Pharmacology & Therapeutics 3 Flashcards
Where is GABA distributed in the brain in high concentrations?
- Cerebral cortex, cerebellum, hippocampus, corpus striatum (basal ganglia) and the hypothalamus
- Dorsal horn of the spinal cord
- Little in the PNS
What types of neurons utilise GABA?
30% of synapses have GABA receptors on their surfaces
- Short inhibitory interneurones
- Some longer tracts e.g. striato-nigral and cerebellar
- Means that it has a widespread inhibitory action in the CNS
What are the functions of GABA?
1) Motor activity- reflected in high concentrations of GABA in the cortex, cerebellum and spinal cord
2) Extrapyramidal activity- reflected by concentrations in basal ganglia
3) Emotional behaviour- reflected by presence in limbic system e.g. hippocampus and amygdala
4) Endocrine function- reflected by high concentration in hypothalamus
What is GABA synthesised from?
Glutamate decarboxylase (GAD) - It is specific for GABAergic neurons.
How is GABA synthesised?
- Glutamate decarboxylase originates from the Krebs cycle
- Alpha-oxoglutarate is converted into glutamate by GABA transaminase (GABA-T) which is converted into GABA
- GABA is broken down to succinic semialdehyde, and then by SSDH to succinate to return to the Krebs cycle- this is known as the GABA shunt
How is GABA stored and released?
- Stored in GABAergic vesicles, which contain high affinity transporters in their membranes
- They pick up GABA from the cytoplasm and transport it into the vesicle
- With arrival of the action potential in the nerve terminal, depolarisation opens voltage sensitive calcium channels. Calcium influx stimulates exocytotic release of GABA
What are the GABA receptors?
GABA-A: type 1 ionotropic, linked to chloride channels
GABA-B: type 2 metabotropic: G-protein coupled
How is GABA inactivated?
- Primarily by reuptake into neurons and surrounding glial cells
- This reuptake is Na+ dependent, ATP dependent and therefore is saturable
- Once reuptake has occurs, metabolism occurs
How is GABA metabolised?
- Broken down by GABA transaminase to succinic semialdehyde. Then again by succinic semialdehyde dehydrogenase to succinic which acid which returns to the Krebs Cycle
- The enzymes are mitochrondiral
Give examples of inhibitors of GABA metabolism
Sodium vaproate (epilim)
Vigabatrin (sabril)
- Inhibitors result in large increase in brain concentrations of GABA. This is associated with an enhancement of GABA-mediated inhibition
What are the properties of GABA-A receptors?
- Pentameric: 2α12β2γ2 - 5 subunits
- Mostly postsynaptic
- Mode of action: Conformational change in the subunits- Opening of Cl channels. Results in increase in Cl- influx into the post-synaptic neurone which leads to hyperpolarisation and inhibition of post-synaptic firing.
What is an agonist of GABA-A receptors?
GABA and muscimol (selective GABA-A agonist
What are antagonists of GABA-A receptors?
- Bicuculline (competitive inhibitor)
- Picrotoxin (non-competitive inhibitor)
- Both are convulsants, tending to generate seizures by reducing GABA transmission. Therefore not used therapeutically
What drugs that interact with GABA-A receptors are therapeutically useful as sedatives?
Benzodiazepines
Barbiturates
What are the properties of GABA-B receptors?
- Mostly presynaptic
- Inhibit NT release on presynaptic autoreceptors as well as heteroreceptors.
- G-protein linked receptors therefore require activation of a G-protein in the pre-synaptic cell membrane, resulting in reduced calcium conductance. This decreases exocytotic NT release and decreases cAMP levels.
What is an agonist of GABA-B receptors?
Baclofen
- Selective for GABA-B receptors.
Therapeutically useful as a skeletal muscle relaxant acting in the spinal cord
- Useful in spasticity associated with MS- is a spasmolytic
What is an antagonist of GABA-B receptors?
Saclofen (competitive)
What four proteins is the GABA-A receptor complex composed of?
- GABA- A receptor
- Barbiturate receptor
- Benzodiazepine
- Chloride channel
- GABA modulin allows the BDZ receptor to link to the GABA receptor protein
What happens when benzodiazepines bind to their receptor on the GABA-A receptor complex?
- Enhancement of GABA action
- Enhancement of GABA binding to the GABA receptor protein and this effect is reciprocated
- Increases the frequency of opening of chloride channels
What happens when Barbiturates bind to their receptor of the GABA-A receptor complex?
Increases the duration of the opening of the chloride channel
How do barbiturates differ from benzodiazepines?
Barbiturates are less selective than benzodiazepines
- Therefore less excitatory transmission and other membrane effects
- Might explain induction of surgical anaesthesia and low margin of safety
What are the clinical uses of Benzodiazepines (BDZ) and Barbiturates (BARB)?
1) Anaesthetics- BARB only: THIOPENTONE
2) Anticonvulsants: Diazepam, Clonazepam, Phenobarbital
3) Anti-spastics- Diazepam
4) Anxiolytics
5) Sedatives
6) Hypnotics
What are anxiolytics?
They remove anxiety without impairing mental or physical activity
- Minor tranquillisers
What do sedatives do?
Reduce mental and physical activity without producing loss of consciousness
What do hypnotics do?
Induce sleep
What barbiturate is used as a sedative/hypnotic?
Amobarbital
- For severe intractable insomnia
- Half life= 20-25 hours
What are the unwanted effects of barbiturates?
1) Low safety margins- depresses respiration so overdosing lethal
2) Alter natural sleep and decreases REM- hangovers/irritability
3) Enzyme inducers
4) Potentiate effect other CNS depressants (e.g. alcohol)
5) Dependence- withdrawal syndrome: insomnia, anxiety, tremor, convulsions, death
What are the pharmacokinetics of benzodiazepines?
1) Administration:
- Well absorbed
- Peak plasma: 1 hour
- Can be given IV for status epileptics for prolonged seizure activity
2) Distribution:
Bind plasma proteins strongly. Highly lipid soluble therefore wide distribution
3) Metabolism: Usually extensive in the liver
4) Excretion: in urine as glucuronide conjugates
5) Duration of action: short acting and long acting (slow metabolism and/or active metabolites)
Give examples of short acting benzodiazepines
Temazepam
Oxazepam
(half life of 8hrs)
Give examples of long acting benzodiazepines
Diazepam
(32 hours)
- Involves metabolism via temazepam and oxazepam or via nordiazepam
What are the uses of long acting benzodiazepines and give examples
Anxiolytics
- Diazepam (valium), Chlordiazepoxide (librium), Nitrazepam
- Oxazepam is used in cases of hepatic impairment to prevent toxicity
What are the uses of short acting benzodiazepines and give examples
Sedatives/hypnotices
- Temazepam, Oxazepam
What are the advantages of benzodiazepines over barbiturates?
- Wide margin of safety (overdose only causes prolonged rousable sleep- treated with flumazenil)
- Mild effect on REM sleep
- Does not induce liver enzymes
What are the unwanted effects of benzodiazepines?
1) Sedation, confusion, ataxia
2) Potentiate other CNS depressants (e.g. alcohol)
3) Tolerance (less than BARBs; only tissue tolerance)
4) Dependence
- Withdrawal syndrome similar to BARBs but less intense
- Withdraw slowly
5) Increase in free plasma concentration of different drugs including aspirin and heparin
What is choral hydrate used for?
Sedatives/hyponotics
- Metabolised in the liver to trichloroethanol (active drug)
What other drugs are used as anzxiolytics other than BDZs and BARBs?
Propranolol: - Non selective beta blocker - Improves physical symptoms on anxiety such as tachycardia and tremor - Used for stage fright Busiprone: - 5HT-1A agonist - Slow onset of action (days-weeks) - Few side effects - Downside is that we don't really understand the interaction with the 5HT transmission
What are the dopaminergic pathways?
1) Nigrostriatal: Cell bodies originate in the substantia nigra zona compacta and project to the striatum
- Control of movement
2) Cell bodies originate in the ventral tegmental area and project to the nucleus accumbens, frontal cortex, limbic cortex and olfactory tubercule
- Involved in emotion
3) Tuberinfundibular system: Short neurones running from the arcuate nucleus of the hypothalamus to the medial eminence and pituitary gland
- Regulates hormone secretion
What are the different dopamine receptors?
D1 family - D1 & D5
D2 family- D2, D3, D4
What are the cardinal signs of Parkinson’s Disease
Rest tremor: Shaking of the limb when relaxed
Rigidity: Stiffness, limbs feel heavy/weal
Bradykinesia: slowness of movement
Postural abnormality
What are the presenting symptoms of Parkinson’s Disease?
- Pill-rolling rest tremor
- Difficulty with fine movements- micrographia
- Poverty of blinking
- Impassive face
- Monotomy of speech and loss of volume of voice
- Disorders of posture- flexion of the neck and trunk
- Lack of arm swing
- Loss of balance- lack of righting reflex retropulsion
- Short steps, shuffling gait
- Symptoms appear on one side of the body at first (unilateral onset)
- Symptoms spread to both sides of the body
What are the non-motor symptoms of Parkinson’s Disease?
- Depression
- Pain
- Taste/smell disturbances
- Cognitive decline/Dementia
Autonomic dysfunction: - Constipation
- Postural hypotension
- Urinary frequency/urgency
- Impotence
- Increased sweating
What brain areas are affected in Parkinson’s Disease?
Principle area: Substantia nigra
And
- Locus coruleus, Dorsal vagus nucleus, Nucleus Basalis of Mynert
What biochemical changes occur in Parkinson’s Disease?
- Marked reduction in caudate nucleus/ putamen dopamine content
- Necessary to lose 80-85% of the dopaminergic neurons and deplete 70% of the striatal dopamine before symptoms appear
- Compensatory mechanisms prevent the appearance of clinical symptoms
What is the dopamine replacement therapy- L-DOPA?
- DOPA is the precursor to dopamine, converted to dopamine in the brain by enzyme DOPA decarboxylase (DD)
- DD is present in peripheral tissues.
- If administered alone, 95% of L-DOPA is metabolised to dopamine in the periphery.
- L-DOPA can cross BBB to be centrally converted to hopamine
What drugs are used in dopamine replacement therapy using L-DOPA?
Peripheral DOPA decarboxylase inhibitor & L-DOPA
Preaparations: Sinamet and Madopar
What does L-DOPA treat?
Hypokinesia
Rigidity
Tremor
What are the acute side effects of L-DOPA?
- Nausea: prevented by Doperidone (peripheral acting antagonist)
- Hypotension
- Psychological effects: Schizophrenia like syndrome with delusions, hallucinations, also confusion, disorientation and nightmares
What are the chronic side effects of L-DOPA?
Dyskinesias: Abnormal movements of limbs and face. Can occur within 2 years of treatment. Disappear if reduce dose but clinical symptoms reappear.
On-off effects: Rapid fluctuations in clinical state. Off periods may last from minutes to hours. Occurs more with L-DOPA
What are the actions of Dopamine Agonists?
- Act on D2 receptors
- Bromocriptine, Pergolide, Ropinerol
- Longer duration of action than L-DOPA
- Smoother and more sustained response
- Actions independent of dopaminergic neurons
- Incidence of dyskinesias is less
- Can be used in conjunction with L-DOPA
What are the adverse effects of dopamine agonists?
Common- confusion, dizziness, nausea/vomiting, hallucinations
Rare- Constipation, headache, dyskinesias
What is Deprenyl (selegiline)?
MAO INHIBITOR
- Selective for MAO-B, predominates in dopaminergic areas of CNS. Actions are without peripheral side effects of non-slective MAO-I’s
- Can be given alone in the early stages of disease
- Or in combination with L-DOPA, reduce the dose of L-DOPA by 30-50%
- Rare side effects: hypotension, nausea/vomiting, confusion and agitation
What is Resagiline?
MAO INHIBITOR
- Shown to have neuroprotective properties by inhibiting apoptosis- Promotes anti-apoptosis genes
Give examples of Catechol-O-Methyl transferase (COMT) inhibitors
Tolocapone (CNS and peripheral)
Entacapone (Peripheral)
What does COMT do in the CNS and peripheral?
CNS- Prevents breakdown of dopamine
Peripheral: COMT in the periphery converts L-DOPA to 3-0-methyl DOPA (3-OMD).
3-OMD and L-DOPA compete for the same transport system across the blood brain barrier
What is the mode of action of COMT inhibitors?
They stop 3-OMD formation.
This increases the penetration of L-DOPA across the blood brain barrier.
This increases brain concentrations, where it is converted to dopamine. L-DOPA dosage can therefore be reduced.
- Has cardiovascular side effects
What are the positive and negative symptoms of schizophrenia?
Positive: Hallucinations, delusions, disorganised thoughts
Negative:
- Reduced speech (even when encouraged to interact- alogia)
- Lack of emotion and facial expression
- Diminished ability to begin and sustain activities (avolition)
- Social withdrawal (associality)
Once Schizophrenia has been diagnoses, what are the four main outcomes?
1) The illness resolves completely, with or without treatment and never returns
2) The illness recurs repeatedly with full recovery after each episode
3) The illness recurs repeatedly, but recovery is incomplete and a persistent defective state develops, becoming more pronounced with each successive relapse
4) The illness pursues a downhill course from the beginning
How is dopamine involved in the positive and negative symptoms of Schizophrenia?
- Excessive dopamine transmission in the mesolimbic and striatal region lead to positive symptoms. Mediated through D2 receptors
- Dopamine deficit in pre-frontal region leads to the negative symptoms. Mediated by D1 receptors
What is the mechanism of action of antipsychotics?
- All neuroleptic drugs are antagonists at dopamine ‘D2 like’ receptors
- Most neuroleptics block other receptors e.g. 5-HT, thus accounting for some of their effects
- Drugs treat positive symptoms, not negative one
- Delayed effects, takes weeks to work
- Initially, neuroleptics induce an increase in DA synthesis and neuronal activity. This declines with time.
How do neuroleptics act as an anti-emetic agent?
- Blocking dopamine receptors in the chemoreceptor trigger zone.
Neuroleptic Phenothiazine is effective at controlling vomiting and nausea induced by drugs, renal failure - Many neuroleptics have blocking action at histamine receptors. This is effective at controlling motion sickness.
What causes the side effects of antipsychotics?
Extrapyramidal side effects.
Blockade of dopamine receptors in the nigrostriatal system can induce ‘Parkinson’ like side effects
What are the side effects of antipsychotics?
Acute dystonia: Involuntary movements- muscle spasm, protruding tongue, fixed upward gaze, neck spasm etc. Often accompanies by Parkinson’s features. Reversible with drug withdrawal or anti-cholinergics.
Tardive dyskinesias: Involuntary movements, often involving the face and tongue but also limb and trunk. Made worse by drug withdrawal or anti-cholinergics
Blocking alpha-adrenoceptors: causes orthostatic hypotension
Blocking 5-HT receptors: weight gain
Blockade of cholinergic muscarinic receptors: Typical peripheral anti-muscarinic side effects e.g. blurring of vision, increased intra-ocular pressure, dry mouth, constipation, urinary retention
What are the endocrine effects of antipsychotics?
- Dopamine is involved in the tuberoinfundibular system and acts to inhibit prolactin secretion via the D2 receptors
- Antipsychotics increase serum prolactin concentrations which can lead to breast swelling (in men and women) and sometimes lactation in women
What are local anaesthetics?
Drugs which reversibly block neuronal conduction when applied locally
- They are weak bases (pKa 8-9)
What are the effects of local anaesthetics?
1) Prevent generation and conduction of action potentials
2) Do NOT influence resting membrane potential
3) May also influence
- Channel gating
- Surface tension
4) Selectively block
- Small diameter fibres
- Non-myelinated fibres
How is surface anaesthesia administered?
- LA applied to mucosal surface (mouth, bronchial tree)
- Spray (or powder)
- High concentration is needed which can lead to systemic toxicity
How is infiltration anaesthesia administered?
- LA applied directly into tissues- sensory nerve terminals
- Minor surgery
- Adrenaline co-injection to reduce side effects and increase duration of action (NOT given at extremities as could lead to ischaemic damage)
How is intravenous regional anaesthesia administered?
- LA injected intravenously, distal to a pressure cuff
- Useful in limb surgery
- Diffuses into surrounding tissue rapidly
- Potential for systemic toxicity if cuff is released prematurely
How is nerve block anaesthesia administered?
- LA injected close to the nerve drugs e.g. dental anaesthesia around dental nerve
- Widely used, low doses. Slow onset
- Co-injection vasoconstrictor (e.g. Felypressin)
How is spinal anaesthesia administered?
- LA injected into the sub-arachnoid space and has effects on the spinal roots
- ‘Intra-thecal’ injection
- Abdominal, pelvic or lower limb surgery
- Risks include a drop in blood pressure
- Unwanted effects- prolonged headache if LA accesses the brain
How is epidural anaesthesia administered?
- LA injected into the fatty tissue of the epidural space, has effect on spinal roots
- Used in abdominal, pelvic and lower limb surgery. Also for painless childbirth.
- Slower onset, need to use higher doses so systemic toxicity is more likely
- Effects on blood pressure less likely as the area is more restricted
What are the properities of lidocaine (local anaesthetic)
Type: Amide Absorption by mucous membranes: Good Plasma protein binding: 70% Metabolism: Hepatic N-dealkylation Plasma half life: 2 hours
What are the properties of cocaine (local anaesthetic)?
Type: Ester Absorption by mucous membranes: Good Plasma protein binding: 90% Metabolism: Liver and plasma but non-specific esterases Plasma half life: 1 hour
What are the unwanted effects of lidocaine?
CNS: - Stimulation - Restlessness, confusion - Tremor - These symptoms are paradoxical as are unexpected CVS: - Myocardial depression - Vasodilation - Hypotension - Due to the Na+ channel blockade
What are the unwanted effects of cocaine?
CNS: - Euphoria - Excitation CVS: - Increased cardiac output - Vasoconstriction - Increased blood pressure
- All symptoms due to sympathetic actions
Why is general anaesthesia clinically desirable?
- Loss of consciousness (low concentrations e.g. isoflurane 100um)
- Suppression of reflex responses (high concentrations e.g. isoflurane 300um)
- Relief of pain (analgesia)
- Muscle relaxation
- Amnesia
What are the gaseous general anaesthetics?
- Nitrous oxide
- Diethyl ether
- Halothane
- Enflurane
What are the intravenous general anaesthetics?
- Propofol
- Etomidate