Patrick Hadoke Flashcards
name the receptor in the effector organ of the sympathetic nervous system
adrenoreceptors
where does the alpha-1,2 beta-1,2 adrenoreceptors located in the SNS?
alpha 2: nerve terminal involve in NA uptake
alpha 1, beta- 1,2: effector organ and mediate effect
name three drugs that target the synthesis of NA and state what they treat
- methyldopa: anti-hypertensive in pregnant woman
- alpha-methyl-tyrosine: tumour (phaeochromocytoma)
- carbidopa: Parkinson’s disease
name which G protein each adrenoreceptor is associated with, name their second messenger and what effect does it have
- alpha-1 + Gq/11: activates PLC which produces IP3 -> smooth muscle contraction
- alpha-2 + Gi: act through inhibiting adenylate cyclase -> decrease cAMP -> decrease [Ca2+]i inhibition of transmitter release
- beta-1-3 + Gs: do the opposite of Gi therefore causes heart muscle contraction, smooth muscle relaxation and glycogenolysis
what action is mediated by endogenous agonist NA and Adr acting on its receptors?
name their unwanted side effects
NA (alpha 1,2 and beta 1): increase BP
Adr (alpha 1,2 and beta 1,2): bronchodilation, increase BP and HR
side effects: hypertension, vasoconstriction, tachycardia
name two drug targets for indirect sympathomimetics
- inhibit MAO
- inhibit uptake 1
name drugs that inhibit uptake 1 and MAO
uptake 1:
- cocaine
- tricyclic antidepressant e.g. imipramine
MAOI:
-amphetamines
name three drugs that are able to displace NA through uptake 1
- tyramine
- amphetamine
- ephedrine
all these drugs can displace NA and stimulate sympathetic NS but due to the methyl substitution, decreases binding affinity
name the side effects of indirect sympathomimetics
- hypertension
- convulsion
- dependence
- cheese reaction (MAOI only) - interaction with food
what would be the effect of cheese reaction?
drastic increase of neurotransmitter in the cleft -> over activation of the sympathetic NS -> vasoconstriction -> increased HR -> hypertenstion
where is the alpha-1 receptor located?
smooth muscle cell (cardiovascular system and lower urinary tract)
name two alpha-1 agonists and state its action and the receptor it targets
name their side effects
methoxamine -> alpha 1 and 2 -> vasoconstriction
phenylephrine -> alpha 1 -> vasoconstriction
side effects: hypertension and reflex bradycardia
name three alpha-1 receptor antagonists, name its target, action, clinical use and unwanted side effects
phenoxybenzamine -> alpha-AR and Uptake 1 (non-sel, irrev) -> vasodilation -> pheochromocytoma (tumour)
prazosin -> alpha -1 AR -> vasodilation -> antihypertensive
tamsulosin -> alpha 1A AR -> relax urinary system -> blocks constriction of urethra
unwanted side effects:
- hypotension
- tachycardia
- nasal congestion
describe the effect mediated by activation of alpha-2 receptors and named the second messenger affected
when stimulated, alpha-2 receptors block adenylate cyclase hence generation of cAMP -> prevent Ca2+ influx -> prevent release of neurotransmitters
name a partial agonist and antagonist of alpha-2 receptors
clonidine - former antihypertensive -> but causes hypotension, oedema and drowsiness
yohimbine -> hypertension or excitement
where is the beta 1 adrenoreceptor located in the body and which second messenger does it use?
cardiac myocyte
uses AC -> cAMP causes contraction of the heart muscle
name a beta-1 receptor agonists, state its action and clinical use, name its side effect
- dobutamine
- positive ionotropy
- cardiogenic shock
where is the beta-2 receptors located?
smooth muscle cell: vein, skeletal muscle artery or bronchiole
name a beta-2 receptor agonists, name its uses and side effects
isoprenaline (non selective) -> asthma
salbutamol (beta-2) -> asthma
side effects: peripheral vasodilation, tremor, dysrythmias
name three beta receptors antagonists, its target receptor, action and clinical use. name the side effects
- propanolol (b1 and 2) -> negative inotropy -> angina, hypertension, cardiac arrythmia, anxiety
- atenolol (metoprolol) -> b1 selective -> same as propanolol
- nebivolol -> b1 and increase NO -> positive inotropy and vasodilation -> hypertension
side effects: bronchoconstriction, cardiac failure, depression
how do beta antagonists exert its anti-hypertensive effect?
- decreases CO
- vasodilation
- CNS effects -> decrease sympathetic act
- blocks the RAAS system which is associated with vasoconstriction, salt retention, hypertrophy
how does b antagonists contribute in preventing heart failure?
blocks sympathetic drive -> causes vasodilation -> prevention of cardiac hypertrophy -> maintain CO
name a drug used to treat glaucoma targeting the beta-2 receptor what is its mechanism of action?
timolol -> release of humour -> decrease pressure
name the features of the alpha subunit of G proteins
alpha:
- hydrolyses GTP back to GDP (GTPase domain)
- provides binding surface for GBgamma and effector proteins
describe what happened to G proteins when agonist binds to GPCRs (general pathway)
- agonist binds
- change loop structure cause high affinity binding for G protein
- GDP dissociates replace with GTP
- dissociation of the protein trimer
- active form of g-protein diffuse freely in the membrane and associate with other enzymes/ion channels
- attachment of alpha subunit increases its GTPase activity
- hydrolysis of GTP -> GDP
name the second messenger used to mediate the action of these G proteins:
Gs
Gi/o
Gq
G12
- AC
- AC
- Rho
- PLC
name the enzyme that breaks down cAMP
PDEs hydrolyse it into 5’-AMP
describe how isoprenaline could cause muscle relaxation (arterial)
- isoprenaline binds to b1 receptor
- stimulates adenylate cyclase to convert ATP -> cAMP
- cAMP activates PK (PKi -> PKa)
- PK phosphorylates MLCK -> MLCK-P -> relaxation
name the receptor in which clonidine binds to and what is its effect?
a2 receptor -> inhibits cAMP which causes contraction through unphosphorylated MLCK
which enzymes does cAMP and cGMP is broken down with?
cAMP - PDE3 and 4
cGMP - PDE5
which enzyme does rolipram targets? and what does it treat?
PDE4 in the treatment of asthma to cause relaxation of smooth muscle
what is the substrate for the membrane phospholipid PLC?
PIP2
which type of receptors uses Gq protein?
M3 and alpha1
explain how activation of PLC in the smooth muscle cell lead to increase in [Ca2+]
activation of PLC cleaved PIP2 to release IP3.
IP3 interacts with IP3R (ligand-gated calcium channel) to control release of Ca2+ from intracellular storage
apart from PIP2 what other protein does DAG interact with and activate?
membrane bound PKC which phosphorylates other proteins (perhaps IP3 -> IP4)
which receptor and G protein mediates the relaxation and contraction of blood vessels?
M3 and Gq
what happened to the response if you rub the inner surface of the vessel and when you expose your tissue to NA?
rub inner surface: contraction
without rubbing: relaxation
ach can both relax and contract smooth muscle. explain this phenomenon
the arterial wall is made up of two cells: endothelium nd smooth muscle cell
when rubbed from the inside, Ach interacts with M3 receptors on the surface of the smooth muscle cell -> increases [Ca2+] -> contraction
without rubbing Ach stimulates M3 receptors on the surface of endothelium -> entry of Ca2+ into cell -> converts L-Arg to NO -> No diffuse to smooth muscle cell -> act through GC -> causes relaxation
what is the name of the calcium-dependent enzyme in the endothelium?
NO-synthase which produces NO
how does NO causes relaxation of the smooth muscle?
NO causes activation of GC -> concerts GTP to cGMP -> phosphorylate PKG -> relaxation
