Adrenergic Pharmacology I Flashcards
Adrenoreceptor activating and other sympathomimetic drugs
drugs that mimic Epi or NE are sympathomimetic
SNS regulates
heart and peripheral vasculature
- especially in response to stress
- SNS stimulation mediated by release of NE
- NE and Epi (from adrenal medulla) activate adrenoreceptors
Direct acting agents
norepinephrine, epinephrin
-stimulate adrenoreceptors
Indirect acting agents
promote release of endogenous catecholamines
- displace stored catecholamines (amphetamine, tyramine)
- inhibit reuptake of catecholamines (cocaine)
alpha1 adrenoreceptors
- contraction of smooth muscle in peripheral vasculature- contraction of smooth muscle–> increased BP by increasing resistance
- PLC activation, stimulating polyphosphoinosotide hydrolysis, formation of IP3 and DAG
alpha2 adrenoreceptors
- most commonly found in NE releasing sympathetic post ganglionic neurons
- presynaptic autoregulation of neurotransmitter release
- inhibit adenylyl cyclase, decrease intracellular cAMP, decreases Ca so decreases ability to release catecholamines
beta 1 receptors
approximately equal affinity for Epi and NE
-heart
beta 2 receptors
higher affinity for Epi than NE
-smooth muscle relaxation
beta adrenoreceptors
- subtypes defined by affinity for Epi and NE
- found in vasculature, lung, eye and most other end organs
- activate adenylyl cyclase, increasing cAMP levels
Dopamine receptors
Also adrenergic receptors
- very important in brain and also splanchnic and renal vasculature
- D1 stimulates, D2 inhibits adenylyl cyclase
receptor responsiveness of adrenoreceptors
can have desensitization or denervation supersensitivity
Phenylethylamine
- parent compound (benzene ring with ethylamine side chain)
- when combined with a catechol (benzene ring with two hydroxyl groups) leads to dopamine (epinephrine and NE are modifications of dopamine)
Effect on CV
Affects blood vessels
- Alpha receptors increase arterial resistance (inc blood pressure)
- Beta2 receptors relax vascular smooth muscle (on some vascular beds to oppose contraction to increase capacitance)
- Skin and splanchnic vessel- predominantly alpha receptors (pure increase in resistance, ppl will turn white because of low blood flow to skin)
- Skeletal muscles- more beta2 receptors (not as much contraction, passive shift of blood flow and more blood goes to skeletal muscles than skin and viscera)
- renin secretion stimulated by beta1
Effect on Heart
Beta1 receptor activity dominates
- Opposing parsympathetic effects of vagus nerve, which is tonically active in heart
- Activation results in increased calcium influx in cardiac cells- positive inotrophy and chronotrophy
- AV conduction velocity increases, refractory period decreased
Effect on eye
- Alpha agonists- contract radial pupillary dilator muscle, which causes mydriasis; can slightly increase drainage of aqueous humor
- beta agonists- increase aqueous humor secretion (ciliary epithelium)- antagonists important in tx of glaucoma (esp open angle)
respiratory tract
- Beta2 receptors relax bronchial smooth muscle and increase airflow through lungs (rescue inhalers)
- alpha1 receptors in upper resp mucosa contraction produces decongestion
GI tract
- beta receptors on smooth muscles mediate relaxation
- alpha2 receptors on myenteric plexus- remove PNS tone
GU tract
alpha1- contract bladder base, urethral sphincter–> urinary retention
beta2 of bladder wall- relax smooth muscle–> urinary retention
Exocrine glands
alpha1 receptors on apocrine (stress glands)- sweating on palms, brow, upper lip
Metabolic effects
- SNS activity shift toward energy liberation and usage
- Beta3 receptor- inc lipolysis, enhances glycogenolysis, glucose relase, inc insulin secretion
- alpha2 receptor activation decreases insulin release
Epinephrine (adrenaline)
- potent vasoconstrictor (alpha1) and cardiac stimulant (beta1)
- pos inotropic and chronotropic actions on heart
- activates beta2 receptors
- mixed TPR, in some vessels inc venous capacitance (skeletal muscle)
Norepinephrine (noradrenaline)
Similar to epi on alpha1 receptors on heart
- similar potency at beta1
- little effect on beta2
- inc peripheral resistance
- inc both diastolic and systolic blood pressure
- compensatory vagal reflexes may lower heart rate but at high doses will directly increase heart rate
- alpha1, alpha2, beta1
Isoproterenol
- synthetic drug
- nonselective beta-receptor agonist (no alpha effects)
- positive chronotropic and inotropic actions
- inc cardiac output
- decrease both diastolic and MAP
- beta1, beta2
Dopamine
- endogenous catecholamines
- D1 receptors imp in renal vasculature
Dobutamine
- synthetic
- relatively beta1-selective and alpha1 selective
- inc MAP, PR, stimulates heart
Phenylephrine
-prototypic alpha1 agonist
-not a catechol derivative
not inactivated by COMT
-longer DOA than catecholamines
-nasal decongestant and cause mydriasis, can raise bp via alpha1 effect
Methoxamine
alpha1 selective
Ephedrine
First orally active sympathomimetic drug
Pseudoephedrine
- widely available OTC decongestant
- indirect effects of releasing endogenous NE
Oxymetazoline, xylometazoline
direct alpha1 agonists
- topical decongestants
- can lead to desensitization of the alpha1 receptors
Alpha2 selective agonists
- clonidine, methyldopa, guanfacine, guanabenz
- coupling of alpha2 receptors- (negative coupling) autoreceptor regulation of norepinephrine release
- decrease endogenoush catecholamine release
- Used as antihypertensives
- diminish SNS outflow
- can lead to orthostatic hypotension
Beta1 selective agonists
- dobutamine (also has alpha1 activity)
- Prenalterol- partial agonist
- Increase CO with less reflex tachycardia
- lack of beta2 stimulated venous dilation
Beta2 selective agonists
- albuterol, salmeterol, terbutaline, ritodrine, imp place in treatment of asthma
- uterine relaxation in premature labor (ritodrine)
Indirect sympathomimetics
amphetamines, methamphetamine, methylphenidate, cocaine, tyramine, ephedrine/pseudoephedrine (also direct)
Amphetamine
indirect sympathomimetic
- amplifies amt of NE released from adrenergic neuron terminal into synapse
- can inhibits or reverses activity of uptake1
- marked stimulant effects on mood and alertness, depressant effect on appetite, common drug of abuse
methamphetamine
similar to amphetamines, with higher CNS effect
Methylphenidate
amphetamine variant, used in ADHD
Cocaine
- local anesthetic
- sympathomimetic due to blockade of uptake1
Tyramine
- releases stored catecholamines
- found in high concentrations in fermented foods such as cheese
- MAO inhibitors potentiate effects
- can produce hypertensive crisis
Sympathomimetics- clinical applications
- conditions in which blood flow or pressure is to be enhanced (hypotension, hypovolemic or cardiogenic shock, cardiac insufficiency)
- conditions in which blood flow is to be reduced (local anesthetic will include epinephrine to contract vascular smooth muscle to reduce blood flow in that area so it isn’t washed away, reducing mucous congestion, heart block, cardiac arrest)
- heart failure (dobutamine, desensitization limits)
- bronchial asthma (bronchodilation by beta2)
- anaphylaxis
- fundoscopic examination of retina- alpha1 mydriasis
- premature labor (uterus relaxed by beta2 agonist)
- narcolepsy- amphetamines produce alertness
toxicity
related to extension of pharmacologic effects in CV and CNS
-htn, tachycardia, CNS- restlessness, tremor, insomnia, anxiety
