ANS Pharmacology Flashcards
Autonomic nervous system
Smooth muscle
Cardiac muscle
Exocrine glands
Adrenergic receptors
Catecholamine
Epi, adrenaline, norepinephrine, noradrenaline
Adrenergic neuron, Adrenergic synapse, Catecholaminergic neuron, Catecholaminergic synapse, Adrenergic receptors
Adrenoreceptors
Cholinergic receptors
Acetylcholine
Cholinergic neuron, Cholinergic synapse, Cholinergic receptors
Cardiac response to adrenergic receptors
Inc heart rate
Inc contractility/conduction
Inc AV conduction
Inc ventricular contractility
Cardiac response to Cholinergic receptors
Dec heart rate
Dec atrial contractility
Dec AV conduction
Dec ventricular contractility
Anatomy of sympathetic nerves
Short preganglionic neuron
Long postganglionic neuron
Anatomy of parasympathetic neurons
Long preganglionic
Short postganglionic neuron
Anatomy of somatic neuron
One neuron
Transmitter at somatic neuron
ACh
Transmitter at sympathetic neurons
Preganglionic - ACh
Postganglionic - NE
(EXCEPTION —> ACh in sweat glands**)
Sympathetic ONE NEURON system (i.e. exception)
Adrenal medulla - direct release of Epi/NorEpi
Transmitter at parasympathetic neurons
Preganglionic - ACh
Postganglionic - ACh
Biochemistry of Catecholamine synthesis
Synthesis in adrenergic nerve terminals
Rate limiting step: tyrosine hydroxylase
Feedback (end product) inhibition - norepi
Dopamine —> norepi —> (in adrenal) epi
Synthesis of epinephrine
In adrenal medulla w/in chromaffin cells (vesicles 80% EPI, 20% norepi)
Whole process occurs in adrenal gland —> same scheme as NorEpi, but final reaction to produce EPI
NE (last step in vesicle) —> EPI conversion in cytoplasm by PNMT (transported back into vesicles for release)
PNMT
Not found in nerve terminals
Converts norepi to epi in ADRENAL MEDULLA
Uptake of norepi vs epi
Active re-uptake of NE in neurons
Epi NOT re-uptake in adrenal gland
Release of Catecholamines from adrenal gland
Stimulation of preganglionic fibers —> release of ACh onto chromaffin cells —> direct release of EPI/NE into blood stream
Mechanism of synaptic transmitter release
Nerve depolarizes —> voltage-gated Na/Ca channels open —> Ca dependent vesicle fusion / exocytosis —> diffusion of NT into synaptic cleft —> receptor binding/activation —> NT action termination / metabolism
Transporters at the synapse
Vesicular monoamine transporter (brings NE into vesicles)
Presynaptic Autoreceptor (feedback inhibition)
Plasma membrane transporter (re-uptake)
Fate of catecholamines after uptake
- reuptake into vesicles
- metabolized (MAO, COMT)
Monoamine oxidase (MAO)
Norepinephrine in cytoplasm degraded by MAO (in outer membrane of mitocondria in nerve terminal)
Competition between vesicle uptake + MAO degradationi
Catechol-o-methyl transferase (COMT)
Located in SYNAPTIC CLEFT
In liver
Metabolizes norepinephrine —> excreted in urine
Receptors for catecholamines
7TM Receptor structure (GPCR)
Adrenoceptors
Stimulate cardiac ionotropy, vascular muscle contraction, skeletal muscle tremor
Relax urinary bladder muscle, uterine muscle, bronchiole muscle
Drug affinity
How tightly a compound binds a receptor
Measured experimentally by a “saturation binding isotherm”
Kd = concentration that compound occupies 50% of receptors at equilibrium
Agonist
Ligand that activates receptors
Antagonist
Ligands that block activation of receptors by cognate agonist
Efficacy
Intrinsic activity of an agonist
maximal amount of system stimulation achievable in presence of saturating concentration of agonist
Potency
Described by EC50
Concentration of drug that results in 50% maximum stimulation
“Rank order” of potency
Comparison of compounds by their EC50
Partial agonist
Does not reach the same maximum response of a full agonist
Potency vs Efficacy
Shifted left —> more potent
Shifted up —> more efficacious
How does activation of adrenergic receptors have different effects in different tissues?
- Relative affinity/potency of amine in activation of alpha or beta receptors
- Density/ratio of receptor type/subtype
- Autonomic tone of organ
- Reflex that organism makes in response to response to Catecholamine action
Adrenergic receptors in the heart
No alpha receptors in atria/ventricles
Beta response —> inc HR, inc conduction velocity, dec refractory period, incr contractility (beta1 receptors)
Cutaneous blood vessel adrenergic receptors
No beta receptors
Alpha receptors —> vasoconstriction
Skeletal muscle adrenergic receptors
Both alpha and B2 receptors (constriction, dilation, respectively)
Interaction of EPI with B2 and a1 receptors
Higher affinity for B2 than a1, but more a1 receptors
At low dose epi: B2 bound - relaxation dominates
At high dose epi: a1 also bound - contraction dominates
Distribution of adrenergic receptors
Heart - beta only
Vessels (skeletal muscle) - a + b
Bronchioles - beta only
GI - a + b
Urinary bladder - trigor/sphincter a only
Eye - radial muscle a; ciliary muscle b
Metabolism - beta (O2 consumption, glycogenolysis, lipolysis)
How activation of adrenergic receptors has different effects in tissues
- Relative affinity/potency of amine in activation of alpha or beta receptors
- Density / ratio of receptor type and subtype in organ
- Autonomic tone of organ
- Reflex (homeostatic adjustment) in response to Catecholamine action
Autonomic tone on blood vessels
Sympathetic autonomic tone predominates
Vasoconstriction with norepi —> antagonist causes vasodilation
Arterioles
Sympathetic tone
Adrenergic receptors
Vasoconstriction
Block: vasodilation/hypotension
Heart
Parasympathetic tone
Cholinergic receptors
Bradycardia (response)
Block: tachycardia
Sweat glands
Sympathetic tone
Cholinergic receptors
Response: hidrosis
Block: anhidrosis
Administration of beta-blocker to healthy human - effect on heart
No significant change
Heart predominated by parasympathetic —> under basal conditions, little NE effect (therefore an antagonist to NE has little effect)
Administration of muscarinic anatongist to normal person - effect of atropine (ACh receptor blocker)
Increase HR
ACh keeps heart rate down by Cholinergic receptor; administration of antagonist will result in tachycardia
Baroreceptor (vagal) reflex
Slows the heart and dilates blood vessels to decrease BP
Baroreceptors detect pressure increase and signal compensatory pathways to decrease BP
Rank order of potency against alpha adrenergic receptors
EPI >= NE > DA»_space; ISO
Rand order potency of beta adrenergic receptors
ISO > EPI >= NE > DA
Isoproterenol
Non-selective beta agonist
Beta1 and beta2
Low does EPI
Beta effects predominate
Norepinephrine activity
Poor activation of B2
Increase HR + force of contraction with no change in vascular resistance
Increase BP
Vasodilation of blood vessels with no change in cardiac output
Decreases BP
Response to alpha1
Vasoconstriction
Response to B1
Inc HR, Inc force of contraction, Inc CO
Response to B2
Vasodilation
Low dose Norepinephrine
Activates B1 in heart —> ^ HR, FC, CO
Activate a1 in vessels —> vasoconstriction —> ^ peripheral resistance
Vagal reflex —> initial increase in BP —> activates reflex —> decrease HR (via ACh)
*** force of contraction still high bc no effect of ACh on ventricles
Low dose epinephrine
Activates B1 in heart —> ^ HR, FC, CO
Activates B2 in vessels —> vasodilation —> dec peripheral resistance
No significant increase in BP —> no vagal reflex
^ HR, FC, CO
High dose epinephrine
Looks like low or high norepi
If concentration high, bind both beta (relaxation) and alpha (contraction) receptors —> overall vasoconstriction
Alpha1 predominate in vasculature —> vasoconstriction
Isoproterenol (low or high dose)
Activates B1 in heart —> ^ HR, FC, CO
Activates B2 —> vasodilation —> dec peripheral resistance
Mean BP unchanged - no vagal reflex
(Looks like low dose epi)
Dopamine
Neuro modulator in CNS
Precursor to NE/EPI synthesis
Highest affinity for DA receptors; but some for a1, a2, b1; really low for b2
Low conc —> activates a1,a2,b1
High conc —> activates a1,a2,b1,someb2
Low vs high DA ~ low vs high EPI
Low dose dopamine
Minimal b1 activation in heart —> ^ HR, FC, CO
No activation of B2
Minimal activation of a1 —> minimal vasoconstriction
Significant D1-mediated vasodilation of mesenteric, renal, coronary vascular bed (peripheral resistance dec)
No vagal reflex
High dose EPI
Activation of B1 in heart —> ^ HR, FC, CO
Significant activation of a1 —> vasoconstriction / inc peripheral resistance
A1 overcomes D1 mediated vasodilation
Vagal reflex —> dec heart rate
Alpha1 adrenergic agonists
Phenylephrine (nasal decongestant)
Oxymetazoline
Tetrahydrozoline (eye redness)
No action on heart
Vasoconstriction (a1 on vessels) —> inc peripheral resistance —> vagal response (slows HR)
Long duration (poorly metabolized by MAO, COMT)
Alpha2 adrenergic agonists
Activation of presynaptic a2 autoreceptor —> dec in NE release from neurons
Activate a2 autoreceptors in CNS —> dec sympathetic outflow to periphery
Stimulate postsynaptic a2 receptors in periphery on VSMC (vascular smooth muscle cell) —> vasoconstriction —> inc BP
Clonidine, xylazine
Potential side effect of a2 adrenergic agonists
Activation of a2 in certain vascular smooth muscle cell beds —> vasoconstriction —> inc in blood pressure
Use of a2 adrenergic agonists
Antihypertensive medications (originally nasal decongestant —> but caused hypotension)
Clonidine
Initial hypertensive effect —> reverses to hypotension (biphasic response)
- activation of a2 on VSMC > transient hypertensive phase
- a2 activation in Brainstem > dec in sympathetic tone > dec in BP
- a2 on peripheral nerves > vascular smooth muscle vasodilation
Xylazine
Analgesia / sedation
CNS-located a2 receptor-mediated
Rebound phenomenon
Abrupt withdrawal of medication —> condition even worse that before treatment
Fast withdrawal of a2 agonist > rebound hypertension
Fast withdrawal of a1 agonist > rebound nasal congestion
Continued use > downregulation of receptors > if stop, regular release of NT, but fewer receptors > increased response
Nonselective beta adrenergic agonist
Isoproterenol
Selective for beta over alpha
Activity b1=b2
Cardiac stimulation - b1
Bronchodilator - b2
B1 adrenergic agonist
Dobutamine (chiral; d - b1 agonist; l - some a1 agonist)
Increases force of cardiac contraction; minimal impact on HR —> DOES NOT inc O2 demand on heart
Short term treatment of heart failure
B2 adrenergic agonists
Albuterol, metaproterenol
B2-specific at low dose; increase b1 as increase dose (spillover)
Inc bronchodilation, smooth muscle relaxation
Asthma, prevent premature labor (uterine smooth muscle)
B3 adrenergic agonist
Treatment of obesity?? - receptors in brown adipose tissue (fat metabolism) - effective in mice, not humans
Overactive bladder treatment (myrbetric)
Indirect sympathomimetics
Transported into nerve terminals (plasma membrane transporter)
Increase release of endogenous catecholamines
DOES NOT induce release of EPI from adrenal gland (no plasma membrane Catecholamine uptake transporter)
Also bind directly to adrenergic receptors
Tyramine, amphetamines, ephedrine
Catecholamine reuptake blockade
Cocaine, imipramine, amitryptyline
Competitively block reuptake of NE from synaptic cleft > inc conc/time NE in cleft
Ephedrine
Sympathomimetic
Release of endogenous NE + direct binding to adrenergic receptors
Not degraded by MAO/COMT > long duration
Inc BP, dec bladder sphincter incompetence, inc bronchodilation
Side effects: hypertension, cardiac arrhythmia
Related to ephedrine
Phenylephrine
Pseudoephedrine
Mechanisms of adrenergic neuron blocking agents
Blockade of transmitter release
Vesicular storage blockers
False transmitter release
NE synthesis blockade
Guanethidine
Accumulates / replaces NE in vesicle, but no transmitter activity; doesn’t cross BBB - no CNS NE effect
Triphasic effect > used as anti-hypertensive
Blockade of transit terminal release
Guanethidine
Bretylium
Clonidine
Bretylium
Blocks NE release from terminal (doesn’t accumulate or replace)
DOES NOT cross BBB; no CNS effect
Not affect EPI from adrenal
Clonidine
A2 agonist > stimulates presynaptic autoinhibitory receptor
Decrease NE release
Antihypertensive
Vesicular storage blockers
Affect Vesicular transporter (VMAT)
Reserpine
Reserpine
Vesicular storage blockage
Does NOT require trasnporter
Prevents accumulation of NE in vesicles (blocks uptake of DA/NE into vesicles by VMAT)
Extracytoplasmic NE degraded by MAO > dec amount of NE
Can dec EPI storage in adrenal, but lesser degree
Long acting horse tranquilizer
False transmitter release
Alpha-methyl-DOPA > taken up and converted to a-methyl-NE
Transporter NOT required
a-methyl-NE > weak/low affinity for a1 receptors —> when release in place of NE, dec activity
May have some a2 activity
Antihypertensive
Norepinephrine synthesis inhibition
Alpha-CH3-p-tyrosine : blocks tyrosine hydroxylase; depletes NE stores (Try > DA conversion)
NE (end product inhibition)
Disulfiram : blocks BbetaH enzyme (DA > NE conversion)
Blockade of Catecholamine metabolism - MAO inhibition
Monoamine oxidase inhibitor - pargyline, moclobemide
Inc in NE stored for release
Blocks deg ration of DA/serotonin in CNS
**need to be careful of tyramine (wine/cheese) intake > lack of metabolism by MAO > hypertensive crisis
Blockade of Catecholamine metabolism - COMT inhibition
Tolcapone
NO clear pharmacological action attribute to COMT blockade
Direct adrenergic receptor blockade
Antagonists - block binding / action of receptor agonists
Uses of alpha-adrenergic receptor blockade
Hypertension
Congestive Heart failure
Peripheral vascular disease
Benign prostatic hyperplasia
Shock
Irreversible alpha receptor blockers
Dibenamine
Phenoxybenzamine
Covalently alkylate receptor
Slow onset, long duration
Recovery requires de novo receptor synthesis
Dec peripheral resistance > hypertension treatment
Reversible alpha receptor blockers
Phentolamine
Non-selective for a1 / a2
Short acting block
Dec peripheral resistance > treat hypertension
Can illicit cardiac complication (block presynaptic a2 NE release)
Selective a1 blocker - prazosin
Prazosin
Reversible, specific/selective a1 blocker
Decrease a1 receptor mediated vascular tone
Does NOT inc NE release
Dec BP with no cardiac tachycardia
Hypertension therapy
Selective a1 blocker - tamsulosin
Reversible postsynaptic a1a blocker
NOT for antihypertensive therapy
Genitourinary tract targeting > improve urination in men with benign prostatic hyperplasia
Selective a2 blocker - yohimbine
Reversible specific a2 blocker
Inc NE release from nerve terminals, no significant direct effect on smooth muscle
Used for reversal of xylazine-induced sedation/analegsia
Side effects of a receptor blockade
Postural hypotension
Reflexive tachycardia
Nasal stuffiness
Increased GI motility
Therapeutic uses of beta blockers
Cardiac arrhythmias
Hypertension
Prophylactic (angina/ischemia)
Anxiolytic
Glaucoma
Non-selective b-blockers
Propranolol
Pin do lol
Timolol
Propranolol
Non-selective beta-blocker
Dec HR, contractility, CO
Membrane stabilization effect at high doses (block impulse conduction in cardiac tissue)
Significant withdrawal/rebound —> upregulation of B1 receptors —> if blocker removed, increased activity due to increased receptors
Pindolol
Non-selective beta blocker
Less membrane stabilization effects
Partial agonist —> less withdrawal, less reduction in HR
High doses can inc HR, BP, cause bronchodilation
Timolol
Non-selective beta blocker
Less membrane stabilization
Used for wide angle glaucoma
Selective B1 blocker
Metoprolol
Cardioselective
As potential as propranolol on B1, but 100x less on B2
Selective B2 blocker
But o amine
Selective for blocking smooth muscle contraction
No pronounced cardiac effects
Side effects of beta blockers
Cardiac failure
Bradycardia
Bronchial asthma
Diabetics using oral hypoglycemics —> block compensatory mechanism of oral hypoglycemic —> hypoglycemic shock
