Drugs in the CNS: Lectures 21-24 Flashcards
Where do drugs primarily act?
On neurons (bulk of the CNS)
How can therapeutic drugs affect us?
Neurologically (brain) - epilepsy, Parkinsons, Arlzheimers Psychotropic (mind/ emotions) - anaethetic, sedatives, antipsychotics and antidepressants.
Why do most drugs not act on the brain?
Have to cross the blood brain barrier - Only gaps are tight junctions - Must be either lipid soluble or use carrier-mediated transport
What are the different sites a drug can affect
Neurotransmission or Neuronal Function Ion channel excitability Receptors- pre and post synaptically Synthesis and delivery of peptide neurotransmitters
How can drugs affect neurotransmission?
Synthesis, removal, uptake, storage - Breakdown of neurotransmitter with MAO - Breakdown of neurotransmitter with COMT
How can drugs affect receptors?
Ionotropic- voltage or ligand gated ion channels - can affect membrane potential and signal transduction Metabotropic - GPCRs - Can affect the phospholipase C and cAMP pathways
What are the molecular targets of drug action?
Enzymes Transporters Receptors (incl ion channels, GPCRs, kinase linked)
What are anxiolytics?
Used to treat anxiety
What is the difference between being ‘normal’ and having ‘anxiety’?
Normal behaviour- defensive, fear, reflexes, alert, down Anxiety- these behaviour with no external cues –> interferes with normal activity
What are the different types of anxiety?
Generalised anxiety disorder, panic disorder, phobias, social anxiety, OCD, PTSD, separation anxiety.
How do you treat anxiety?
Psychologically with benzodiazepines. Two types- sustained action e.g. diazepam, or short action e.g. lorazepam.
How do benzodiazepines treat anxiety?
Binds at top of GABA receptor between alpha 1 and gamma 2. Affects the GABAa receptor (selectively permeable to Cl- causing hyperpolarisation (inhibits depolarisation)) –> increased inhibition
What are the affects of benzodiazepines and possible side effects?
Reduced anxiety, reduced muscle tone and coordination, Sedation, Amnesia Develop tolerance over 1-2 weeks
What is the problem with the development of tolerance
Decreased effectiveness –> need more to have the same effects Builds up a dependence to the drug.
What are other anxiolytic options other than benzodiazepines?
Beta-blockers to treat the symptoms? Adrenoceptor-mediated activation
What is the purpose of hypnotic drugs?
Psychoactive drugs used to induce sleep in insomnia and anesthetics
What are some examples of hypnotics
Flurazepam, zalepon
What decides whether a drug such as a benzodiazepine is a hypnotic or anxiolytic.
Doseage as most of the drugs work at the same site.
Describe the basics of epilepsy.
Electrical disturbances in the brain causing breif, chronical, recurring and rapid onsetting seizures.
How do anti-epileptics work?
Use dependent block of sodium channels Acting on the GABAa receptor Inhibiting GABA breakdown
How does use dependently blocking sodium channels combat epilepsy?
Drug accumulates with the increased opening and activity of the channel. It therefore blocks depolarisation and excitation (inhibits channel) when rapid firing occurs - Phenytoin
How does the drug action on GABAa receptors combat epilepsy?
Potentiates the effects of GABA –> increased inhibition Inhbition leads to decreased chances of a seizure
How does inhibiting GABA breakdown combat epilepsy?
Decreased inhibition leads to increased GABA –> increased inhibition
Why are there different ways of combating epilepsy?
Different drugs with different mechanisms - a combination of drugs as no drug works for all patients.
What defines depression?
Intense or prologoned sadness often without external cues. Can display signs- pain, digestive or respiratory difficulties. –> high chance of suicide
What are the causes of depression?
Genetic and environmental - varies between people - Neurochemical imbalance - External factors : death, loss, separation - Biological amine theory - deficit of neurotransmitters
What are the different mechanisms of treatment for depression?
Increasing transmission of neurotransmitters - Inhibit re-uptake - Inhibit metabolism - Enhance release
How does inhibiting re-uptake treat depression?
Generally either serotonin or Noradrenaline or both! - Use serotonin-noradrenaline-re-uptake inhibitors (SNRIs) Leads to an increase in the synaptic concentration - Not specific but selective –> side effects E.g.s tricylcic antidepressants, prozac, fluoxetine
How does inhibiting metabolism of neurotransmitters treat depression?
Increase in the amount of MAO inhibitors –> NT taken up into vesicles and then recycled Can work reversibly or irreversibly Leads to a requirement for re-synthesis E.g. phenelzine
How does enhancing the release of neurotransmitters treat depression?
Alpha-2 adrenoceptor antagonists e.g. mirtazapine –> inhibition of pre-synaptic receptors which produce inhibitory feedback mechanisms –> increased release / increased synaptic concentration
Why does antidepressant treatment take a while to take effect?
Requires neuronal adaptation or neurogenesis
What is neuronal adaptation?
Change in the number of receptors –> often a decrease with desensitisation –> takes longer for an effect to occur Can be triggered by antidepressants –> decrease in pre-synaptic auto-receptors and transports –> increased neurotransmission
What is neurogenesis?
The creation of new neurons Produced due to antidepressant treatment –> increase in neurotrophins and neurotransmitters –> increase in growth factors –> increase in neurons
How do you treat bipolar disorder?
Stabilised through acute and long-term control - Acute use drugs- benzodiazepines, antipsychotics - Long term: increase the amount of lithium i.e. lithium carbonate
How does the increase in the amount of lithium increase stability in bipolar patients?
Stabilise the Galpha q PLC pathway - uncompetitive inhibition —> increased activity –> increased inhibition —> Lithium used by an enzyme that inhibitis inositol production.
What are some examples of psychomotor stimulants?
Amphetamines, MDMA, Cocaine
What are the effects of amphetamine?
Structurally realted to noradrenaline (targert specific) –> Both taken up by uptake 1 and have a weak affect on adrenoceptors.
What mechanism does amphetamine work by?
In synapse –> uptake 1 –> exchanged by VMAT for the NA in vesicles –> increased NA release On uptake it causes the inhibition of MAO leading to decreased degradation of NA leading to increased concentrations Noradrenaline floods the synapses
What are the clinical uses of amphetamines?
Narcolepsy - used in preventing excessive daytime sleeping and also Attention Deficit Hyperactive Disorder (ADHD).
What are the recreational uses of amphetamines?
SPEED (snorted or injected) –> euphoria, confidence, hyperactivity Side effects: hypertension, insomnia, tremor
What are the issues with taking MDMA / ectasy?
Cause sudden death due to feeling hot causing people to drink a lot. MDMA causes renal faliure and therefore the intake of liquid leads to death. Can also lead to long term CNS damage.
What are the effects of taking cocaine?
Intense and immediate euphoria when snorted Smoked - side effects: cardiac problems, stroke like symptoms, foetal development issues
How can cocaine be used clinically?
Local anaesthetic –> prevents action potentials
By what mechanism does cocaine work?
Blocks re-uptake –> increased neurotransmitter in the synapse.
What are psychoses?
Changed perception of reality, intellect, mood, motivation, motor ability.
Psychoses can lead to schizophrenia, what are the positive and negative symptoms.
Positive: hallucinations, disorganised speech, behavioural changes Negative: change in normal behaviour Positive and negative symptoms must be treated differently - different antipsychotics.
What are the ways of treating different parts of schizophrenia?
Postive and negative symptoms are treated with antipsychotics. Cognitive dysfunction - requires clinical treatment.
What is aetiology?
A developmental brain disorder. Large amounts of changes in neuropathological pathways Changes in metabolism, blood flow, body chemistry
What causes aetiology?
Over activity of dopaminergic systems –> changes in mesolimbic system. This in turn causes changes in cognition and emotions
What are the different types of anti-psychotics drugs used?
Group 1 - chlorpromazine Group 2 Group 3 - haloperidol Less common- clozapine, olanzapine
What is the basic mechanism for anti-psychotics?
All drugs are the antagonists of different GPC dopamine receptors - commonly D2 receptors (suggestive that schizophrenia caused by dopaminergic systems.
How could dopaminergic systems be linked to the onset of schizophrenia?
Increased number of receptors –> increased activity.
What does the effectiveness of drugs depend on?
Interactions with neurotransmitter systems. - affinity for other receptors. –> causes side-effects: stiffness, shakiness (parkinsons like).
Why are less common drugs being used more frequently nowadays?
Reduced side effects but different side effects: weight gain, diabetes, sexual problems, saliva production. Reduce negative symptoms - suicidal and negative emotions, lack of emotions.
Why could decreasing glutamate be an effective therapy?
Tackles both positive and negative symptoms.
What are opoid analgesics used for?
Pain reduction - morphine and codeine Recreationally - opium –> euphoria, analgesia, sleep, diarrhoea relief, ADDICTION
Define Opiod, Opiate and Endorphin
Opiod- any agonist with morphine like activity Opiate- any drug derived from the opium poppy Endorphin- endogenous substrate with morphine like properties
What are the effects of opiods?
Analgesia and euphoria, nausea, sleepiness, mood change, reduced bowel movement, decrease HR and Respiration.
What are the three types of opiod receptor?
All GPCRs distributed in grey matter Mu (where morphine acts), Kappa, and delta
What opoid and precurosor proteins act on the different receptors?
Reproopiomelanocortin –> endorphin–> delta Preprokephalin –> met or leu encephalin –> kappa Preprodynorphin –> dynorphin –> mu or kappa
How does opoid action link to GPCRs
Couple to Gi –> decreased production of cAMP Direction action of by (beta gamma) subunit -Increased K+ channel conductance –> hyperpolarisation, faster repolarisation, increases AP rate. - Decreased opening of VGCC —> decreased neurotransmission
What is the difference between somatic and visceral pain?
Somatic pain - close to surface Visceral pain - deep tissue
What are the affects of visceral pain (deep tissue damage)
Sweating, nausea, change in emotions
Why is morphine often used in cancer treatment.
Stabilisation of emotions Treatment of visceral pain
What mechanism does morphine work by?
Acts primarily on the mu receptor in the CNS Causes inhibition of primary afferent neurons —> INHIBITS post-synaptic excitability, neurotransmitter release, modulation of pre-synaptic AP firing
Define tolerance:
The need to increase the drug doseage due to decreased effectiveness of response
What are the possible mechanisms which can lead to tolerance?
-Increased metabolic tolerance - drugs broken down faster (up regulation of metabolism) - Cellular-adaptive - cellular response is altered –> often due to a change in receptor number - Behavioural conditioning- environment changes –> changes in effectiveness
Define physical dependence:
adaptive state which leads to intense physical disturbance if drug removed
Describe withdrawal or abstinence syndrome
Drug specific physiological and psychological symptoms - opposite of the drugs effects - pain, depression, anxiety Increases desire to take drug again Extent of dependence measured by severity of withdrawal
Define psychological dependence:
cravings or desire to take a drug- feel like its necessary - neurochemical basis (reward) –> reward / desire may have an external cue —> predictive cue: taking any drug (placebo)–> effect
What is the best way to combat an overdose?
A high affinity competitive antagonist is required - Naloxone removes agonist (heroin)
How is opiod addiction often treated?
Partial agonists are used as a replacement - Buprenorphine Higher affinity than drug but lower efficacy –> wean off –> simultaneously prevent the use of opiods.
