Wakade - Adrenergic Pharmacology III Flashcards
Receptors in the vascular beds of kidneys:
EPI/NE effects
ISO effects
Kidney: mostly alpha1 receptors
EPI/NE: vasoconstriction
ISO: slight vasodilation
Skeletal muscle receptors:
Results in:
Skeletal Muscle: alpha1 and beta2 receptors
Can result in vasoconstriction or vasodilation, depending on the sympathomimetic amine used and its concentration
Skeletal muscles:
NE and PE: only act on
Effect of concentration of EPI
NE and PE: only act on alpha1 R –> only cause VASOCONSTRICTION
EPI gives vasodilation at lower concentrations, but vasoconstriction at higher concentrations.
Effects of ISO on skeletal muscle vasculature
Over wide range of ISO there is only vasodilation (beta2).
Attraction of EPI to alpha and beta receptors in skeletal muscle vasculature.
Effects
Apparently EPI has higher affinity for beta-than for alpha-receptors here, but as beta receptors become “saturated” at higher concentrations of agonist, action mediated by alpha-receptors dominate and results in vasoconstriction.
Receptors types in liver and splanchnic areas:
Effects of low vs high EPI:
Liver and Splanchnic Area: alpha1 receptors (and a small beta R component)
Low [EPI]: some vasodilation
Higher [EPI]/NE: good vasoconstriction
Coronaries:
Type of receptors:
NE/EPI/ISO effects:
Important Point
What does increased stimulation of the heart cause?
Coronaries: beta2 receptors
NE/EPI/ISO: dilation of blood vessels (partly due to action on beta2 R)
Important Point: dilation of the coronaries by these amines only PARTLY due to action on beta2 receptors
When heart is stimulated (ie. exercise), increased mechanical activity causes vasodilation by action of ADENOSINE on smooth muscle
Pulmonary Circulation: type of receptors
Effects of EPI/NE
o Pulmonary Circulation: alpha and beta receptors are both dominant
EPI/NE: some vasoconstriction, but weak compared to that in other organs
Vascular beds of the pancreas:
Receptor types in alpha cells:
Beta cells:
Alpha cells: betaR –> stimulation of secretion of glucagon
Beta cells: alphaR –> inhibition of insulin secretion
Low [EPI] effects on blood pressure:
Systolic effects
Diastolic effects
Change in blood pressure
Systolic increase: due to increase in CO
- CO increase: due to ↑ venous return + ↑ force of contraction
Diastolic decrease: decrease in TPR
- TPR decrease: beta2 activation vasodilation in skeletal muscles
Mean BP: small increase or no change
High NE/[EPI] effects on blood pressure:
Systolic effects Diastolic effects Change in CO Eventually what happens? - Give atropine: - Cut vagus
Systolic increase: due to ↑ TPR and ↑ force of contraction
Diastolic increase: ↑TPR
o TPR increase: alpha1 activation –> vasoconstriction in skeletal muscle
CO: only slightly changed or even decreased (HR not increased for long)
o Initial ↑ in HR (stimulation of pacemaker cells by NE)
Eventually, vagus stimulation –> release of ACh –> ↓HR
- Give atropine (AChR blocker): no decrease in HR
- Cut vagus: no decrease in HR
Isoprenaline (ISO) effects on blood pressure:
Systolic effects Diastolic effects TPR effects If vasodilation is too extreme: Effect on mean BP
Some systolic increase: due to ↑ force of contraction (beta1 stimulation of heart)
Large diastolic decrease: due to ↓ TPR
TPR decrease: beta2 activation –> vasodilation in skeletal muscle
Important point: if vasodilation is too extreme, blood may pool in capacitance vessels and ↓ venous return –> ↓ CO
Mean BP: decreased
Broncial smooth muscles:
Receptor types:
How to bronchodilate:
Bronchial: beta2 receptors
Bronchodilation: use of agonists in asthma
Iris Radial Muscle smooth muscles:
Receptor types:
How to contract radial smooth muscles:
Iris Radial Muscle: alpha1 receptors
Contraction of radial smooth muscles: mydriasis (dilation of pupil)
GI tract smooth muscles:
Receptor types:
Causes:
Exception:
GI Tract: alpha1 and beta2 receptors (both cause inhibition*)
Both cause relaxation
Activation of alpha1 R causes hyperpolarizaion –> prevents APs from firing
Exception: sphincters (stimulation of alpha1 R causes contraction)
Bladder smooth muscles:
Receptor types:
What is dominant in detrusor?
What is dominant in trigone?
Bladder: beta2 and alpha1 receptors
Beta2 R: dominant in detrusor muscle –> activation causes RELAXATION
Alpha1 R: located in trigone region –> activation causes CONTRACTION
Uterus:
Receptor types:
NE stimulates:
EPI stimulates:
Specific beta2 agonists:
Uterus: alpha1 and beta2 R
NE: stimulates contractions
EPI: biphasic effects
Specific beta2 agonists: cause relaxation (used in delaying premature labor)
Spleen:
Receptor types:
Contraction results in:
Spleen: alpha1 receptors
Contraction: results in blood expulsion
Vas Deferens and seminal vesicles:
Receptor types:
Contraction results in:
o Vas Deferens and Seminal Vesicles: alpha1 receptors
Contraction: alpha1 activation causes membrane depolarization and generation of AP –> expelling of contents
Metabolic effects of Beta-R Activation
Beta R Activation: in ALL tissues discussed, activation associated with an ↑ in synthesis of cAMP
Beta R Activation
Results in: (4)
Hyperglycemia
Hyperlactemia
Increase in free fatty acids
Overall increase in calorigenic effect
Beta R Activation
Increase in cAMP leads to activation of: (2)
Increase in cAMP leads to activation of protein kinases, which:
Activate lipases (break down triglycerides to glycerol and FFAs, which can enter the Kreb’s cycle to increase production of ATP)
Activate phosphorylases (help break down glycogen to glucose to form ATP)
Direct Acting Sympathomimetic Amines (NE/EPI) and the BBB:
Do NOT CROSS the BBB readily
CNS effects of EPI: (3 manifestations)
EPI: when given systemically, may cause CNS manifestations
- Respiratory stimulation (or apnea of BP rises rapidly)
- Restlessness
- Anxiety
CNS effects of NE
NE: may also produce the same CNS manifestations as EPI, but to a LESSER degree
Note: not clear if these effects result from action in the CNS or as the indirect result of systemic effects
Effects of Adrenergic Neurons in the Brain:
Neurons containing NE located in:
Adrenergic Neurons in the Brain:
Neurons containing NE located in locus cereleus
Presence of adrenergic receptors and NET have also been confirmed
Role of Adrenergic Transmission in the Brain: many possibilities, including the following: (4)
Modulating mood
Sleep-wake cycle
Motivation
Pain
INDIRECT ACTING SYMPATHOMIMETIC DRUGS:
General:
Indirect acting agents: (4)
Mechanism: Stimulate what? Cause release of NE from: Ca req? DBH?
Indirect Acting Agents:
o Phenylethylamines: tyramine, amphetamine and ephedrine
o Dopamine: recall indirect effects
Mechanism:
o Do not directly stimulate adrenergic receptors
o Cause release of NE from SS neurons via a non-exocytotic process (diffuses out)
Ca++ not required
DBH and other synaptic vesicle contents not released along with it
Tyramine:
Effects;
Mechanisms:
Source:
Issue with MAO-Is
BBB
Effects: dose-dependent increase in BP, HR and other effects mimicking NE (last several minutes)
Mechanism:
o Tyramine enters adrenergic neurons via NET
o Enters synaptic vesicles in nerve terminal and displaces NE –> Diffuses out of nerves
o Delays oxidation of NE by MAO (also a substrate for it) –> Also causes diffusion out of nerves
Source:
o Occurs naturally in aged cheeses and wines (product of decarboxylation of tyrosine)
- Normal Metabolism of Tyramine:
o Ingested into gut –> Oxidized by MAO in the gut mucosa and liver
Issue with MAO Inhibitor Drugs:
o Tyramine taken in orally –> Not oxidized in the gut –> Effects potentiated and large amounts of NE released –> Hypertensive crisis
Does NOT cross the BBB*
Amphetamine and Ephedrine:
Mechanism/difference from tyramine:
BBB
Duration
Mechanism: similar to mechanism to tyramine
o Major Difference: have a high affinity for MAO but are NOT metabolized by it (presumably due to branched chain)
- Ingestion NOT inactivated in GI tract –> Accumulate in adrenergic nerves
Cross the BBB: produce CNS arousal by releasing NE and/or DA
Duration of Action: several hours
Amphetamine and Ephedrine:
Effects: on CV and smooth MM: CNS effects: Acute overdose: Chronic overdose:
Tachyphylaxis:
CV and Smooth Muscle: similar to NE
CNS Effects: restlessness, tremor, reduction of fatigue, loss of appetite
Acute Overdose:
CNS: severe confusion and anxiety
CV: increased BP, angina, cardiac arrhythmias
Chronic Overdose: can produce psychotic behavior
Tachyphylaxis:
o Chronic administration may lead to development of tolerance for some autonomic effects
o Occurs due to gradual depletion of NE stores, resulting in a decrease in the release of NE
Endogenous stores being depleted with no chance to regenerate
Difference Between Amphetamine and Ephedrine:
Very similar, except ephedrine also has minor direct agonist effects on adrenergic receptors
Ephedrine is no longer used in the US
Former use: management of asthma and to dilate pupils
Pseudoephedrine: isomer that is used as an OTC decongestant
Antihypertensive Agents:
- General:
Most important use:
Interferes with:
Lower SS tone:
Most important use of adrenergic drugs in the management of high blood pressure disease
Interfere with sympathetic neurotransmission at different steps
Reduce release/action of NE to lower SS tone in vascular smooth muscle and heart
Actions lead to fall in BP
Alpha-Methyl Tyrosine:
Historical use:
Mech:
former uses:
Side Effects:
Historical importance only: no longer used
Mechanism: specific inhibitor of tyrosine hydroxylase enzyme
Former Uses: pheochromocytoma (catecholamine releasing tumor of chromaffin cells) prior to removal of tumor
Side Effects: had to use extremely high doses that crystallized in the kidney tubules, causing damage
Adrenergic receptors responsible for inducing mydriasis are:
alpha 1
Which one of the following ranks of order of potencies of adrenergic drugs in the heart is correct A. EPI>NE>ISO>>PE B. NE>>PE>ISO>EPI C. ISO> EPI>>PE>NE D. ISO>EPI>NE>>PE
C. ISO> EPI»PE>NE
Which one of the following compounds will NOT produce increase in force of contraction of the heart in a heart–transplanted patient. A. NE B. EPI C. Tyramine D. ISO E. excess cAMP ( cell permiable form)
C. Tyramine
Which types of adrenergic receptors are associated with inhibition or relaxation of intestinal smooth muscle? A. Beta1 B. Beta2 C. Alpha1 D. Alpha2 E. Alpha1 plus Beta2
E. Alpha1 plus Beta2
Reserpine:
Mech:
Other effects:
Mechanism:
Progressive loss of tissue NE stores by influencing NE storage:
Reserpine irreversibly blocks the vesicular monoamine transporter (VMAT)
Blocks NE carrier of synaptic vesicles (blocks NE transport and permits NE to accumulate in cyosol where it is metabolized by MAO)
May block DA transport into synaptic vesicles, impairing the synthesis of NE in the ANS and depleting DA from the brain
Other Effects:
Depletes 5HT from serotonergic neurons
Depletes histamine from platelets
Reserpine:
Effects:
Duration:
Use:
SEs:
Effects: most pronounced in neurons that are very active
Duration: irreversible (can persist for longer than 1 week after the last dose)
Use: one of first drugs for essential hypertension
Although rarely used, some doctors will still use it in low combinations with a diuretic for the treatment of HTN
Side Effects: PS function not impaired, so SE profile can be predicted
Miosis
Hypersecretion (salivation, gastric secretions etc.)
Hyperperistalsis and diarrhea
Bradycardia and hypotension
Severe emotional depression in tremors (CNS effects)
Guanethidine:
Mechanism:
blocks
taken up by
method of exocytosis
Chronic use:
Use:
Mechanism: blocks exocytosis of NE vesicles
Taken up by NET transporter
Method of exocytosis block unclear (does not interfere with Ca++)
Chronic Use: can lead to reduced NE storage similar to reserpine
Use: formerly used for management of severe essential HTN
Lowered BP, HR and renin secretion
Similar SE profile to reserpine with marked postural hypotension
No longer used in the US
Guanethidine has 3 distinct pharmacological actions in adrenergic synapse:
- Enters sympathetic
neurons and blocks transmission (acute). - Blocks NE membrane transporter, NET (acute).
3.Reduces NE stores (chronic).
Clonidine:
Mechanism:
Acts on:
Use:
Mechanism: highly specific agonist of alpha 2 receptors
Acts on presynptic alpha2 receptors to decrease SS outflow
Also acts on imidazoline R to decrease SS outflow (activation in rostral ventrolateral medulla causes reduction in SS outflow to periphery)
Use:
Essential HTN
Diarrhea (?)- asked on discussion board
Diabetic neuropathy
Narcotic and alcohol withdrawal (analgesic effects)
Quit smoking
Reduce menopausal hot flashes
Comparison of receptor binding with: Clonidine Alpha-methyl NE NE phenylephrine
clonidine (alpha 2 receptors) > alpha- methyl- NE> NE> >»_space; phenylephrine (alpha 1 receptors)
Clonidine:
Side effects:
Sudden withdrawal:
o Side Effects:
Common: dizziness, nausea, impotence, dry mouth
Sudden Withdrawal: can be life-threatening
Over-activity of SNS causing a hypertensive crisis
Symptoms include nervousness, headache, tachycardia, HTN, sweating etc.
Clonidine Related Agents and Their Uses:
Apraclonidine and Brimonidine: reduce intraocular pressure (glaucoma)
Dexmedetomidine and Tizanidine: analgesic effects and help in withdrawal symptoms from addictive drugs and alcohol
Other alpha 2 agonists: Treat HTN, ADHD and PTSD
Methyldopa:
Enters CNS and is metabolized as:
Binds:
Alpha-CH3-NE is stored in:
interaction with imidazoline-R:
Overall effect:
Use:
Mechanism: similar to clonidine
Alpha- CH3 - DOPA—-> Alpha –CH3- DOPAmine–> Alpha- CH3- NE—> Binds Alpha 2 receptors
Alpha-CH3-NE stored in adrenergic neurons and released the same way NE is, but due to its high affinity for alpha2 receptors, will bind them and cause a reduction in SS activity
Unlike clonidine, has poor activity at imidazoline R
Overall Effect: reduce SS nerve impulse activity originating in the area of the nucleus tractus solitarus of the medulla by activation of these alpha2 receptors
- Also reduces renal vascular resistance
Use: hypertension
TCAs
imipramine, desipramine, amitryptyline
Imipramine and Desipramine
Block:
Enhance:
Desipramine is the most potent inhibitor of:
Imipramine and Desipramine: block neuronal membrane transport (NET) and ENHANCE action of NE
Desipramine is the most potent inhibitor of NET; also a weak inhibitor of 5HT transporter
Amitryptyline:
Inhibits transport of both 5HT and NE equally well (20x less potent than desipramine)
Cocaine:
Mechs
Low concentrations:
High concentrations:
Low Concentrations: reversibly binds to NET in CNS and periphery to block uptake of NE and EPI Marked enhancement in responses of NE and EPI
High Concentrations: local anesthetic actions (blocks conduction of nerve impulses)
Amphetamines:
Use:
Acute overdose:
Narcolepsy
ADHD (Methamphetimine/Ritalin, dextroamphetime/Dexedrine, Adderall)
Effects: causes CNS arousal and suppresses appetite and sleep
Acute overdoses produce severe confusion and anxiety, elevated B.P., angina, cardiac arrhythmia and other adrenergic effects.
