Adrenoceptors Flashcards
What are adrenoceptors?
Receptors that mediate actions of adrenaline (epinephtine)/noradrenaline (norepinephrine).
How are adrenoceptors useful therapeutically?
Treatment of hypertension and cardiovascular diseases
Treatment of asthma and respiratory diseases
Treatment of depression and phychiatric/neurological disorders
Treatment of ADHD
How do adrenergic agents vary?
Different ranges of specificity and durations of action.
What is adrenaline and where is it produced?
A hormone released from the chromaffin cells of adrenal medulla of adrenal glands.
What is noradrenaline and where is it produced?
A neurotransmitter released by noradrenergic in CNS and ANS.
What is the regulatory function of noradrenaline?
Regulation of: Attention Perception Learning/memory Arousal
What is the locus ceruleus?
The site of origin of most of the noradrenergic projections
What does the locus ceruleus innervate?
Cortex Amygdyla Hippocampus Hypothalamus Brainstem nuclei Spinal cord
What is another name for isoprenaline?
Isopronetol
What is another name for salbutamol?
Albuterol
How does the adrenergic system contribute to the fight or flight response?
Adrenaline boosts the response. Sympathetic nervous system innervates the adrenal medulla to prompt adrenaline release. A hormonal response supplements the neuronal activity.
What are varicosities?
Neuro-effector junctions connecting efferent axons with tissues.
What is released from varicosities?
Noradrenaline
Describe the pathway of noradrenaline synthesis.
Tyrosine is converted to DOPA by tyrosine hydroxylase.
DOPA converted to Dopamine by DOPA decarboxylase.
Dopamine converted to Noradrenaline by Dopamine beta-hydroxylase.
Where within the axon is noradrenaline synthesised?
In a noradrenergic vesicle, tyrosine enters the vesicle and is synthesised to NA.
How is adrenaline synthesised from noradrenaline?
NA is transported out of the vesicle for this step. NA released from varicosities into the adrenal medulla. Chromaffin cells express Phenylethanolamine N-methyltransferase. NA converted to adrenaline in the cell.
What is the rate determining step in the synthesis of noradrenaline?
Conversion of tyrosine. Rate of tyrosine hydroxylase is limiting.
What triggers NA release?
Depolarisation at the nerve terminal.
Calcium influx and vesicle migration to the presynaptic membrane.
How is the noradrenergic signal transmitted?
NA release from presynaptic axon. NA binds to pre and postsynaptic receptors.
How is the noradrenergic signal terminated?
High affinity uptake 1 rapidly removes NA from the cleft. Any leftover NA is taken up by the low affinity uptake 2
What is NA metabolised by?
MAO - Monoamine oxidases
COMT - Catechol O-methyltransferase
How can synthesis of NA in the CNS be interrupted?
Application of alpha-methyltyrosine. Competitive inhibitor of Tyrosine hydroxylase.
Other than alpha-methyltyrosine, what else can be used to inhibit NA synthesis in peripheral neurones?
Carbidopa. DOPA decarboxylase inhibitor.
Why can’t Carbidopa be used to inhibit NA synthesis in CNS?
Can’t cross the blood-brain barrier.
What effect does alpha-methyldopa have on noradrenergic signalling?
Acts as a false substrate. Poor metabolisation lets it linger longer and accumulate.
Acts as a false transmitter. Occupies presynaptic alpha2-adrenergic receptors which reduces neurotransmitter release.
What effect does 6-hydroxydopamine have on noradrenergic signalling?
Destroys adrenergic terminals.
What effect does reserpine have on noradrenergic signalling?
Blocks NA uptake into vesicles. Causes NA depletion in neurons.
What are adrenergic blocking drugs used for? Give an example.
Local anaesthesia. Guanethidine.
How does guanethidine cause local anaesthesia?
Partially block reuptake of NA causing depletion of NA from vesicles.
Name 3 sympathomimetic agents that act indirectly on neuro-effector junctions.
Tyramine
Amphetamine
Ephedrine
How do sympathomimetic agents perform their function?
Taken up into synaptic vesicles.
Cause leaking of NA.
NA leaks into cleft without electrical stimulation.
Give 2 examples of uptake 1 inhibitors.
Amitriptyline
Imipramine
What is the site of action of uptake 1 inhibitors?
CNS.
What is the function of presynaptic receptors?
Inhibitory autoreception. Decrease NA release from the terminal
What type of receptor is the presynaptic NA receptor?
Alpha2-adrenoceptir. A Gi/o-protein coupled receptor.
How do alpha2-adrenoceptors decrease NA release?
The GPCR decreases adenylyl cyclase activity. Decrease calcium VGC opening.
What is the basis of adrenoceptor classification?
Agonist potency ranking.
What is the agonist potency order of alpha-adrenoceptors?
Adrenaline>Noradrenaline>Isoprenaline
What is the agonist potency order of beta-adrenoceptors?
Isoprenaline>Adrenaline>Noradrenaline
What effect does activation of alpha-adrenoceptors have?
Arterial vasoconstriction.
What effect does activation of beta-adrenoceptors have?
Atrial contraction.
Name a selective antagonist for alpha adrenoceptors.
Phentolamine
Name a selective antagonist of beta-adrenoceptors.
Propanolol
What are the subclasses of Alpha1 adrenoceptors?
Alpha1A
Alpha1B
Alpha1D
What is the specific function of Alpha 1 adrenoceptors?
Vasoconstriction of non-essential blood vessels.
How do Alpha1 adrenoreceptors perform their function?
Couple positively with PLC via a Gq/11-proteins.
What are the subclasses of Alpha2 adrenoceptors?
Alpha2A
Alpha2B
Alpha2C
How do Alpha2 adrenoceptors perform their function?
Couple negatively with adenylyl cyclase via Gi/o-proteins.
What are the subtypes of beta adrenoceptors?
Beta1
Beta2
Beta3
What is the function of Beta1 adrenoceptors?
Cardiac contraction
Lipolysis (together with Beta3)
What are the chronotropic effects of Beta1 receptors?
Regulation of rate of contraction/dilation of cardiac muscles.
What are the ionotropic effects of Beta1 receptors?
Regulation of force of contraction/dilation of cardiac muscles.
How can the effects of Beta1 adrenoceptors be strengthened?
Sympathetically released blood-borne adrenaline.
Name a selective agonist for Beta1 adrenoceptors.
Dobutamine.
What are the Beta2-adrenoceptors responsible for?
Bronchodilation
Dilation of blood vessels in exercising muscles and airways
What type of cell surface receptor are Beta-adrenoceptors?
GsPCR
Describe the structure of adrenoceptors.
7TM terminals
Ligand binding pocket between domains
GPCRs
Which adrenoceptor agonists are used for treatment of cardiovascular diseases?
Isoprenaline
Adrenaline
Dobutamine
Which cardiovascular diseases can be treated using adrenoceptor agonists?
Heart failure
Cardiac arrest
Heart block
Which adrenoceptor agonists are used for theatment of respiratory diseases?
Salbutamol
Terbutaline
Which respiratory diseases can be treated using adrenoceptor agonists?
Bronchoconstriction/asthma
Which anaphylactic reactions can be treated with adrenoceptor agonists?
Type 1 Hypersensitivity
Which adrenoceptor agonists can be used to treat anaphylactic reactions?
Adrenaline
Which Alpha1-adrenoceptor antagonists can be used to treat cardiovascular hypertension?
Prazosin
Doxazosin
Which Beta-adrenoceptor antagonists can be used to treat cardiovascular diseases?
Propanolol
Atenolol
Which cardiovascular disorders can be treated with beta-adrenoceptor antagonists?
Hypertension
Angina
Pectoris
Cardiac disrhythmia
Which Beta-blockers are used to treat glaucoma?
Timolol
What are beta-blockers?
beta-adrenoceptor antagonists.
Which Beta-blockers are used for treatment of benign essential tremors?
Alaprenolol
Oxprenolol
Give examples of the common respiratory diseases.
Bronchitis
Chronic obstructive pulmonary disease
Adult respiratory distress syndrome
Bronchial asthma
What are the common stimuli that trigger asthma?
Cold air
Exercise
Pollen
House dust
What is the physiological cause of asthma?
Chronic smooth muscle hyper-responsiveness. Inflammation causes the muscle to be more sensitive to stimuli.
What are the permanent effects that may be caused by asthma?
Hypertrophy - increase in muscle tissue volume.
Hyperplasia (increase in number of cells) of smooth muscle
Describe the events that occur during an asthma attack’s immediate phase.
Stimulus acts on Immunoglobin E (IgE) mast cells to release spasmogens and chemotaxins.
Spasmogens cause a bronchospasm leading to an asthma attack.
What are the mediators released in immediate phase of an asthma attack?
Spasmogens: cysLTB4 - Cysteine Leukotriene B4 Hydrogen PGD2 - Prostaglandin 2 Other: Interleukine-4 Interleukine-5 Interleukine-13 Macrophage inflammatory protein 1alpha Tumour necrosis factor alpha
What reverses the bronchospasm?
Beta2-adrenoceptor antagonists
cysLT receptor antagonists
Theophyline
What chemicals is bronchospasm initiated by?
ACh
Histamine
Leukotrienes
What is the role of chemotaxins/chemokines during an asthma attack?
Attracting leukocytes into the affected area.
Prompting Th2 cells to release cytokines.
Activation of eosinophils.
Setting the stage for late phase of the attack.
What are eosinophils?
Inflammatory cells.
What is chemotaxin release inhibited by?
Glucocorticoids
Describe the events of the late phase of an asthma attack.
A continuation of the early phase.
Th2 cells are infiltrated by chemokines and cytokines.
Th2 cells release cytokines.
Activation of eosinophils by chemokines/cytokines causing release of cysLTs, interleukins and toxic proteins.
Release of the mediators causes airway inflammation and hyper-activity.
Leads to bronchospasm, wheezing and coughing.
Which interleukins are released during late phase of asthma attack?
IL-3
IL-5
IL-8
Name the toxic proteins released from eosinophils during the late stage of asthma attack.
Eosinophil cationic protein (ECP)
Eosinophil major basic protein (EMBP)
Eosinophil-derived neurotoxin
What is the effect of toxic proteins released during late phase asthma attack?
Epithelial damage.
What inhibits the late phase of asthma attack?
Glucocorticoids
Why is asthma treated prophylactically?
To prevent/reduce inflammation
What therapeutics are used in prophylactic treatment of asthma? Give examples.
Corticosteroids: Beclomethasone (Asmabec) Fluticasone (Flixotide) Non steroidal: Cromoglycate Nedocromil
What are the consequences of corticosteroid overdose?
Cushing’s syndrome.
Describe the symptoms of Cushing’s syndrome.
Thin skin Oedema Poor wound healing Obesity due to increased apetite Osteoporosis
How has the risk of developing Cushing’s syndrome been reduced?
Invention of fluticasone.
Poor systemic absorbance means it is less likely to enter bloodstream
First pass metabolism. If fluticasone does enter blood, it will be renally excreted after a single kidney filtration.
How do non-steroidal drugs prevent asthma attacks?
Prevent release of chemicals from mast cells.
Which pharmaceuticals are used for symptomatic relief of asthma?
Salbutamol (Ventolin)
Terbutaline (Bricanyl)
Salmeterol (Serevent)
How is symptomatic relief from asthma achieved?
Reversing bronchoconstriction with Beta2-adrenoceptor agonists (cause bronchodilation)
What is FEV1?
Forced Expiratory Volume in 1 second
How is FEV1 affected during an asthma attack?
Reduced within minutes
Why are Beta2-adrenoceptor antagonists effective in treating the symptoms of asthma?
Relax bronchoconstriction irrespective of cause.
Inhibit mucous secretion to free up airways further
Stimulat mucous clearance
Decrease swelling (oedema)
May have an anti-inflammatory effect
Could Beta2-adrenoceptors be used as anti-inflammatory drugs?
No, they may have such function but there are therapeutics devoted to anti-inflammatory action
How do ACh/Histamine/LTs elicit muscle contraction?
Interact with GPCRs of smooth muscle.
Cause calcium influx (GqPCR?).
Leads to Calcium/calmodulin dependent activation of Myosin Light Chain Kinase (MLCK)
Causes myosin phosphorylation which induces muscle contraction.
How do Beta2-adrenoceptor agonists cause bronchodilation?
Via GPCR activation.
Leads to activation of adenylyl cyclase hence increased cAMP production (GsPCR?)
Leads to decrease in intracellular calcium via activation of efflux and inhibition of influx.
Inhibition of myosin phosphorylation via MLCK.
Promotion of myosin dephosphorylation.
Leads to relaxation of muscle.
Which Beta2-adrenergic agonists give a longer-lasting prophylactic action against bronchospasm?
Salmeterol
Formoterol
In what instance may Salbutamol be used over Salmeterol to treat asthma?
During an acute attack. Salbutamol is fast acting.
In what instance may Salmeterol be used over Salbutamol to treat asthma?
In prophylaxis. Salmeterol is active for 12-18h (2x to 6x longer)
What is a LABA? Give examples.
Salmeterol
Formoterol
What physical property of LABAs give them a longer lasting action?
Long hydrophilic tail acts as a leash to stay close to the Beta2-adrenoceptor.
What are the common therapies used to treat asthma? Give examples.
Inhalation of Beta-adrenoceptor agonists e.g.:Formoterol, Terbulatine Inhalation of corticosteroids e.g.:Budesonide, Beclometasone Inhalation of LABA+Corticosteroid e.g.:Salmeterol+Fluticasone (Seretide)
What are the less common approaches of treating asthma? Give examples.
Muscarinic receptor antagonists e.g.:Ipratropium, Tiotropium Leukotriene receptor antagonists e.g.: Zafirlukast Anti-IgE antibody e.g.:Omalizumab
What are the 5 possible outcomes of drug use?
Cure Cessation Reduction Symptomatic relief Aggravation
What are the properties of a good drug target?
Association with the disease
Expression of proteins specific to the site/organ
Drugability
What are common drug targets? Give examples.
Proteins with an active site DNA Adhesion molecules GPCRs Ion channels Enzymes
Which drug targets are used as a last resort and why?
Antibodies - Used when protein can’t be modulated by smaller molecules
siRNA - Reduce expression of the prefered drug target.
