
• ↑ amount of serotonin in the synapse
Ø Serotonin and norepinephrine reuptake inhibitors (NSRI; e.g. venlafaxine)
Ø Norepinephrine and dopamine reuptake inhibitors (e.g. bupropion)
G PROTEIN-COUPLED RECEPTORS
Neurotransmitter binds to a receptor
The receptor changes its conformation to
Médicament bind to the G protein
ROLE OF THE ENZYME
Converts the substrate into a different molecule (product)
DRUGS THAT TARGET ENZYMES
o Antidepressant
Ø Monoamine oxydase inhibitors (MAOI; e.g. phenelzinde): • Monoamine oxydase
• Enzyme that degrades monoamines (5-HT, NE, DA)
• ↑ amount of 5-HT, NE and DA in the synapse
o Drug used to treat cognitive impairment
Ø Acetylcholinesera inhibitors (e.g. rivastigmine)
ION CHANNELS
o Transmembrary proteins with integrated ion channel that activate following a change in membrane voltage
o When the electric current arrives, change of conformation which allows specific ions (e.g. Na, Ca, K) to cross the cell membrane
o Important in the propagation of the action potential in the neurons of the brain
VARIATIONS IN PHARMACOLOGICAL RESPONSE
o Receptor desensitization
o Tolerance
o Dependence
o Placebo effect
Receptor desensitization
G protein-coupled receptors trigger adaptive mechanisms to regulate pharmacological response :
- Change in receptor conformation
- Neurotransmitter depletion (tachyphylaxis)
- Loss of receptors (e.g. internalization)
Can gradually lead to the development of tolerance
Tolerance
- ↓ pharmacological response following
chronic administration of a drug (loss of efficacy) - Higher plasma concentrations required to replicate initial pharmacological effect
Dependence
Psychological dependance
- Patient cannot get rid of the need to consume the substance
Physical dependance
- Symptoms of withdrawal if sudden cessation of substance or rapid dose
Placebo effect
Placebo
- Placebo effect = the drug’s real beneficial effect, but not related to its mechanism of action, only to the psychological effects of taking the drug
- Experimental tool to assess the clinical effect of any treatment that has a variable
Define what synergy is in pharmacology.
amplified effects
What is the enzyme that degrades monoamines? Why is this enzyme an interesting target for some psychotropic drugs?
Ø Monoamine oxydase inhibitors (MAOI; e.g. phenelzinde): • Monoamine oxydase
• Enzyme that degrades monoamines (5-HT, NE, DA)
• ↑ amount of 5-HT, NE and DA in the synapse
Interesting for psychotropic drugs because if we block enzyme, monoamines won’t be degraded = more monoamines = treat depression, for example
What happens when a ligand binds to a receptor coupled to a G protein? Give examples of drugs that are antagonists to these receptors.
Neurotransmitter binds to a receptor
The receptor changes its conformation to
Médicament bind to the G protein
activates secondary messenger, makes a response
Drugs that target serotonin acts on what targets? Give examples for each target.
SSRIs: transporter
MAOI: enzymes
Mirtazapine: g protein
What is the effect of an agonist, partial agonist or antagonist on intrinsic activity?
Agonist: generates intrinsic activity
Partial agonist: generates lower intrinsic activity than agonist 0-99% ex: abilify
Antagonist: no intrinsic activity
What neurotransmitters are used for during neurotransmission?
Produce an effect on the post-synaptic neuron
Ø The same effect as that generated by stimulation
of the pre-synaptic neuron
Ø Interact with the post-synaptic receptor in a specific way