PHARM 8: SNS Agonists Flashcards
briefly go over the mechanism of action of adrenoceptor a1
a1 = PLC –> IP3 + DAG
a1 –> causes vasoconstriction
briefly go over the mechanism of action of adrenoceptor a2
a2 = decrease cAMP
briefly go over the mechanism of action of adrenoceptor b1 + b2
b1 + b2 = Increase cAMP
b1 –> increase HR + contractility
What is meant by directly acting?
Directly acting = mimics the actions of A + NA
- through stimulating adrenoceptors
Compare between selectivity for NA and A
NA
more alpha selective
A
more beta selective
Describe metabolism of NA
- using tyrosine hydroxylase, tyrosine from diet = converted to DOPA
- DOPA = then converted to dopamine
- dopamine = converted to NA
- then uptake of NA occurs –> into nerve terminal itself / extra neuronal tissue
What is the significance of Presynaptic Alpha 2 Receptors ?
–> has negative effect on synthesis / release of NA
- if conc of NA = high, stimulates presynaptic alpha 2 receptors
- -> which reduces NA synthesis + release
NOTE: NA binds to presynaptic a2 –> which interferes with NA exocytosis
- controls secretion of NA
List some directly acting SNS agonists
- Adrenaline - non-selective
- Phenylephrine - Alpha 1
- Clonidine - Alpha 2
- Dobutamine - Beta 1
- Salbutamol - Beta 2
describe how selectivity depends on concentration for directly acting SNS agonists
at low conc, drugs will be relatively selective –> but when you increase conc chance of binding to other receptors increases
Describe the onset of hypersensitivity reactions
1st exposure –> antibodies to antigen = generated
- these antibodies circulate around the body
- and binds to mast cells
on next exposure:
- mast cells = already primed with antibody on their surface
SO
- antigen cross links antibodies on mast cells
–> then you get massive release of mediators
List some symptoms of hypersensitivity
- endothelial cells in blood vessel memb moves apart –> more fluid moves into tissues –> circulating fluid volume falls –> BP falls
- anaphylactic shock
- bronchial smooth muscle contraction
- vomiting + diarrhea –> as GI tract smooth muscle constricts
Why is adrenaline more effective than NA as treatment for anaphylaxis?
A acts more on beta receptors than NA
–> which stimulates bronchodilation + relaxation of throat muscles –> helps breathing (V IMPORTANT)
- A also stimulates alpha receptors –> vasoconstriction
- A also slows down histamine release from mast cells (via beta 2 receptors)
What are some unwanted actions of adrenaline?
- REDUCED + THICKENED MUCOUS
- CVS EFFECTS
- -> tachycardia, palpitation, hypertension, pulmonary oedema etc.
- TREMOR
Phenylephrine
selective for =
resistant to =
- very alpha 1 selective
- most similar to adrenaline
- resistant to metabolism by COMT (lasts longer in the system)
Phenylephrine is chemically related to adrenaline.
but it is resistant to _______
Phenylephrine is chemically related to adrenaline.
but it is resistant to COMT
note: but not MAO
Why might phenylephrine be used as a decongestant?
- inflammation in nasal sinus
- congestion –> fluid leakage from blood vessel
- vasoconstriction through a1 agonist
- less leakage of fluid through the blood vessels
list some clinical uses of phenylephrine
clinical uses:
- vasoconstriction
- mydriatic
- nasal decongestant
How does Clonidine cause a fall in TPR and BP ?
- clonidine stimulates presynaptic alpha 2 receptors
- -> which has negative effect on NA synthesis + release
- less NA release –> less stimulation at effector organ
- so less vasoconstriction –> fall in TPR + BP
–> causes reduced sympathetic effect
What is the action of clonidine on the brainstem?
- clonidine works on baroreceptors on brainstem –> reduces sympathetic drive coming out of brain
–> less NA released –> TPR reduced
What are the 2 routes of action for clonidine ?
- stimulates presynaptic alpha 2 receptors –> so less NA released
- acts on baroreceptors on brainstem –> reduces sympathetic drive –> less NA release
NA usually binds to Beta 1 receptors in the kidneys and …..
NA usually binds to Beta 1 receptors in the kidneys and stimulates renin release
list some clinical uses of clonidine
- hypertension treatment
- migraine treatment
- -> vasodilation of blood vessels to the brain
What is glaucoma characterized by?
- increase in intraocular pressure
What causes glaucoma?
- poor drainage of the aqueous humour
What happens in the development of glaucoma?
- ciliary body produces aqueous humour
- which flows out into anterior chamber of eye
- gets drained through canals of schlemm
- if poor drainage of the aqueous humour
- increase in intraocular pressure
-b1 facilitates the production of aqueous humor
b2 inhibits production of aqueous humour
a1 - causes vasoconstriction of blood vessels that deliver the humour
a2 - causes decrease in humour formation
Why is adrenaline good for glaucoma?
- alpha receptors on blood vessels in ciliary body
- beta receptors controls enzyme that makes aq humour
ADRENALINE:
- stimulates alpha receptors in vessels within ciliary body
- -> causes vasoconstriction
so less blood = delivered to ciliary body
- production of aq humour = reduced
give other clinical uses of adrenaline
- cardiogenic shock
- spinal anaesthaesia
- local anesthesia
Isoprenaline is chemically related to adrenaline but is more resistant to ….
Isoprenaline is chemically related to adrenaline but is more resistant to MAO + Uptake 1
Give some clinical uses of isoprenaline
- cardiogenic shock
- acute heart failure
- myocardial infarction
Give some clinical uses of dobutamine
- cariogenic shock
- administration = IV infusion
What is the plasma half life of dobutamine?
2 mins
What is salbutamol?
- synthetic catecholamine derivative with relative resistance to MAO + COMT
What are some clinical uses of Salbutamol?
- treatment of asthma
- -> causes B2-relaxation of bronchial smooth muscle
- -> inhibits release of bronchoconstrictor substances from mast cells
- treatment of threatened premature labour
- -> causes B2-relaxation of uterine smooth muscle
Why is adrenaline used in the treatment of anaphylaxis?
- reverses effect of histamine
- b1 effect on heart –> tachycardia
- B2 on lungs –> bronchodilator
- a1 –> vasoconstriction
- beta receptos on mast cells –> surppresses mediator release
In what other situations may adrenaline be used?
refer to effects on b1, b2, a1
b2
- airway mediator release
- for asthma
- acute bronchospasm
b1
- for inotropic effects
- e.g cariogenic shock
a1
- for spinal anesthesia –> to maintain BP
- for local anesthesia –> to keep drug in area for longer
- reduce blood flow to the particular region –> so less likely for drug to be washed away from an area
How effect does phenylephrine have on the pupil
- bind to a1 receptor on iris and promote pupil dilation
–> mydriatic
Why might B2 receptor stimulation by isoprenaline be a problem
- b2 receptors are in vascular smooth muscle in the skeletal muscle
- vasodilation occurs
- -> causing fall in BP
- baroreceptors respond to this
- and sends signal back to heart
- to increase HR
- you want normal cardiac output
- but you interfere with rate generation –> less rhythmical contractions
- which can leads to cariogenic shock
SUMMARY = to treat cardiogenic shock - you want a normal CO
–> but if you give isoprenaline –> then you get reflex tachycardia which interferes with the stable rate generation
dobutamine better for cardiogenic shock?
- dobutamine = more B1 selective
- so it has less side effect of reflex tachycardia compared to isoprenaline
