Pharmacology Exam III Content

1) phenoxybenzamine (PBZ) 2) phentolamine

1) ______________: α-nonselective antagonist which is IRREVERSIBLE (long-acting) and NON-COMPETITIVE 2) ______________: α-nonselective antagonist which is REVERSIBLE (short-acting) and is COMPETITIVE

1) pseudoephedrine - mainly just a direct agonist on adrenergic receptors (alpha-1 and beta-1 receptors), but also inhibits NET; is present in OTC medications, 2) methylphenidate and dexmethylphenidate - are also direct agonists on adrenergic receptors (only alpha-1 receptors), but in addition are "amphetamine-like" since they inhibit BOTH NET and DAT (unlike pseudoephedrine)

"mixed mechanism" drugs are drugs that act both directly and indirectly: methylphenidate and dexmethylphenidate, and pseudoephedrine 1) directly, they act as agonists on adrenergic receptors this includes ___________, which is present in OTC medications 2) indirectly, they can cause release NE and DA (in this way, they're known as "amphetamine-like compounds") these include _________ and __________, which, like amphetamines, are schedule II-class drugs that have a high potential for abuse

phenelzine selegiline entacapone carbidopa

(4) enzyme inhibitors

PBZ and phentolamine effects: 1) vasorelaxation results in a compensatory tachycardia response 2) increased NE release also results in tachycardia ***so, tachycardia from these drugs is induced via 2 separate mechanisms, which is serious*** 2) used preoperatively for pheochromocytoma surgery to avoid hypertension

1) phenoxybenzamine (PBZ): IRREVERSIBLE (long-acting) non-competitive antagonist non-competitive: means that increasing the amount of agonist doesn't reverse the antagonism 2) phentolamine: REVERSIBLE (short-duration, meaning fast onset and fast offset) effects (both): 1) vasorelaxation leads to decreased total peripheral resistance (TPR) and a decreased blood pressure (due to α1 effects) that triggers a compensatory _________ response, increasing CO and heart rate 2) increased NE release from nerve terminals (due to α2 effects), which in-turn stimulates β1-receptors in the heart, also contributing to __________ because of this dual-mechanism tachycardia, their therapeutic use is limited: 1) they're mostly used in cases of emergency, such as a hypertensive crisis associated with catecholamine excess, such as with MOAi use or the abrupt interruption or withdrawal of clonidine (an α2-agonist) 2) used preoperatively for ____________ surgery to avoid hypertension (since, during surgery, there's a high probability of rupture of the adrenal tumor, containing lots of catecholamine, which would cause an abrupt increase in blood pressure and a potential hypertensive crisis) 3) can also treat vasoconstriction and vasospasms in the extremities, such as with the fingers (Raynaud's syndrome)

MAO-A - breaks down all catecholamines MAO-B - breaks down dopamine preferentially

MAO: general information: when catecholamines [note: we're referring to NE, DA (dopamine) and 5-HT (serotonin, which isn't specifically a catecholamine)] are being taken back up into the presynaptic membrane (during reuptake), they are inactivated, being degraded by MAO, before being stored in vesicles however, if MAO is inhibited, these neurotransmitters (catecholamines) simply return to the vesicles to be stored without degradation, ready to be released upon depolarization of the neuron MAO exists in 2 isoforms: MAO-A and MAO-B; MAO-A is not selective, so it breaks down ALL of the catecholamines, but MAO-B preferentially breaks down _________

dobutamine: more selective to β1 receptors than dopamine drug of choice for cardiogenic shock

dobutamine: like dopamine, is also only used in emergency situations via IV, and is also very short-acting it's (more/less) selective to β1-receptors than dopamine, and doesn't stimulate dopaminergic receptors therapeutic indications: 1) increase heart contractility 2) may see some action on α1-receptors to cause a small degree of vasoconstriction IMPORTANT: it's the drug of choice for ______________ different to dopamine: 1) doesn't cause vomiting 2) doesn't increase renal and mesenteric blood flow

dry mouth (also called xerostomia) dry mouth is a common side effect of drugs that treat depression; anti-muscarinic effects like these are also known as atropine-like effects, since atropine is an anti-muscarinic

TCAs: (tricyclic antidepressants) adverse effects: excess catecholamine (NE) and serotonin, due to their main mechanism of action, results in: 1) in the CNS: confusion and hallucinations, due to their anti-muscarinic effects 2) in the PNS: 2.1) postural hypotension (due to their anti-α1-receptor effects) 2.2) atropine-like effects (due to their anti-muscarinic effects), which includes tachycardia, urinary retention, and __________ note: anti-muscarinic effects are also known as atropine-like effects, since atropine is an anti-muscarinic drug (it's an antagonist for muscarinic receptors)

1) on most of them, E has a higher affinity than NE, but 2) they have equal affinity on β1, and 3) NE has greater affinity on β3 note: we also have synthetic E and NE, which have the same properties as our endogenous catecholamines

direct agonists can be selective or non-selective, continued: in general E and NE are potent stimulants of all these receptor subtypes (α1-2, β1-3), but: 1) __ has a higher affinity than ___ on most of them, 2) for ____, they have equal affinity, and 3) on _____, NE has greater affinity

1) G-protein 2) in high concentrations, selective agonists may lose their selectivity

direct agonists can be selective or non-selective: the subtypes of adrenergic receptors, which our endogenous agonists (the catecholamines E and NE, as well as dopamine) can stimulate, include: α1 α2 β1 β2 β3 1) all of these receptors are coupled to a ________, meaning that the receptor's stimulation leads to the production of secondary messengers that amplify the triggered signal direct drug agonists mimic our endogenous catecholamines as selective or non-selective agonists on these receptors selective agonists bind with high affinity to a specific receptor (such as an α1-agonist binding and activating α1-receptors) 2) however, in high concentrations above the therapeutic dose, drugs may lose their ________

apraclonidine and brimonidine

________ and ______: these other α2-agonists are used via the topical intraocular route (as eyedrops) the α2 receptors in the eye are essential for the outflow of the aqueous humor, so in patients with accumulation of this fluid, specifically in open-angle glaucoma (where, among other factors, aqueous humor outflow is impaired, contributing increased intraocular pressure), these drugs are locally applied

oxymetazoline and naphazoline

________ and _________: these selective α1-agonists are mostly available for topical use (not expected to cause systemic effects unless they reach blood circulation), and are OTC medications therapeutic indications include acting as nasal decongestants and eyedrops to reduce ocular congestion

pseudoephedrine 1) inhibits NET 2) direct α1 and β1 agonist

________ is an OTC "mixed-mechanism" medication used to treat symptoms of the cold, sinus congestion, etc.; there was restrictions on its sale initially since it can be used as a precursor for the illicit manufacture of amphetamines mechanisms of action: 1) indirect: inhibits ____, thus increasing NE release; this is similar to amphetamines, but promotes less CNS stimulation 2) direct: ___ and ___ agonist (direct sympathomimetic agent); has low affinity for β2 receptors, similar to phenylephrine effects: CNS and periphery; similar to amphetamines, but less CNS stimulation therapeutic uses: nasal decongestant (topical and oral), mainly due to α1 stimulation (causing vasoconstriction and less congestion in the mucosa)

sympathomimetics can be: 1) direct, either as selective or non-selective agonists OR 2) indirect, by: A) inhibiting enzymes that degrade catecholamines (enzyme inhibitors) B) inhibiting the catecholamines' uptake (uptake inhibitors) C) stimulating catecholamines' release from neurons (releasing agents) OR 3) both direct and indirect

adrenergic stimulants in the CNS and PNS systems (sympathomimetics): they can be... 1) direct (direct stimulants on adrenergic receptors), acting as: A) _________ agonists or B) _________ agonists OR 2) indirect stimulants, that act mainly in the adrenergic nerve endings by: A) __________________ B) __________________ C) __________________ OR 3) both (direct and indirect)

adverse effects of amphetamines (and its derivatives): in the PNS: tachycardia and/or tachyarrhythmias; hypertension in the CNS: insomnia, reduced appetite

adverse effects of amphetamines (and its derivatives): in the PNS: 1) β1: ____________, increased CO (increasing oxygen demand, which can cause serious problems in patients with coronary heart disease) 2) α1: vasoconstriction-induced __________ 3) hypotension (due to vasodilation of some vessels, etc.) in the CNS: 1) at low doses, improve mood and attention, causing euphoria, resistance to fatigue, and enhances task performance, particularly those that require a sustained attention over a long period of time; it also causes _______ and reduced ________, leading to a significant weight loss over a short period 2) at higher doses, or prolonged use, they may trigger compulsive and psychotic-like behaviors, such as hallucination and paranoia; overdose can lead to cardiac arrest and seizures

sotalol is the only one (only β-blocker) that can treat one disease only, which is cardiac arrythmia

all β-blockers can be indicated to treat more than one disease, but ______ is the only one that can only treat one disease, which is cardiac arrythmia this is because it blocks sodium-potassium channels, affecting action potential conduction in the heart

increased insulin secretion, particularly with terbutaline

direct β2 agonist adverse effects 1) tremor 2) tachycardia 3) increased ________ secretion, particularly with ________

all β-blockers decrease heart rate besides this direct effect on reducing blood pressure, reduction in blood pressure can also be explained by other mechanisms: 1) nebivolol - produces NO 2) the partial agonists (labetalol and pindolol) - activation of β2-receptors #2 further explanation) these stimulate β2 in some vessels (only indirectly contribute to decreased blood pressure), as well as stimulate a small amount of β2 in the nerve endings, causing some NE to be released, activating their own α2 auto-receptors (which are coupled to Gi-protein) in their nerve terminals, inhibiting their own release (ultimately decreasing NE release) 3) non-selective antagonism of "regular β-blockers (without ISA) - decreased release of NE 4) carvedilol and labetalol - blockade of α1-receptors 5) carvedilol - blockade of calcium entry 6) carvedilol also has antioxidant properties 7) decreases renin in the juxtaglomerular apparatus

all β-blockers, selective or non-selective, act as antagonists or partial agonists in the heart, so they all (increase/decrease) heart rate, which in general contributes to reducing blood pressure, which is more effective in long-term use besides this direct action, reduction in blood pressure causing antihypertensive effects can also be explained by: 1) production of _____via nebivolol 2) activation of β__-receptors, which only occurs with the partial agonists (due to ISA), which ultimately lead to activation of their own α2 auto-receptors, inhibiting their own release of NE, via pindolol and labetalol 3) (increase/decrease) release of NE from nerve terminals due to the non-selective β2 antagonism of "regular" β-blockers without ISA 4) blockade of _______ receptors via carvedilol and labetalol 5) blockade of __________ entry via carvedilol, which causes vasorelaxation 6) carvedilol also has ___________ properties, protecting against vascular endothelial cell oxidation by ROS (also protecting against impairment of NO production, a potent vasodilator) note that the disease of hypertension itself is a huge producer of ROS 7) antagonism of β1 receptors also (increases/decreases) renin in the juxtaglomerular apparatus

orthostatic hypotension

apraclonidine and brimonidine adverse effects: only if drugs reach systemic circulation, they can cause ____________

2) carbidopa + levadopa note: you may ask, why not use all 3 as a triple therapy? this is only done in severe cases Parkinson's in patients with advanced degeneration excess dopamine can cause problems; recall that dopamine in the periphery is cardiostimulatory, causing tachycardia, arrhythmia, and even hypertension; in the CNS, excess dopamine is associated with schizophrenia, and can precipitate schizophrenia if the patient has a history of the disorder; along with these, dopamine also regulates hormones such as prolactin

between the following drug combinations, which is the preferable treatment for Parkinson's? 1) entacapone + levadopa 2) carbidopa + levadopa

3) orthostatic hypotension 4) rebound hypotension

clonidine's adverse effects are associated with the actions of clonidine on the α2 receptors on other organs, so we might have: 1) dry mouth (xerostomia) 2) sedation and/or fatigue 3) ___________, especially in geriatric patients, who may fall 4) abrupt cessation of clonidine causes ____________

clonidine DOES cross the BBB therapeutic uses include treating: 1) hypertension and 2) treating symptoms of opioid withdrawal

clonidine: pharmacokinetics: well-absorbed via oral administration, and (does/does NOT) cross the BBB to reach α2 receptors in the brainstem [this is why it's called a "central-acting" adrenergic agonist, since this allows it to reduce NE discharge in the CNS (decreases sympathetic outflow from the brain)] therapeutic uses: 1) __________ 2) relief from physically uncomfortable symptoms of opioid ___________, such as tachycardia and sweating

cocaine is only really used as a local anesthetic via topical application (including eyedrops)

cocaine acts in both nerve endings, dopaminergic and adrenergic, to inhibit the uptake of both DA and NE the consequence is increased availability of both DA and NE, so it's a potent sympathomimetic agent in the PNS, but also cross the BBB very easily, so it's potent in the CNS as well, particularly in the pleasure and reward centers (primarily with DA) therapeutic use: 1) very minimal; only really used as a local ________ by topical application (including in eye drops), and has no systemic effects it's a potent anesthetic since it blocks sodium channels important for depolarization of cells, and combines that with vasoconstriction (which is due to its indirect sympathomimetic effects increasing the availability of NE, which stimulates α1-receptors) note: lidocaine, a cocaine derivative, is much more widely used as an anesthetic

mainly (or most often) causes: ("THAP") 1) tachycardia 2) hypertension 3) agitation 4) paranoia

cocaine adverse effects: 1) ________, _______, ________, ________, (these are the main ones), as well as seizures, angina pectoris, myocardial ischemia, and hyperthermia 2) sudden death, via seizures, cardiac and/or respiratory arrest 3) repeated "snorting" can cause chronic rhinitis, cartilaginous necrosis, sinusitis, and nose bleeds

therapeutic uses: 1) severe congestive heart failure 2) cardiogenic shock with hypotension at lose doses: 1) increases renal blood flow, increasing diuresis 3) but can cause vomiting at high doses: 1) causes vasoconstriction, essentially mimicking the effects of E, causing arrhythmias

dopamine: pharmacokinetics: very short-acting (since it's a substrate for transporters and enzymes), so its effects are dose-dependent (see graph) therapeutic uses (through IV) via a moderate dose (blue curve in graph), include: 1) ______________ 2) ______________ at a low dose (green curve): 1) increases _______ blood flow, thus increasing _______, which is also beneficial to decrease symptoms of heart failure 2) also acts on mesenteric vascular beds 3) however, an adverse effect is _____, which is caused by stimulation of dopaminergic (D2) receptors in the CNS at a high dose (red curve): 1) causes __________ due to its effect on α1-receptors, essentially mimicking the effects of _______, increasing peripheral vascular resistance, CO, and heart rate, all of which causes arrhythmias

1) inhibit enzymes, such as MAO, COMT, and DD (DOPA decarboxylase) 2) act as uptake inhibitors 3) and act as releasing agents

indirect adrenergic stimulants include drugs that 1) ____________ 2) ____________ 3) ____________ all in order to increase the availability of catecholamines in our systems

entacapone it's effectiveness is slow, since DA doesn't cross the BBB as a monotherapy, can only really treat MILD Parkinson's; so we give it with Levadopa, which CAN cross the BBB and be converted to DA

inhibitors of catecholamine metabolism: COMT inhibitor: ___________: inhibits COMT (inhibits the degradation of dopamine, DA) in the periphery since it has low penetration into the CNS as a consequence, it enhances the conversion of L-DOPA to DA; however, its effectiveness is slow since DA (does/doesn't) cross the BBB therapeutic use as a monotherapy is limited: 1) patients with mild ______________ so, what we do is give it with another drug called ________ (similar to our L-DOPA), which isn't an inhibitor of any of these enzymes, but enhances the consequence of the enzyme's inhibition since it (can/can't) cross the BBB and be converted to DA it can reach the CNS (to become converted to DA) since we're increasing the substrate for the enzyme that converts L-DOPA to DA, DOPA decarboxylase, in the periphery, and its enzymatic activity becomes saturated, leaving space for some to cross the BBB

carbidopa again, we use it in combination with Levadopa

inhibitors of catecholamine metabolism: DOPA decarboxylase inhibitor: _________ also has low penetration into the CNS (as with entacapone), but is more commonly used to treat Parkinson's this is because it functions to inhibit DOPA decarboxylase in the periphery, which in-turn inhibits the conversion of L-DOPA to DA in the periphery this allows more L-DOPA (via its now extended half-life) to cross the BBB and then be converted to DA by DOPA decarboxylase in the CNS, however, this amount that crosses the BBB is still low since COMT is still active so, what do we do? again, we use it in combination with __________ therapeutic use: 1) Parkinson's Disease

1) phenelzine 2) selegiline both of these cause irreversible inhibition of MAO 1) phenelzine - depression 2) selegiline - Parkinson's

inhibitors of catecholamine metabolism: MAO inhibitors (MAOi): 1) ____________: inhibits both MAO-A and MAO-B, so it inhibits the degradation of every catecholamine, resulting in increased activity for all of them (increases activity for NE, DA, and 5-HT) 2) ____________: selectively inhibits MAO-B, which specifically breaks down DA; so, this results in increased activity of DA both drugs cause an (reversible/irreversible) inhibition of MAO therapeutic uses: 1) phenelzine: __________ (since it increases activity for all neurotransmitters) 2) selegiline: ___________ (and other diseases related to low levels of dopamine)

terbutaline albuterol formoterol salmeterol

list the (4) selective β2-agonists we talked about

1) prazosin - hypertension 2) doxazosin and terazosin - intermediate levels of effectiveness against hypertension and BPH 3) tamsulosin - best for BPH

major therapeutic uses of the selective α1-antagonists: 1) __________: best for hypertension, (as well as nightmares from PTSD and anxiety, but this part is off-label, or not FDA-approved, despite positive outcomes); this is best for hypertension, since it has the highest affinity for a specific subtype of α1-recpetors mostly found in the vessels) 2) ______ and _______: hypertension and symptoms of BPH; these have intermediate affinities for the α1-receptor subtypes in both the vessels and in prostate tissue 3) __________: best for symptoms of BPH (best for the prostate, since it has the highest affinity for a specific subtype of α1-receptors mostly found in prostatic tissue but less commonly in vessels) symptoms of BPH include: incomplete bladder emptying, urinary retention

1) nebivolol 2) acebutolol and betaxolol 1) carvedilol 2) labetalol

selective β1-antagonists and additional mechanisms: 1) ___________: stimulates production of NO in endothelial cells, causing vasodilation 2) _______ and ______: block Ca2+ channels, blocking Ca2+ influx nonselective β1-antagonists and additional mechanisms: 1) __________: also acts as an α1-antagonist, as an antioxidant, and also blocks Ca2+ channels, blocking Ca2+ influx 2) __________: also acts as an α1-antagonist

this is a prodrug often used for hypertension during pregnancy or breastfeeding it's the drug of choice for pre-eclampsia note: methyldopa also has an additional mechanism by which it can act as a false neurotransmitter

methyldopa: pharmacokinetics: this (is/is not) a prodrug, and is very well distributed throughout the whole body, including the placenta and BBB (it's highly lipid-soluble) note: although it crosses the placenta and is present in breast milk, it doesn't harm the fetus or the baby like clonidine, it acts on α2 receptors in the brain to reduce NE discharge in the CNS (decreases sympathetic outflow from the brain) therapeutic uses: 1) hypertension 2) specifically, hypertension during ________ and _______ IMPORTANT: it's the drug of choice for _________ (condition marked by hypertension and presence of protein in urine in pregnant women)

1) directly, they act as α1-adrenergic agonists 2) indirectly, they inhibit NET and DAT (DA and NE transporters)

methylphenidate and dexmethylphenidate are structural analogs of amphetamine 1) their direct mechanism of action is in acting as an ____-adrenergic agonist 2) their indirect mechanism of action involves inhibiting _______ and ______; so, these drugs increase the availability of DA and NE in both the PNS and CNS in the CNS, this accumulation of neurotransmitters in areas associated with learning and memory are indicated to improve symptoms of ADHD, enhancing attention as a therapeutic use but, because they stimulate α1 receptors, leading to vasoconstriction, patients with a history of hypertension should not use these drugs, as well as patients with a history of prostate hyperplasia

supine hypertension urinary retention

midodrine adverse effects: 1) hypertension, particularly _________, as well as 2) contraction of the urinary bladder sphincter, resulting in _____________

midodrine is a prodrug, and its active metabolite DOESN'T cross the BBB it's often used to treat orthostatic/postural hypotension

midodrine: pharmacodynamics: α1-adrenergic agonist this (is/is not) a prodrug its active metabolite (does/doesn't) cross the BBB its therapeutic uses are related to vasoconstriction: it causes an increase in blood pressure since it causes vasoconstriction via α1 receptor stimulation, so it's used to treat hypotension particularly, it treats ____________ hypotension (also called __________ hypotension, which occurs when blood pressure falls when the patient stands up from sitting or laying down)

3) urinary retention

mirabegron's adverse effects are mainly due to residual action in other β-adrenergic receptors, such as: 1) tachycardia (β1) 2) tremor (β1 and β2) 3) __________ (β3)

mirabegron: doesn't cross the BBB it causes detrusor muscle relaxation in the bladder, allowing it to expand and store more urine

mirabegron: pharmacokinetics: has an excellent bioavailability after oral administration, but it (does/doesn't) cross the BBB pharmacodynamics: it causes stimulation of β3-adrenergic receptors, causing inhibitory action, particularly resulting in detrusor muscle (relaxation/contraction) in the bladder consequence? the bladder stores more urine it's indicated to treat symptoms of frequent or urgent urination, as well as urinary incontinence due to an overactive bladder (OAB)

the TCA MOA is to inhibit reuptake of: 1) CNS NET transporter 2) serotonin (5-HT)

more reuptake inhibitors: the TCAs: (tricyclic antidepressants): 1) imipramine 2) desipramine 3) amitriptyline 4) nortriptyline main mechanism of action: these inhibit _____ in the CNS, the NE transporter, leading to NE accumulation there, but also ________ reuptake in the CNS this combination means that these drugs are associated with mood, and are thus suitable to treat depression therapeutic uses: 1) depression 2) peripheral neuropathy 3) chronic pain

phenylephrine (PE) midodrine oxymetazoline nafazoline

name the (4) selective α1 agonists we talked about

PBZ and phentolamine

name the 2 drugs that can induce tachycardia via 2 separate mechanisms, the vasorelaxation-induced reflex tachycardia and the increase in NE

1) formoterol 2) salmeterol these are (LABA - long-acting β2 agonists)

of the selective β2 agonists, 1) which is FAST ONSET and LONG-ACTING, and 2) which is SLOW ONSET and LONG-ACTING

albuterol and terbutaline (SABA - short-acting β2 agonists)

of the selective β2 agonists, which 2 are: FAST ONSET and OFFSET (meaning short-acting)

contraindicated in patients with myocardial ischemia

phenoxybenzamine (PBZ) and phentolamine adverse effects: 1) hypotension 2) reflex tachycardia other side effects include dry mouth and urinary retention, which are mainly caused by PBZ both are contraindicated in patients with _________ since they increase CO and heart rate, increasing cardiac oxygen demand

PE: doesn't cross the BBB, and is metabolized by MAO used most often as a nasal decongestant, as an oral or nasal spray

phenylephrine (PE): pharmacokinetics: (does/does NOT) cross the BBB, and is metabolized by (MAO/COMT), making it much more potent than E pharmacodynamics: is an α1-adrenergic agonist therapeutic uses are related with constriction due to its selective stimulation of α1-adrenergic receptors: A) causes vasoconstriction, as most α1-receptors are found in vascular smooth muscle, including small arterioles B) α1 stimulation is also associated with reduced broncho-secretion C) because of these, it's used most often as a... D) it's also administered via parental routes to avoid hypotension (to maintain blood pressure), which often occurs during anesthetic procedures (because of its vasoconstrictive action) E) since α1-receptors also exist on the radial eye muscle, this drug also causes contraction there, leading to pupil dilation (so it can be used in ophthalmic procedures to cause mydriasis)

reflex bradycardia

phenylephrine adverse effects, continued (IMPORTANT CARD): PE can cause severe systemic adverse effects, with these potential problems being related to blood pressure; it can cause hypertension and then ___________, why? BP (blood pressure) = CO (cardiac output) x TPR (total peripheral resistance) α1 receptor stimulation on the blood vessels causes vasoconstriction, increasing the TPR, thus increasing BP then, the body produces this in response to compensate for this increased BP by decreasing its HR and CO

rebound nasal congestion

phenylephrine's adverse effects are related to an excess of vasoconstriction, or its effect on other organs although it doesn't cross the BBB, it can cause some CNS effects since some patients are more sensitive to it than others, or due to drug-drug interactions; it can cause: 1) insomnia at high doses, in a more sensitive patient, or due to interaction with MAO inhibitors A) in patients that take a MAO inhibitor, degradation of the drug is reduced, increasing its bioavailability, and then increasing the likelihood of CNS effects 2) may worsen prostatic hyperplasia, since there's α1-receptors in the prostate, or may cause urinary retention (stimulation of α1-receptors can cause contraction of the urinary bladder sphincter) note: this isn't really a problem unless there's a history of prostate hyperplasia and take phenylephrine chronically the problem is that phenylephrine is an OTC medication, so patients may not even be aware of these effects 3) most common issue is a ________ of nasal congestion after short-term use (even after 3 consecutive days), precipitating sinusitis and/or rhinitis

1) these inhibit NE re-uptake transporters 2) are transported into vesicles via VMAT, displacing NE

reuptake inhibitors: amphetamine and its derivates: methamphetamine and lisdexamfetamine these drugs become very well distributed in our bodies; they're highly lipid-soluble, penetrate the BBB even after oral administration, and have a long duration of action mechanism of action: 1) causes ____ transporter inhibition since they're strong substrates for this transporter, preventing that transporter's catecholamine from being taken up, so it accumulates in the synaptic cleft 2) also, once in the cytosol, amphetamine (and its derivatives) are transported into the vesicles by ________, displacing NE, which is transported by a reverse transporter to the synaptic cleft, independent of vesicle exocytosis consequence: results in an increased amount NE that can act on adrenergic receptors in both the PNS and CNS

1) postural (or orthostatic) hypotension 2) syncope (fainting), usually after the 1st-dose ((1st-use phenomenon) syncope is much more common with prazosin

selective α1-antagonist adverse effects: 1) ____________ 2) ____________ (usually occurs after the ___ dose); much more common with ________

these are competitively reversible, meaning that increasing the amount of agonist DOES reverse the antagonism

selective α1-antagonists: 1) prazosin 2) doxazosin 3) terazosin 4) tamsulosin these (are/aren't) competitively reversible: general effects: 1) normal α1-antagonist effects in arteries and veins, which leads to decreased peripheral resistance and reduced venous return, leading to a reduction in the cardiac workload (low effect on CO output, so they don't trigger reflex tachycardia) 2) relaxes smooth muscle of the prostate, ameliorating symptoms of BPH

selective β2 agonists: primary indications are COPD and asthma albuterol and terbutaline are the drugs of choice for acute bronchospasm, usually via inhalation

selective β2 agonists: albuterol and terbutaline: fast onset and offset (short-acting) - "SABA" formoterol (fast onset) and salmeterol (slow onset): long-acting - "LABA" effects due to β2 activation (all of them cause): 1) bronchorelaxation 2) reduced airway inflammation 3) reduction of episodic bronchospasm due to allergens primary clinical indications: 1) ________ and 2) ________ _______ and _______ are the drugs of choice for acute bronchospasm, primarily administered via inhalation note: terbutaline has an "off-label" use, in which it's administered parenterally to delay premature labor, as a "tocolytic (means to delay premature labor, since it inhibits uterine smooth muscle contractions)" use "off-label" means it's not officially approved for this clinical use, despite very good results in this capacity

2nd neuron releases mostly NE (80%), and E (20%)

sympathetic nervous system ("fight or flight" reaction): part 1: this results in tachycardia, bronchodilation, and vasoconstriction in most blood vessels, but vasodilation in some (such as those that irrigate skeletal muscle, bringing more blood there) these neurons come from the thoracolumbar regions of the spinal cord, and are mainly organized in the paravertebral ganglia the 1st neuron releases ACh to communicate with the 2nd one, which then releases mostly ____ (80%) and ____ (20%) dopamine can also be released here, but it's not the main catecholamine with this system; it mainly acts to control renal vascular tone

adrenal glands release mostly E (80%), and less NE (20%), as mixture known as "adrenaline"

sympathetic nervous system: part 2: dopamine can also be released here, but it's not the main catecholamine with this system; it mainly acts to control renal vascular tone at the kidneys the adrenergic gland was initially a neuron, so it acts like a 2nd neuron as part of the endocrine system it's also stimulated by ACh, but then releases mostly ____ (80%) and less _____ (20%), which is opposite that which happens in the neurons (note: this distinct mixture is what's known as "adrenaline")

1) anaphylaxis 4) causes mydriasis 6) stops bleeding, acting as a hemostatic agent 7.A) increases bronchodilation

synthetic E and NE as drugs, continued: E: has much more therapeutic indications than NE, including: 1) rapid relief of __________ reactions 2) increases bronchodilation due to β3 stimulation 3) increases blood pressure due to α1 stimulation (recall that hypotension and bronchoconstriction are both serious events in anaphylaxis) 4) causes ________ (dilation of pupils) via acting on α-receptors to dilate the iris and acting on β-receptors to relax the sphincter 5) prolongs the effects of local anesthetics due to vasoconstriction via acting on α1-receptors because of vasoconstriction, local anesthetics get trapped in the local infiltration and doesn't spread into systemic circulation as fast 6) stops ________ (acting as a hemostatic agent), again by the same mechanism (via α1-induced vasoconstriction) 7) is beneficial for asthma emergency through IV-infusion (in life-threatening situations): A) via β2 activation decreases antigen-induced increase of inflammatory mediators, and increases __________ B) via α1 activation: decreased bronchial secretions and congestion in the mucosa

used to control cardiogenic shock, in severe hypotensive crises

synthetic E and NE as drugs: NE: results in increased total peripheral resistance, acting as an α1-adrenergic agonist, leading to vasoconstriction of the vessels that regulate blood pressure, leading to increased diastolic and systolic blood pressure it's usually used to control ________ shock in intensive care (emergencies), in which patients have a severe hypotensive crisis (so it's only used in emergency situations, and by IV infusion), to raise or support blood pressure because of this vasoconstrictor effect in general, its use is very limited due to a low bioavailability 1) quickly inactivated by COMT and MAO in the liver and gut 2) has a short duration of action due to its fast metabolization and lack of selectivity

1) narcolepsy 2) ameliorates symptoms of ADHD 3) lisdexamfetamine is particular for treating binge-eating disorders + severe obesity

the treatment for dose-problems related to amphetamines, like seizures, includes benzodiazepines therapeutic use for amphetamines is very limited, which includes: 1) __________ (chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden attacks of sleep) 2) helps to ameliorate symptoms of ________ 3) ____________ can also treat ADHD, as well as binge-eating disorders and severe obesity note: methamphetamine is much stronger than amphetamine, but all of them have a high potential for abuse

3) metoprolol and carvedilol - treat heart failure 4) esmolol - cardiovascular emergencies 5) propranolol - anxiety and migraines 6) timolol - open-angle glaucoma 7) all β-antagonists - hypertension, except for sotalol; labetalol is used in pregnant women (and for pre-eclampsia)

therapeutic uses for β-blockers: 1) some kinds of arrhythmias (all β-blockers are class II antiarrhythmic drugs, but only sotalol is classified as a class III antiarrhythmic drug) 2) most β-blockers can treat angina (reduce frequency of angina attacks), some conditions of myocardial infarction, and ischemic heart disease (improves exercise tolerance, decrease cardiac workload) 3) _________ and ________ can treat heart failure (where there's cardiac hypertrophy due to overactivation of the sympathetic nervous system) 4) for cardiovascular emergencies, ________is preferred; although this drug has a short duration, it has a very fast onset 5) for anxiety and migraines, __________ is preferred (because of its effects on the CNS) 6) for open-angle glaucoma, ________ is preferred, which decreases intraocular pressure (IOP) since it reduces the secretion of aqueous humor 7) for hypertension, all β-antagonists (except _______), but for pregnant women (and pre-eclampsia), ________ is used

hypertensive crisis

tyramine adverse effects: tyramine-containing foods + MAOi = _____________ this happens because the displacement of NE by tyramine causes an overactivation (primarily) in the cardiovascular system, leading to vasoconstriction (α1) and tachycardia (β1)

taking MAO-inhibitors while ingesting exogenous tyramine-containing foods can cause an excess of NE release this can cause a hypertensive crisis

tyramine is a releasing agent this isn't a drug, but the importance of learning about it is due to its drug interaction this is an amine; although we have some endogenous production of tyramine as a byproduct of tyrosine metabolism, it's not significant we only have traces of endogenous tyramine, and it doesn't affect our systems the problem with tyramine is that, when it's absorbed exogenously while the patient is taking drugs that inhibit the enzyme that degrades tyramine in the gut (MAO, which is found also in the liver and neurons); this can cause an excess of tyramine, which in-turn causes an excess of _____ to be released this happens because, like with amphetamines, tyramine gets taken up into the presynaptic vesicles by VMAT, displacing NE there, causing an excess of NE to be available in the cytosol and won't be degraded by MAO this can cause a _______________ foods that contain higher levels of tyramine include most cheeses, wine, soy sauce, and fermented dairy products (sour cream, yogurt, etc.) normally, tyramine doesn't cause any systemic effects unless it's absorbed, which is when the patient is taking MAO-inhibiting drugs

tachycardia

usually, the dobutamine adverse effect is ________

dobutamine dopamine

what are the (2) selective β1 agonists we talked about?

phenoxybenzamine (PBZ) phentolamine

what are the (2) α-nonselective antagonists we talked about?

methylphenidate dexmethylphenidate pseudoephedrine

what are the (3) mixed-mechanism drugs we talked about?

amphetamine methamphetamine lisdexamfetamine cocaine

what are the (4) reuptake inhibitors we talked about (besides the tricyclic antidepressants)?

the "-osins": prazosin doxazosin terazosin tamsulosin

what are the (4) selective α1-antagonists we talked about?

clonidine methyldopa apraclonidine brimonidine

what are the (4) selective α2 agonists we talked about?

"-ines": imipramine desipramine amitriptyline nortriptyline

what are the (4) tricyclic antidepressants we talked about? these are also reuptake inhibitors

1) propranolol 2) timolol 3) carvedilol 4) sotalol 5) labetalol 6) pindolol these aren't full antagonists, and act as partial agonists, since they have ISA (intrinsic sympathomimetic activity)

what are the (6) non-selective β-blockers (antagonists at both β1-and β2-receptors), including the (2) that aren't full antagonists?

"NAMEBBA": 1) nebivolol 2) atenolol 3) metoprolol 4) esmolol 5) betaxolol 6) bisoprolol 7) acebutolol this isn't a full antagonist, and acts as partial agonist, since it has ISA (intrinsic sympathomimetic activity)

what are the (7) selective β-blockers (selective for β1-receptors), including the (1) that isn't a full antagonist?

tyramine

what is the (1) releasing agent we talked about?

isoproterenol

what is the β1 AND β2 agonist we talked about?

mirabegron

what is the β3 agonist we talked about?

α2 receptors are coupled to Gi proteins 3) in the eyes, increase aqueous humor outflow 4) in the pancreas, decreased insulin secretion

α2 receptors are coupled to a ________, meaning that their activation stimulates inhibitory effects, such as inhibition of ACh and NE release from the nerve endings so, stimulation of α2 receptors causes: 1) in nerve terminals: decreased neurotransmitter exocytosis 2) in the postsynaptic brainstem adrenoreceptors (CNS): decreased sympathetic nerve activity 3) in the eyes: (increased/decreased) aqueous humor outflow 4) in the pancreas: (increased/decreased) insulin secretion