General Flashcards
What is the major disadvantage of clinical therapy involving drugs that act on ANS?
Lack of specificity
Parasympathetics control…
cardiac and smooth muscle
gland cells
nerve terminals
Parasympathetic presynaptic
nicotinic cholinergic
Parasympathetic postsynaptic
muscarinic cholinergic
Sympathetic (sweat glands) postsynaptic
muscarinic cholinergic
postsynaptic motor neurons
nicotinic cholinergic
sympathetic (cardiac and smooth muscle, gland cells, nerve terminals) postsynaptic motor neurons
adrenergic (alpha and beta)
Sympathetic (renal vascular smooth muscle) postsynaptic motor neuron
dopamine receptor
Adrenal medulla
nicotinic cholinergic receptor
releases Epi, NE
Cholinergic receptor types
muscarinic
Nicotinic
muscarinic subtypes
M1, M3, M5…Gq coupled
M2, M4….Gi coupled
Gq coupled muscarinic receptors
M1
M3
M5
Gi coupled muscarinic receptors
M2
M4
Nicotinic subtypes
Nm (neuromuscular/muscle type)
Nn (neuronal, or ganglion type)
Adrenergic subtypes
alpha 1, alpha 2
beta 1, beta 2, [beta 3]
Dopamine receptor subtypes
D1-D5
Other receptors
for NANC transmitters
- -NO
- -vasoactive intestinal peptide
- -neuropeptide Y
5 key features of neurotransmitter function that provide targets for drug therapy?
Synthesis Storage Release Reuptake Degredation
If Synthesis and Storage blocked…
usually rate-limiting steps, so…
produce long-term effects, but not immediately effective
If release blocked…
Rapid action and effective
If reuptake blocked…
Increased synaptic neurotransmitter concentrations (selective or non-selective)
If metabolism blocked…
reversible or irreversible:
increases transmitter levels
If recognition is blocked…
Receptor antagonists and agonists…high specificity
Sympathomimetic
mimicks… effects of impulses conveyed by adrenergic postganglionic fibers
Sympatholytic
anti adrenergic…
Fundamental difference b/w methods of inactivation of acetylcholine vs. norepinephrine
acetylcholine–>degraded
NE–>reuptake
hemicholiniums
EXPERIMENTAL, NOT CLINICAL
block CHT (that transports Na and choline in)
Vesamicol
EXPERIMENTAL,, NOT CLINICAL
blocks VAT
Cotransmitters
modulation (enhance or diminish cholinergic activity)
Cholinergic Autoreceptors
ACh activates the receptors, but this inhibits further release of ACh
Blocking the Ca channels…
inhibits sweating?
Metabotropic
function through secondary messanger system
Muscarinic receptors
Ionotropic
ion channels
nicotinic
M1, M3, M5
Metabotropic
Gq
–>PLC–>IP3–>INCREASES INTRACELLULAR CALCIUM!!!
M2, M4
Metabotropic
Gi
blocks adenylate cyclase from making cAMP
inhibitory response
opens K channels (GiRK)
nicotinic receptors
ionotropic
increase intracellular Calcium, Na, PKC
amplifies effect
If drug not susceptible to cholineterase, then…
improves longevity of drug
i.e. carbachol chloride and bethanechol chloride
metyrosine
inhibits tyrosine hydroxylase
tyrosine synthesis to dopamine
Reserpine
Blocks VMAT
Cocaine, tricylic antidepressants
block NET (prevents neurotransmitters from being broken down/ repackaged)
What process is critical for catecholamine neurotransmission?
reuptake!
Phenylephrine
Methoxamine
(receptor affinity)
alpha agonists
alpha1>alpha2»»»»»>beta
Clonidine
methylmorepinephrine
(receptor affinity)
alpha agonists
alpha2>alpha1»»»»»»beta
Norepinephrine (receptor affinity)
mixed alpha and beta agonists
alpha1=alpha2
beta1»beta2
epinephrine (receptor affinity)
mixed alpha and beta agonists
alpha1=alpha2
beta1=beta2
Does norepinephrine widen pulse pressure?
no
Why does epiniephrine widen the pulse pressure?
b/c of beta 2 receptors
dobutamine (receptor affinity)
beta agonists
beta1>beta2»»»>alpha
isoproterenol
beta agonist
beta1=beta2»»»alpha
Albuterol,
terbutaline
metaproterenol
(receptor affinity)
beta agonists
beta2»beta1»»»alpha
dopamine
dopamine agonist
d1=d2»beta»alpha
Fenoldopam
dopamine agonist
D1»D2
ACh and muscarinic receptors have inhibitory effect on…
adrenergic and enteric neuron terminals
NE and alpha2 receptors have inhibitory effect on…
adrenergic neuron terminals
alpha1 adrenergic receptors
metabotrophic
Gq
GDP–>GTP–>phospholipase C–>IP3–>Calcium!!!–>protein kinase activation
beta catechloamine receptors
Metabotrophic
stimulatory
Gs
–>GDP–>GTP–>adenylate cyclase–>cAMP–>protein kinease–>enzyme-PO4–>biologic effect
alpha2 adrenergic receptors
Metabotrophic
inhibitory
Gi
–>GDP–>GTP–>BLOCKS adenylate cyclase!!!
beta2 agonist effect on smooth muscle
relaxes
asthma treatment!
Ca channel blockers effect on smooth muscle
relaxes
COMT
catechol-O-methyl transferase
drug target
involved in catecholamine degredation/ synthesis
MAO
monoamine oxidase
drug target
involved in catecholamine degredation/ synthesis
Pheochromocytma
chromaffin tumors typically arising in adrenal glands secreting excessive catecholamines
how to diagnose pheochromocytoma
look for urinary catecholamine metabolites metanephrine and vanillylmandelic acid
L-DOPA
dopamine precursor
can be used in treatment of Parkinson’s
–b/c can cross blood brain barrier (unlike dopamine)
–give w/ inhibitors in the periphery (where we don’t want its effects)
MAOA inhibitors
block tyramine metabolism
- ->increased tyramine in blood circulation
- ->cheese rxn!! (must avoid many many foods)
Desensitization process
- G-protein coupled receptor
- drug ligand binds (dynamics of binding somewhat different than endogenous ligand)
- duration and extent of drug binding causes…
- accumulation of BETA-ARRESTINS
- Receptors taken down from cell surface into cell in vesicles
- fewer receptors means “less bang for the buck”
beta-arrestins
proteins involved in desensitization
Tachyphylaxis
“loss of activity” in relatively short space of time (tolerance to drug b/c of chronic, constant administration)
- -changes of metabolism
- -clonal expansion of resistant tumor
- -ect
what can stimulate glycogenolysis and gluconeogenesis in liver and why?
alpha1 and beta2 receptors in response to hypoglycemia
Why are beta blockers a problem for diabetics?
–nonselective beta blockers delay recovery from hypoglycemia in type 1 diabetics
–can interfere w/ counter-regulatory effects by blunting perception of hypoglycemic symptoms (tremor, tachycardia, nervousness)
Beta1-selective antagonist is preferred!
Pancreatic beta cells and insulin…
alpha2 activation significantly…
decreases insulin secretion
Pancreatic beta cells and insulin…
beta-2 activation…
inreases insulin secretion
The target tissue and insulin sensitivity…
beta receptor activation…
increases receptor sensitivity
The target tissue and insulin sensitivity…
beta-blockers
decrease insulin sensitivity
The target tissue and insulin sensitivity…
beta-blockers (vasodilating…3rd generation… drugs
increase insulin sensitivity in pts w/ insulin resistance
Hormone sensitive lipase…
non-selective beta-blockers…
lower HDL cholesterol and increase TGs
little effect on LDL and total cholesterol
alpha1 receptors involved in…
vascular tone
urethral tone
ejactulation process
maintaining contractile state of penile arteries
alpha1 receptor blockage can result in…
orthostatic hypotension
relieved symptoms of BPH
sexual dysfunction
persistent priapism
Why, when alpha1-receptors blocked by promethazine, does the blood pressure drop, but the heart rate is still able to increase?
the receptors blocked are dominant in vessels but not in heart
peripheral anticholinergic effects
no innervation of blood vessels, but there are still receptors
xerostomia caused by ACh inhibition in salivary glands
treatment of hypersalivation
blurred vision; cycloplegia; mydriasis
constipation (b/c inhibition of GI smooth muscle)
IBS
urinary retention secondary to decreased muscle tone
muscarinic agonist or AChE inhibitor
NO
vasodilator
GDP–>cGMP–>smooth muscle relaxation
Sidenafil (viagra)
vasodilator
inhibits cGMP break down to GMP
–>prolonged smooth muscle relaxation
what can blocking cholinergic and GABAergic pathways connected in hippocampus and basal forebrain complex do?
make us sleepy
Drugs w/ anticholinergic activity
1st generation antihistamines
antidepressants
etc.
Sumpathetic NS drugs
alpha-blockers beta-blockers centrally-acting drugs transmitter depleting drugs ganglionic blocking drugs
cardiotonic drugs
beta-agonists
alpha-agonists
muscarinic antagonists
