Pulmonology Flashcards
Corticosteroids
work through broad anti-inflammatory action by inhibiting the infiltration by lymphocytes, eosinophils, and mast cells.
Do not directly cause bronchial relaxation.
Often given in the morning following endogenous adrenocorticotropic hormone secretion has peaked (to prevent adrenal suppression)
Given as aerosols
They are “controllers” meaning they are only effective so long as they are taken (not curative)
Drugs: beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone
Cromolyn and Nedocromil
Anti-asthmatics
Rarely used any more, but used to be used a lot in child
Ineffective in reversing asthmatic bronchospasm; they are only of value when taken prophylactically
MOA: Thought to alter function of delayred chloride channels inhibiting activation of cells (like mast cells among others)
Could be used shortly before exercise or unavoidable exposure to an allergen (acute prophylactic)
Can also reduce symptoms of allergic rhinoconjunctivitis
Has been replaced by low-dose corticosteroids and leukotriene pathway inhibitors. Orally administered.
Zileuton
A 5-lipoxygenase inhibitor used to treat asthma
Can be taken orally (twice daily), but is less often prescribed due to its likelihood of causing liver toxicity.
Effects on symptoms, airway caliber, bronchial reactivity, and airway inflammation are not as marked as inhaled corticosteroids, but they are equally effective at decreasing frequency of attacks.
Zafirlukast
A LTD4 receptor inhibitor used to treat asthma
Can be taken orally (twice daily)
Effects on symptoms, airway caliber, bronchial reactivity, and airway inflammation are not as marked as inhaled corticosteroids, but they are equally effective at decreasing frequency of attacks.
Montelukast
A LTD4 receptor inhibitor used to treat asthma
Can be taken orally once daily. Used a lot in children (approved for children as young as 6) and can be taken without regard to meals
Effects on symptoms, airway caliber, bronchial reactivity, and airway inflammation are not as marked as inhaled corticosteroids, but they are equally effective at decreasing frequency of attacks.
Omalizumab
Anti-IgE Monoclonal Antibodies; murine antibody that is humanized
MOA: Inhibits the binding of IgE to mast cells; does not activate the IgE already on the mast cell; may inhibit B cell synthesis of IgE.
After 10 weeks, plasma IgE is undetectable.
reduces frequency and severity of asthma exacerbations and decreases the corticosteroid requirements.
Use: chronic asthma not controlled by Glucocorticoids+beta-agonists
Isoniazid
Antimycobacterial
MOA: inhibits mycolic acid synthesis (cell wall component); activated by KatG (an oxidase/peroxidase) which then reacts w/ NAD to inhibit a reductase of FA synthase II, InhA, and DHFR
Can be used to treat prophylactically
Some people acetylate drug faster/slower (different isoforms of NAT2)-> determines dosage
MOR: mutation of activating enzyme (catalase peroxidase KatG gene), target enzyme (INHA gene), or NADH dehydrogenase
Causes Vit B6 deficiency-> prophylactic administration of pyroxidine prevents peripheral neuritis
Tox: convulsions, optic neuritis, optic nerve atrophy, hepatotoxicity
Rifamycins
Rifampin, Rifapentine, Rifabutin all used for treatment of mycobacterial disease
MOA: binds beta subunit of DNA-dep RNA polymerase (RpoB)and suppresses chain formation in RNA synthesis
Inhibits most gram-positive (very active against S aureus), M. tuberculosis, and gram-negatives like E. coli, Pseudomonas, Klebsiella. Prophylactic for meningococcal disease
MOR: alteration of the target of the drug RpoB. higher resistance in AIDS
Induces cytP450s-> contraindicated for PTs on HIV drugs; Rifabutin- used for HIV PTs (no P450 effects)
Tox: possible additive hepatotoxicity in combo w/ isoniazid,; nephrotoxicity-> red-orange urine. Hypersensitivity
Take rifampin on an empty stomach, rifapentine with food
Ethambutol
Antimycobacterial used for Mycobacterium avium complex (+ macrolide); Bacteriostatic for isoniazid-resistant M. tuberculosis
MOA: inhibits mycobacterial wall synthesis by blocking arabinosyl transferases
Tox: optic neuritis-> cannot differentiate green and red; gout
MOR: mutations in embB gene (codes for arabinosyl transferases), increased efflux pump
Watch for renal failure as 80% is excreted this route
Often given with combination with Isoniazid if the organism shows initial resistance to isoniazid (bacteriostatic for isoniazid resistant TB)
Pyrazinamide
Antimycobacterial
MOA: blocks mycobacterial FA synthase I gene involved in mycolic acid biosynthesis-> inhibits cell wall synthesis; reduceds intracellular pH, disrupts membrane transport
Tox: gout (decreased urate excretion); hepatotoxicity
MOR: pyrazinamidase with reduced affinity for drug (normally serves to activate drug)
Used in combination with isoniazid or rifampin to reduce duration of TB
Streptomycin
Antimycobacterial aminoglycoside
MOA: binds 30S ribosomal subunit and interferes with protein synthesis
Contraindications: pregnancy
Amikacin
Antimycobacterial aminoglycoside
MOA: binds 30S ribosomal subunit and interferes with protein synthesis
MOR: decreased access, increased deactivation, altered ribosome structure
Ototoxicity; nephrotoxicity; neuromuscular blockade
Capreomycin
Antimycobacterial- 2nd line
MOA: cyclic peptide that decreases protein synthesis
Given IM for multidrug resistant TB
Tox: deafness, hearing loss, tinnitis
Cycloserine
Antimycobacterial- 2nd line;
MOA: Cycloserine is an analog of alanine, thus it can inhibit enzymes needed to racemize L-alanine to D-alanine. Lack of D-alanine blocks cell wall synthesis
Tox: neurotoxicity (nickname “psych-serine”): headache, somnolence, psychosis, seizures, and suicidal ideas
Ethionamide
Antimycobacterial- 2nd line
MOA: activated by mycobacterial redox system; same MOA as isoniazid-> inhibits mycolic acid synthesis (cell wall component); reacts w/ NAD to inhibit a reductase of FA synthase II
Low cross resistance w/ isoniazid
Tox: nausea/vomiting; GI; neurotoxicity (pyridoxine relieves the neurologic symptoms)
Azithromycin, Clarithromycin
Antimicrobial Macrolide; Antimycobacterial- 2nd line
Effective against gram + cocci like S. pneunomiae; Also used for Mycobacterium avium complex (+ ethambutol)
MOA: binds 50S peptidyltransferase to block translocation;
Drug interactions: decrease cytP450s (except azithromycin); Large tissue distribution, high cellular concentration (not erythromycin)
MOR: efflux pumps; these drugs induce methylation of 50S and cannot bind-> cause resistance to self
Tox: hypersensitivity; GI problems; arrhythmia (QT prolongation); hepatitis (erythromycin)
Aminosalicylic acid
Antimycobacterial- 2nd line
MOA: looks like PABA; inhibits thymidylate synthase (TS)-> interrupts folate pathway
MOR: mutation of TS
Side Effects: GI effects limit patient adherence
Acetycholine
Bethanachol
partial muscarinic receptor agonist [M2 (cardiac) and M3 (smooth muscle/ glands)]
used for postoperative and neurogenic ileus (atony or paralysis of the stomach or bowel following surgical manipulation) and urinary retention
Longer duration of action than ACh (Active for 30 min to 2 hours)
Adv: Rule out GI and urinary obstruction before use (due to possible exacerbation of problem and may cause perforation as result of increased pressure). Excessive parasympathomimetic effects, esp. bronchospasm in asthmatics. Additive with other parasympathomimetics
Pilocarpine
Partial Muscarinic agonist similar to Bethanechol
Tx: Glaucoma; dry mouth in Sjogrens syndrome
Decreases intraocular pressure by contracting ciliary body to allow outflow of aqueous humor.
Physostigmine
Like neostigmine, but natural alkaloid tertiary amine; enters CNS
Intermediate-Acting AChE Inhibitor (Carbamate). Well absored and longer lasting (0.5-2 hours).
Tx: Myasthenia gravis (MG), acute angle-closure glaucoma (initial therapy with pilocarpine), postoperative and neurogenic ileus and urinary retention. Used to treat the CNS and PNS effects of atropine, scopolamine and other anticholinergic drug overdoses.
Adv: More toxic. Reverse effects with atropine.
Moderate doses: Modest bradycardia and ↑BP
High doses: marked bradycardia and hypotension
Edrophonium
Short-Acting AChE Inhibitor
“Tensilon Test”
Test for myasthenia gravis (will have improvement in muscle strength after injection), ileus, arrhythmias (rare)
An alcohol (doesn’t cross BBB) that electrostatically and by H bonds binds briefly to active site of AChE
Echothiophate
Organophosphate insecticide
Not absorbed well by the skin like Malathion
“Aging” will occur with AChE and Echothiophate
Long duration of action with time (~100 hours)
Adv: Brow ache, uveitis, blurred vision
Hexamethonium
Nicotinic Antagonist
Uses: obsolete (was for HTN)
Effects: NN/NG blockade (blocks opening; not Ach binding site); decrease BP; increase HR; arteriolar and venomotor tone largely under sympathetic control; decreased vagal tone causes tachycardia
SE: postural hypotension, sympatho/parasympatho-plegia, sexual dysfunction, mydriasis, constipation, dry mouth
Nicotine
Lipid soluble, so can be absorbed across the skin and crosses the BBB
Activates autonomic postganglionic neurons (sympathetic and parasympathetic) and somatic motor because of nicotinic receptors of skeletal muscle at neuromuscular junction
NM: Skeletal muscle - Na+/K+ depolarizing ion channel
NN: Postganglionic cell - Na+/K+ depolarizing ion channel
Muscarine
Parasympathomimetic alkaloid
Muscarinic receptor agonist. Binds irreversibly to AChE
Quaternary amine so it does not cross the BBB –> has more peripheral effects.
Tox: ↑ salivation, lacrimation, perspiration, abdominal pain, nausea, blurred vision
First source of muscarine: Amanita muscaria (mushroom). Interestingly, effects mimic atropine poisoning more than muscarine excess.
Trimethaphan
Nicotinic Antagonist
Uses: HTN (malignant HTN); induce hypotension during surgery
Effects: NN/NG blockade (blocks opening; not Ach binding site); decrease BP; increases HR;
arteriolar and venomotor tone largely under sympathetic control.
decreased vagal tone causes tachycardia
SE: postural hypotension, sympatho/parasympatho-plegia, sexual dysfunction, mydriasis, constipation, dry mouth
Kinetics: Short acting; given IV only
Atropine
Muscarinic Cholinergic Antagonist
Tx: Antidote for organophosphate poisoning
MOA:
competitive (reversible) antagonist at all M receptors, thereby prevents release of IP3 & adenylyl cyclase
Eye: dilation (mydriasis), cycloplegia (paralysis of ciliary muscle = loss of accommodation), reduced lacrimation, tachycardia (M2 receptors), bronchodilation
Adv: Blind as a bat, mad as a hatter, red as a beet, hot as a hare, dry as a bone, the bowel and bladder lose their tone, and the heart runs alone –> Total PNS block.
Relatively safe for adults
Rapidly cleared in urine
*be careful of closed angle glaucoma
Scopolamine
Tertiary amine alkaloid (like atropine)
Muscarinic Cholinergic Antagonist (can also block H1 receptor and cause sedation)
Tx: Reduces vertigo, post-operative nausea, prevention of motion sickness (Transdermal patch)
MOA: M1 receptor
rapid onset and primarily CNS effects
Adv: Same effects as atropine + CNS: delirium , drowsiness, amnesia, excitement, hallucinations, coma
Ipratropium
Antimuscarinic
Uses: asthma, COPD (more common)
Effects: Synthetic analog of atropine; Bronchodilator ; decreases mucus production; blocks vagal activity in the lung when inhaled.
SE: postural hypotension, sexual dysfunction, mydriasis, cough, Xerostomia,
Inhaled; not as effective as beta agonists but can be used in combination
Epinephrine
(α1=α2=β1=β2) Adrenergic Receptor agonist
Effects: increases BP (α1), increases HR (β1 direct effect, β2 blocks vegal reflex), relative decrease in diastolic BP (β2 on skeletal muscle causing vasodilation)
CI: acute angle glaucoma, pregnancy
Kinetics: metabolize by COMT and MAO
Epinephrine Reversal: Pretreatment with α antagonist converts an epinephrine infusion from a pressor response to a depressor response. (ie, β2 dilation predominates)
Note: all direct adrenergic agonists can cause angina, MI, and arrhythmias; Released from adrenal medulla endogenously
Norepinephrine
(α1=α2=β1>>β2) Adrenergic Receptor agonist
Uses: emergency hypotension; eg: to maintain coronary or cerebral flow (NOT C/I in closed angle glaucoma)
Effects: increases BP (α1), decrease HR (net effect of β1and vagal reflex); increase contractility (β1)
Kinetics: metabolized by COMT and MAO
C/I: pregnancy
α1: vascular SM (Gq; increase IP3/DAG, [Ca]i)
α2: presynaptic and in CNS (Gi; decrease cAMP)
β1: heart and juxtaglomerular cells (Gs; increase cAMP)
β2: vascular SM (in skeletal muscle & heart) and bronchial SM (Gs; increase cAMP)
Albuterol
Beta-2 Selective Agonist
Use: bronchodilator for asthma pts
Effects: work through Gs to increase cAMP; smooth muscle relaxation; increase activity of cilia; inhibit mast cell degranulation
Side Effects: tachycardia (inhibits vagus nerve presynaptically); decreases BP; skeletal muscle tremor; lowers PaO2 transiently due to pulmonary vasodilation of underventilated regions.
Given as metered-dose inhaler or nebulizer
Only the R isomer is active at the beta-2 receptor
Bronchodilation: onset 15-30 minutes and DOA 3-4 hrs
Terbutaline
Beta-2 Selective Agonist
Use: bronchodilator for asthma pts; uterine relaxation (delay labor)
Effects: work through Gs to increase cAMP; smooth muscle relaxation; increase activity of cilia; inhibit mast cell degranulation
Side Effects: tachycardia (inhibits vagus nerve presynaptically); decrease BP; skeletal muscle tremor; lowers PaO2 transiently due to pulmonary vasodilation of underventilated regions.
Given as metered-dose inhaler or nebulizer
Only the R isomer is active at the beta-2 receptor
Bronchodilation: onset 15-30 minutes and DOA 3-4 hrs
MAOI
Monoamine oxidase inhibitors
MAO normally metabolizes tyramine. If taking MAOIs, tyramine found in meat, cheese, and wine can build up and displace stored catecholamines
Use: Tx depression
Tyramine
Amphetamine-like Indirect-Acting Sympathomimetic
normal by product of tyrosine metabolism and produced from diets rich in proteins
Readily metabolized by MAO in liver and inactive when taken orally due to first pass effect.
MOA: causes release of stored catecholamines (similar to NE MOA)
*contraindicated with MAOIs
Reserpine
Adrenergic Neuron Blocker
Uses: moderate HTN, but not used due to adverse effects
Effects: irreversible VMAT inhibitor; enters CNS and depletes NE, E, DA, 5-HT decreases BP (lowers CO/PVR but reflexes intact)
SE: sedation, mental depression, EPS, diarrhea, cramps, parkinsonism; depletion of cerebral amines
Low doses: orthostatic hypotension
CI: PUD, mental depression
Guanadrel
Central Acting anti-HTN
Uses: HTN
Effects: Block NN inhibits NE release from SNS (Doesn’t enter CNS but causes sympathoplegia); decreases HR, CO, BP (from decreased CO at first; decreases PVR with prolonged use); compensatory Na+ and H2O retention
SE: pharmacologic sympathectomy: postural hypotension, diarrhea, impaired ejaculation
CI: cocaine, amphetamine, tricyclics, phenoxybenzamine
Ephedrine
Indirect Acting sympathomimetic
MOA: Displaces stored catecholamines
TX: Narcolepsy, Enuresis, Idiopathic postural hypotension
Side effects: low addiction liability;
Compared to epinephrine: longer duration, orally active, low potency
Not used for asthma
Pseudoephedrine
Mixed-Acting Sympathomimetic
A B-receptor agonist
Used in over the counter decongestant medicine and has been abused in the synthesis of methamphetamine
Cocaine
local anesthetic with peripheral sympathomimetic action via inhibition of transmitter reuptake at noradrenergic synapse
amphetamine-like psychological effect that is shorter lasting and more intense than amphetamine
Inhibits DA reuptake into neurons in the “pleasure centers” of the brain giving you a wild ride
Cocaine is a hell of a drug
Highly addictive (relative risk of 5/5). heated in an alkaline base to become “crack cocaine” which can be smoked producing an instant “rush”
In PNS, inhibits voltage gated Na channels. In CNS, cocaine blocks reuptake of DA, NE, serotonin. The DAT block increases DA in nucleus accumbens is the rewarding aspect of the drug
By blocking NET, causes increase in arterial pressure, tachycardia, ventricular arrhythmia
Toxicities: intracranial hemorrhage, ischemic stroke, MI, seizures, coma, death
Amphetamine
Indirect-Acting Sympathomimetic
Displasces stored catecholamine transmitters.
Important chiefly because of its use and misuse as a CNS stimulant
Readily enters the CNS; effects mediated through the release of norepinephrine and dopamine
Esmolol
(β1>>β2) Adrenergic Receptor Antagonist
Uses: HTN (intra-op/post-op or hypertensive emergency), SV arrythmia
Effects: (-) inotropic, chronotropic, and dromotropic effects; decreases BP (no reflex tach); inhibits the renin/angiotensin/aldosterone system
Kinetics: ultra-short acting; half-life about 10 minutes; rapidly metabolized by RBC esterases; given as IV
SE: bradycardia; hypotension
CI: asthma (bronchoconstriction); ok for COPD
Lebetalol
Mixed antagonist for adrenoceptor
alpha1-selective and B-antagonistic effects.
Used for hypertensive emergencies and treating hypertension of pheochromacytoma
Less tachycardia seen compared with phentolamine.
Phentolamine
(α1=α2) Adrenergic Receptor Antagonist
MOA: minor competitive antagonist of H1, H2, and M as well.
Uses: Tx of ED, HTN secondary to pheochromocytoma
Effects: decrease BP, increase HR (vagal reflex); α2 (located presynaptically) block enhances NE release [therefore, sympathetic cardiostimulation and enhanced baroresponse is observed]; minor inhibition of serotonin receptor and minor agonist at M
SE: MI, tachycardia, arrhythmias, headache, nasal congestion
CI: PUD
Phenoxybenzamine
(α1>α2) Adrenergic Receptor Antagonist
MOA: Irreversible blockade (long duration; 14-48 hrs); H1, AchR, 5-HT receptor block; Indirect baroreflex activation (inhibition of NE reuptake)
Effects: decreases BP (only when sympathetic tone is high [eg: low blood volume]); attenuates catecholamine induced vasoconstriction; increase HR from reflex.
SE: Postural hypotension, tachycardia, nasal congestion, sedation, nausea, sexual SE;
Uses: HTN secondary to pheochromocytoma
Related to nitrogen mustard
Prazosin
(α1>>α2) Adrenergic Receptor Antagonist
Uses: HTN (especially in combo w/ β blocker), benign prostatic hyperplasia
Effects: decreases BP (dilation of resistance and capacitance vessels; more pronounced when in the upright position); some reflex tachycardia (less than nonselective α antagonists (phentolamine) because NE negative feedback on α2)
SE: Orthostatic hypotension(less than nonselective α antagonists), increases HDLs, salt and water retention, dizziness, headache, ANA development
Kinetics: half-life= 3 hours; extensive 1st pass hepatic metabolism; oral bioavailability = 50%
Terazosin
(α1>>α2) Adrenergic Receptor Antagonist
Reversible blocker
Uses: HTN, benign prostatic hyperplasia
Effects: not much reflex tachycardia; decreases BP (dilation of resistance and capacitance vessels; more pronounced when in the upright position)
SE: Orthostatic hypotension upon first dose
Kinetics: half-life= longer than Prazosin; extensive 1st pass hepatic metabolism
High bioavailability
Half life 9-12 hrs
Tamsulosin
α1 antagonist
selective for alpha-1a so primarily relaxes prostatic SM.
Uses: benign prostatic hyperplasia
Propranolol, Metoprolol, Atenolol
Propanolol (B1=B2), Metoprolol/ Atenolol (B1>>>B2) (CI in asthmatics)
Metoprolol is an inverse agonist. Metoprolol has shown a reduction in mortality in patients with stable severe heart failure.
Propanolol is the prototype but comes with toxicities: sedation, vivid dreams, depression, worsening of asthma, bradycardia, fatigue, cold hands; has been replaced by Metoprolog and Atenolol
Propanolol can treat Hypertension: less reflex tachycardia in comparison to direct vasodilators. MOA mainly from depression the renin-angiotensin-aldosterone system.
Toxicity of propanolol: withdrawal causes nervousness, tachycardia, increase intensity of angina, increase BP.
Metoprolol is as effective as propanolol in inhibiting beta 1, but way less potent in beta 2. Better agent in treating those with asthma, diabetes, peripheral vascular disease.
Atenolol is less effective in treating hypertension due to the lack of maintaining adequate blood levels of the drug.
Beta-Blockers reduce mortality following an MI
Pindolol
(β1=β2) Adrenergic Receptor Antagonist
Uses: HTN (especially patients with PVD or bradyarrhythmias)
Effects: partial agonists actually; less decrease HR/CO than other β blockers; lowers BP (TPR); potentiate antidepressants
SE: fatigue, vivid dreams, cold hands
CI: asthma (bronchoconstriction)
Nitric Oxide
Nitric oxide drugs and drug classes
NO (aka EDRF)– elevates cGMP in vascular smooth muscle; vasodilator; decreases pulm. resist. when inhaled; inhibits platelet aggregation; inhibits atheromatous plaque formation
immune function: NO is a microbicide, excessive NO increases tissue injury
Nervous system: synaptic plasticity (learning) in CNS; NANC neurons in PNS
Uses: pulmonary HTN; hypoxic respiratory failure
SE: methemoglobinemia.
Superoxide Dismutase – NO scavenger prolonging DOA by protecting against NO inactivation from superoxide.
Methylene Blue – soluble guanylate cyclase (sGC) inhibitor that prevents the action of NO and can reverse NO induced hypotension.
Soluble Guanalyl Cyclase Inhibitors
NO Synthase substrates and products
L-Arginine is substrate for NOS that forms NO and L-Citrulline.
L-NMMA – comp. inhibitor binding to arginine-binding site in NO
NOS requires cofactors: heme, tetrahydrobiopterin, FAD
Cytosolic Ca binds Calmodulin which binds and activates eNOS or nNOS.
iNOS is not Ca regulated and is purely transcriptionally regulated (induced by TNF and IL-1).
Desflurane
Very low blood:gas partition coefficient
Rapid onset and recovery
widely used for outpatient surgery
can promote coughing due to irritiation of tracheobronchial tree, meaning they normally only use this for maintenance of anesthesia as opposed to induction.
Marked increases in heart rate are occasionally seen.
