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Has been replaced by low-dose corticosteroids and leukotriene pathway inhibitors.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.
Enflurane
Volatile anesthetic
Relatively slow rate of onset and recovery
Not really metabolized unlike halothane. Even though enflurane’s solubility is lower, it’s eliminated more slowly.
adverse: more severe depression of normal cardiac contractility than others. Only inhaled anesthetic with frank clinical seizures
Toxicities: metabolites are nephrotoxic
Not used in patients with seizure disorders
Halothane
Volatile anesthetic (has low vapor pressure and thus high boiling points so that liquid at room temperature/ sea-level pressure)
The driving force for an inhaled anesthetic is the alveolar concentration. This concentration changes based on inspired concentration or partial pressure, and alveolar ventilation
Relatively slow rate of onset and recovery
Solubility is 2X and 10X more than nitrous oxide in brain tissue and blood, respectively. Therefore, elimiantion and recovery is less rapid.
Hepatotoxicity (halothane hepatitis):
adverse: more severe depression of normal cardiac contractility than others
Still often used in children, as they seem to be more immune to adverse side effects
40% of halothane is metabolized so that elimination occurs more quickly than would be be expected based on tissue solubility.
Isoflurane
Volatile anesthetic
Relatively fast rate of onset and recovery
Isoflurane, sevoflurane, halothane, enflurane produce initial activation of EEG at low doses and subsequent slowing when given doses of 1.0-1.5 MAC. Isoflurane EEG is silenced at 2.0-2.5 MAC.
Pungency makes it less suitable for patients with active bronchospasm, usually used following induction of anesthesia with a different drug
better choice for patients with impaired myocardial function/ischemic heart disease
Methoxyflurane
Inhalation Anesthetic
MAC 0.16
metabolism: >70%(fluoride); High solubility
renal insufficiency from hepatic metabolism to fluoride compound.
Nitrous Oxide
MAC >100%;
metabolism: none; only anesthetic that does not decrease VT and increase RR
Sevoflurane
Low solubility
MAC 2.0%
metabolism: 2-5% (flouride)
Must make sure it is not used with an anesthesia machine in which the CO2 absorbent has been dried. The reaction of sevoflurane with desiccated CO2 absorbent can produce CO.
Also, reaction with dessicated CO2 absorbent can cause fires and explosions.
Bronchodilation (good for induction with obstructive dx pts); little increase in cranial pressure; decreases TPR; ideal inhalable anesthetic
Carbon Monoxide
Colorless, tasteless, odorless, nonirritating gas. Comes from incomplete combustion. Affinity for hemoglobin that is 220 times that of oxygen
Signs: hypoxia in the following sequence
1) psychomotor impairment
2) headache and tightness in temporal area (15% CO-Hb)
3) loss of visual acuity and impairment
4) tachycardia, tachypnea, syncope, coma (40% CO-Hb)
5) convulsion, respiratory failure
Tx: hyperbaric O2 reduces CO elimination half-life to 20 minutes from a normal of 320.
Sulfur Dioxide
Colorless, irritant gas; comes from combustion of sulfur-containing fossil fuels and forms sulfurous acid on contact with moist membranes
Bronchoconstriction upon inhalation mediated by Parasymppathetic
Asthma pts are hypersensitive
Signs:
1) acute asthma
2) delayed-onset pulmonary edema
Nitrogen Oxides
Brownish, irritant gas associated with fires; found in silage (silofiller’s disease in farmers)
Effects: pulmonary edema, eyes and nose irritation, dyspnea, fibrotic destruction of terminal bronchioles (bronchiolitis obliterans)
Ozone and Solvent Vapors
Ozone:
• bluish irritant gas; absorbs UV light
• occurs around high voltage equipment
Effect: irritates mucous membranes
1) moderate exposure: upper respiratory tract irritation
2) severe exposure: deep irritation and pulmonary edema
Longterm exposure: fibrosis, bronchitis, and emphysematous changes
Solvent Vapors:
Halogenated Aliphatic Hydrocarbons:
• eg: chloroform, freon
• carcinogenic but are still used in dry cleaning
• Cause: CNS depression and liver, kidney, and heart damage.
Aromatic Hydrocarbons:
• Eg: benzene, toluene, Xylene
• Components of gasoline
• Acute effect: CNS depression
• Chronic exposure to Benzen: bone marrow suppression and leukemia.
Ganglion Blocking Drugs
Tetraethylammonium, Hexamethonium, Mecamylamine, Trimethaphan.
Trimethaphan and hexamethonium impair transmission by competing with ACh for nicotinic sites, or blocks channel.
Use of ganglionic antagonists in treating hypertension/ autonomic hyperreflexia: Blood vessels have sympathetic innervation causing them to constric and cause a decrease in arteriolar and vasomotor tone. Using these drugs, this constriction is inhibited and so blood pressure will be lowered.
Diminished contractility and b/c SA node is dominated by parasympathetic system, tachycardia.
Inhaled Anesthetics (brace yourself)
Blood:gas Partition Coefficient – describes solubility of gas in blood.
Low B:G implies Low solubility which means the partial pressure of gas in arterial blood (tension of the gas) rises quickly relative to the amount of dissolved gas particles. Rapid equilibration with brain tissue and fast onset of action characterized by anesthetics with low B:G.
Pulmonary Ventilation: The rate of rise of anesthetic partial pressure in blood depends on minute ventilation.
low B:G implies arterial tension of anesthetic is quickly maxed out and the rate of induction will hardly be modified by increased ventilation.
Moderate to high B:G means is takes significant time for blood tension to reach adequate levels. Increasing ventilation substantially decreases the time it takes for this equilibration.
Arteriovenous gradient: results from anesthetic uptake by tissues. The more uptake into tissues, the longer it takes for arterial blood (and brain tissue) partial pressure to reach equilibrium with alveolar.
Tissue uptake is a function of the solubility (B:T) of the drug in various tissues, and the relative perfusion of each of these tissues.
Brain, heart, liver, kidneys, and splanchnic bed are heavily perfused at rest (75% of CO) and account for most of the A-V gradient.
Elimination:
Lung Clearance - anesthetics insoluble in blood and brain result in rapid recovery. For soluble anesthetics, recovery depends on length of exposure (due to slow accumulation and elimination from muscle, skin and adipose tissue)
Hypercapnia releases catecholamines which attenuate the depression caused by the inhaled anesthetic. (usually observed by the arterial blood pressure slowly rising during the duration of a surgery to almost normal values). Arrhythmias from inhalable anesthetic occur in the setting of sympathomimetics.
Respiratory: decreases tidal volume, increase respiratory rate, decrease ventilation; inhalable anesthetics are respiratory depressants (defined by decrease response to CO2 level changes)
MAC
MAC: median concentration that results in immobility in 50% of patients exposed to a noxious stimulus.
Corresponds to ED50 of quantal dose-response curve, but gives no information of slope of dose-response curve. Assume the response curve has a steep slope and 1.1 MAC achieves immobility in >95% of pts.
Changing MAC: MAC decrease with age and hypothermia and when used in conjunction with CNS depressants.
MAC increases with pregnancy and tolerance from chronic use of CNS drugs or alcohol.
MAC is additive with multiple anesthetics: nitrous oxide cannot achieve a 1 MAC dose at barometric pressure.
Giving a gas mixture with 60% NO2 usually corrsesponds to 40% of a MAC (60% tension; 40% MAC) meaning this mixture must also contain a dose of another anesthetic corresponding to 70% MAC to get the total 1.1 MAC.
Cisplatin and Carboplatin
The platinum coordination complexes have broad antineoplastic activity and have become the foundation for treatment of ovarian, head and neck, bladder, esophagus, lung, and colon cancers.
Do not form carbonium ion intermediates like other alkylating agents, but still covalently bind to nucleophilic sites on DNA to form inter- and intrastrand crosslinks (especially between guanines). These are recognized by p53, which halts growth.
Both are divalent water soluble platinum containing complexes. They enter the cell through a copper channel and are pumped out through ABC copper transporters and by multidrug resistance protein 1 (MRP 1). Resistance may also be caused by loss of function of the MMR proteins which recognize platinum-DNA adducts and intiate apoptosis.
Once in the cell, the chlorides/active groups are replaced by waters to become reactive compounds that can damage DNA. This is important because it explains why chloride diuresis helps prevent nephrotoxicity.
The two drugs show cross-resistance
Effects of cross linking are most pronounced during S phase, and are also associated with formation of a secondary leukemia.
Cisplatin
Cisplatin penetrates CNS poorly, most is covalently bound to plasma proteins (in contrast to carboplatin).
It is inactivated by aluminum, so must avoid contact with aluminum needles.
Side effects: can cause nephrotoxicity if not treated with chloride diuresis. Causes ototoxicity that is not helped by chloride treatment (more pronounced in children). Nausea and vomitting occur in almost all patients. Also causes myelosuppression, peripheral motor and sensory neuropathy.
Associated with development of AML
Often used following surgical resection of Stage I and II non-small cell lung cancer
Carboplatin
Relatively well tolerated, causing less nausea, neurotoxicity, ototoxicity, and nephrotoxicity than cisplatin. It also remains in its parent form in blood as it is less reactive than cisplatin.
It’s dose limiting toxicity is myelosuppression (thrombocytopenia)
Used the same as cisplatin in cases of non-small cell lung cancer and extensive-stage small cell lung cancer
Pemetrexed
A folate analog that differs from methotrexate in its transport properties and sites of action. It has proven useful in treating mesothelioma and non-small cell carcinomas of the lung.
It is a pyrrole-pyrimidine structure
Exerts effects on both thymidilate synthase and early steps in purine biosynthesis (TS, DHFR, ribonucleotide transformylase). Unlike methotrexate, it produces little change in the pool of reduced folates.
Enters cells mainly through the reduced folate transporter, which is upregulated in ALL cells
Active against mesothelioma and non-small cell adenocarcinomas of the lung, especially non-squamous tumors.
Main toxicity is myelosuppression, along with prominent erythematous and pruritic rash (which can be treated with dexamethasone). Some patients have unexpected severe myelosuppression (treat with folate)
Etoposide
Like the anthracyclines, they form a ternary complex with topoisomerase II and DNA and prevent resealing of the break that normally follows topoisomerase binding to DNA. The enzyme remains bound to the free end of the broken DNA strand, leading to an accumulation of DNA breaks and cell death
S and G2 hit the hardest
Resistance: amplification of mdr-1 gene, mutation of topo II, or mutations of p53
Used to treat small cell carcinoma of the lung (in combination with cisplatin and ifosfamide)
Can cause hypotension and bronchospasm if given too quickly.
Dose-limiting toxicity is leukopenia. Also has side effects of nausea, vomiting, et c. Hepatic toxicity is evident after high-dose treatment (toxicity increases with decreasing serum albumin)
Camptothecin Analogs
Irinotecan and Topotecan
Potent, cytotoxic neoplastic agents that target topoisomerase I (allow single strand cleavage but prevent Topo I from coming unbound).
Irinotecan is a pro-drug, topotecan is not.
S phase–specific cytotoxic agents
Resistance: Topotecan is a substrate for P-glycoprotein (mdr-1), but Irinotecan is not. Resistance can also result from mutated or decreased expression of Topo I.
Topotecan
Has relatively greater CNS penetration, and hepatic metabolism is not significant.
Used to treat patients with small cell lung cancer and ovarian cancer (2nd line treatment for small cell behind cisplatin/carboplatin combined with etoposide)
Dose-limiting toxicity is neutropenia (doesn’t have diarrhea side effect).
Irinotecan
Targets topoisomerase I
Converted to active form SN-38 by carboxylesterases in the liver.
Has a longer half-life than topotecan, but hepatic metabolism is significant (through glucuronidation).
Dose limiting toxicity is delayed diarrhea (treat with loperamide). The second most common toxicity is myelosuppression. Can also lead to an anticholinergic syndrome with diarrhea, hypersalivation, lacrimation, et c.
No longer used to treat non-small cell lung cancer due to difficulty in achieving proper blood levels.
Vinorelbine
Microtubule binding vinca alkaloid (like vincristine)
Administered in normal saline IV. Used with cisplatin for treatment of small cell lung cancer.
Primary toxicity is granulocytopenia (with less neurotoxicity as other vinca alkaloids)
An oral formulation is active in small cell carcinoma
Vincristine
Vinca alkaloid that blocks cell mitosis by blocking polymerization of microtubules.
Resistance: mdr-1, mutations in B-tubulin
Has limited myelosuppression, which makes it useful for combination with other drugs with myelosuppression as a side effect.
Metabolized by the liver and excreted in bile (as are all vinca alkaloids)
Side effect is neurologic toxicity, seen more in adults than in children
Gemcitabine
Pyrimidine Analog
Inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase, cell cycle-specific for the S-phase of the cycle (also blocks cellular progression at G1/S-phase). It can also hit non-proliferating cells via inducing apoptosis
Gemcitabine is phosphorylated intracellularly by deoxycytidine kinase to gemcitabine monophosphate, which is further phosphorylated to active metabolites gemcitabine diphosphate and gemcitabine triphosphate. Gemcitabine diphosphate inhibits DNA synthesis by inhibiting ribonucleotide reductase; gemcitabine triphosphate incorporates into DNA and inhibits DNA polymerase (chain terminator).
Can be used to treat non-small cell lung cancer
Activity greatly enhanced by combination with cisplatin/carboplatin
Myelosuppression is generally the dose-limiting toxicity, can’t use with radiation therapy
Resistance is through increased deactivation by deoxycytidine deaminase or decreased activation by deoxycytidine kinase
Paclitaxel and Docetaxel
Taxanes (docetaxel is synthetic congener of pacitaxel)
albumin-bound nanoparticle solutions that bind to a different B-tubulin site as the vinca alkaloids and inhibit disassembly of microtublues (very limited water solubility, but docetaxel is more soluble)
Resistance: mdr-1, B-tubulin mutations, an increase in survivin, alpha aurora kinase.
Does not depend on p53
Dose limiting toxicity of paclitaxel is neutropenia (treat with filgrastim). Also causes hypersensivity reactions (avoid by pre-treating with dexamethasone, diphenhydramine). Also causes peripheral neuropathy
Docetaxel causes more neutropenia but less neuropathy. Fluid retention is a problem here
Doxorubicin
Anthracycline
Intercalater of DNA, Topo II inhibitior, free radical generator.
Can be given with an iron chelator to prevent as much free radical formation to protect against dilated cardiomyopathy.
p53 or caspase dependent
Resistance: mdr-1, decreased activity/mutated Topo II, enhanced ability to repair strand breaks
Given IV, does not cross the BBB
Can turn urine red
Myelosuppression is dose limiting toxicity.
Gefitinib and Erlotinib
EGFR Inhibitor
Binds to the kinase domain and reversibly blocks enzymatic funtion of EGFR, killing EGFR cell lines
Monitor warfarin (INR) while on these drugs
Gefitinib: orally administered, used for non-small cell lung cancer. Most likely to be affective in nonsmokers, Asians, or women. Diarrhea and papular rash occur in 50% of patients. Intersitial lung disease occurs in 2%. Higher response rate happens in patients in activating mutations in EGFR
Erlotinib: orally administered (should not be taken with food). Approved for second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer. Side effects similar to Gefitinib, along with hepatic toxicity
Resistance: secondary mutations that change binding site. Amplification of met oncogene which amplifies downstream of EGFR.
Cetuximab
Monoclonal antibody that binds to the extra-cellular surface of EGFR to block receptor dimerization.
Given IV
Used for squamous cell carcinomas of the head and neck, colon cancer
Side effects: acneform rash in majority of patients, along with pruritis, nail changes, headache and diarrhea. May cause anaphylactoid reactions during infusion, especially among patients in southern US.
Bevacizumab
An anti-VEGF-A humanized monoclonal antibody which serves to reverse the “leakiness” induced by VEGF. This “leakiness” prevents adequate drug delivery to tumors.
When combined with carboplatin and paclitaxel increases survival in non-small cell lung cancer by 2 months (also for colon cancer, renal cell carcinoma)
Given IV
Contraindicated in patients with a history of hemoptysis, brain metastasis, or a bleeding diathesis. It also makes surgery more risky, and can cause severe hypertension and proteinuria. Can occosionally cause strokes, MIs, and gastric perforation.
Contraindicated in patients with squamous cell tumors due to unacceptably high rates of life-threatening hemoptysis in early phase clinical trials
Kinins
Kallikrein: located in plasma (creates bradykinin) and tissues (creates Kallidin); plasma prekallikrein activated by trypsin, Hageman factor, and kallikrein itself
Kininogens: located in plasma (LMW and HMW), lymph, and interstitial fluid (LMW)
Kinins: formed by Kallikreins or Kininogenases cleaving kininogens. (Bradykinin and Kallidin=Bradykinin+lysine)
Effects: arteriodilator peptides (decrease BP briefly), Venoconstriction (increase capillary P) and Endo cell contraction (leaky capillaries). Rapidly produced after injury and result in 4 classic signs of inflammation.
MOA: B1 and B2 receptors. B antag: anti-inflammatory; inhibit bronchoconstriction; pain mgmt..
Metabolism: Kininase I (made by liver) and Kininase II (ACE; found in lung)
Aprotinin: Kallikrein inhibitor; inhibition reduces bradykinin formation
Aspirin: prostaglandin mediates some actions of kinins
ACEinh or B agonist: enhances bradykinin effects (anti-HTN)
Salmeterol
Beta-2 Selective partial Agonist (new generation)
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); decrease BP; skeletal muscle tremor; decrease 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 >12 hrs (long acting don’t use for acute bronchospasm)
Tiotroprium
Antimuscarinic
Uses: asthma, COPD
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
24 hr DOA (long acting)
Asthma
Allergens: antigens that provoke IgE; most commonly proteins from dust mite, cockroach, dander, pollen, molds.
Mediators:
1) Early: (mast cells) histamine, LTC4, LTD4, PGD2, tryptase
2) Late: IL-5,9,13 results in inflam cells and reactivity
Triggers: viral infxn, cold air, etc. (usually not the antigen itself)
Testing: decreased FEV1 during methacholine inhalation
Note: Bronchoconstriction results from released mediators as well as from neural pathways (vagus nerve, NANC)
Asthma Tx:
Short-term(relievers): β agonist (salmeterol, formoterol), Theophylline
Long-term(controllers): inhaled corticosteroid, Leukotriene antagonists, cromolyn, nedocromil (inh mast cell degranulation)
when prescribing: first try β-agonist as needed only, if FEV1<80% predicted then add low dose steroid; finally add long acting β-agonist if symptoms not controlled.
Management of acute/ chronic asthma
Chronic asthma: anti-IgE omalizumab, reduces lymphocytic, eosinophilic bronchial inflammation
Acute asthma: Beta 2 agonist for mild attacks. Severe attacks require oxygen, albuterol, prednisone or methylprednisolone
COPD: not reversible with bronchodilator. Relieve acute symptoms with albuterol or ipratropium bromide. For persistent symptoms: long acting salmeterol, long acting tiotroprium. Antibiotics and theophylline (improve ventilation)
Theophylline
Methylxanthine
MOA:
1) PDE4 inhibitor, which increases cAMP (SM relaxation and decreased immune cell activation). Bronchodilation
2) inhibit adenosine receptors and therefore increases adenylyl cyclase activity. Adenosine normally causes bronchoconstriction, just like Acetylcholine does.
3) histone deacetylation: reduced transcription in immune cells.
Effects: bronchodilation and anti-inflammatory in asthma; cortical arousal; increases HR, BP (catecholamine release); increases secretion of gastric enzymes; diuretic
Well absored by GI tract
Note: narrow therapeutic range
Side effects: anorexia, nausea, vomiting, headache, anxiety, arrhythmia, death, insomnia
Roflumilast: PDE4 inhibitor used for COPD but not asthma
Histamine
Lungs dont have feedback inhibition of H2 histamine. Causes vasodilation, leakage of plasma mediators of acute inflammation, and antibodies. Attracts neutrophils, eosinophils, basophils, monocytes, lymphocytes
Released from degranulation of mast cells and basophils via IgE stimulation and cross linking.
Nervous system: H1 mediated. Urticarial response and neurons signaling inspiration and expiration, appetite and satiety.
Cardio: decreases systolic and diastolic blood pressure and increases heart rate. Vasodilation via H1. H2 receptors cause increased contractility and pacemaker activity.
Bronchiolar smooth muscle: bronchoconstriction by H1.
H1: In the smooth muscle, endothelium, brain. Gq, increase IP3 and DAG. Histaprofiden is a partial agonist. Mepyramine, triprolidine, cetirizine are partial antagonists or inverse agonist.
H2: Gastric mucosa, cardiac muscle, mast cells, brain. Gs increases cAMP. Amthamine is partial agonist. Cimetidine, rantidine, tiotidine are partial antagonists or inverse agonists.
1st generation antihistamines
H1 Antagonist
1st Generation: Readily enters the CNS
Rapidly absorbed; peak blood at 1-2 hrs
Other effects: slight sedation, anti-motion sickness
Uses: Allergic Rhinitis (Hay Fever), urticaria (very effective when given before exposure); largely ineffective in bronchial asthma and involves many mediators other than Histamine.
Cyclizine: DOA 4-6 hrs
Meclizine: DOA 12-24 hrs
Hydroxyzine: DOA 4-6 hrs
Carbanoxamine: ethanolamine: DOA 12-24hrs
Chlorpheniramine, Brompheniramine
Diphenhydramine
Benadryl
H1 Antagonist
1st Generation: Readily enters the CNS
Rapidly absorbed; peak blood at 1-2 hrs; DOA 4-6 hrs
Ethanolamine (like carbinoxamine)
Other effects: anticholinergic (blurred vision), marked sedation, anti-motion sickness activity, suppresses EPS from antipsychotics; Na+ channel block (more potent than procaine)
Uses: Allergic Rhinitis (Hay Fever), urticaria (very effective when given before exposure); largely ineffective in bronchial asthma and involves many mediators other than Histamine.
Dimenhydrinate
Dramamine
H1 Antagonist
1st Generation: Readily enters the CNS
Rapidly absorbed; peak blood at 1-2 hrs; DOA 4-6 hrs
Ethanolamine
Effects: anticholinergic, marked sedation, anti-motion sickness activity
Uses: marketed almost exclusively for motion sickness (Note for Scopolamine and H1 antag’s: best motion sickness achieved when combined with ephedrine/amphetamine)
Promethazine
H1 Antagonist
1st Generation: Readily enters the CNS
Rapidly absorbed; peak blood at 1-2 hrs; DOA 4-6 hrs
Phenothiazine
Other effects: anticholinergic (blurry vision), moderate sedation, antiserotonin, α-adrenoceptor block (orthostatic hypotension); Na+ channel block (more potent than procaine as local anesthetic)
Uses: Allergic Rhinitis (Hay Fever), urticaria (very effective when given before exposure); largely ineffective in bronchial asthma and involves many mediators other than Histamine; motion sickness; antiemetic
Cyproheptadine
Anti-serotonergic (& H1 Antagonist)
1st Generation: Readily enters the CNS
Rapidly absorbed; peak blood at 1-2 hrs; DOA 4-6 hrs
related to Phenothiazines
effects: moderate sedation, anticholinergic, antiserotonin (5-HT2),
Uses: cold-induced urticarial; SM manifestations of carcinoid tumor (ie; relieves bronchoconstriction), serotonin syndrome
Loratadine (Zyrtec)
H1 Antagonist
2nd Generation: Not likely to block H autonomic receptors; don’t distribute to the CNS; DOA 12-24 hrs (Longest acting)
Rapidly absorbed; peak blood at 1-2 hrs
Uses: Allergic Rhinitis (Hay Fever), urticaria (very effective when given before exposure); largely ineffective in bronchial asthma and involves many mediators other than Histamine.
Cetirizine (children’s zyrtec):Other: Inhibit Mast cell release of Histamine.(Beneficial in the treatment of rhinitis for children)
Fexofenadine: me too drug
H2 receptor antagonists
Cimetidine and Ranitidine
H2 receptor antagonists counteract the gastric secretions promoted by histamine.
OTC agents used to help treat PUD
Corticosteroids and stimulation of lung maturation in fetus
Corticosteroids and stimulation of lung maturation in fetus: treating mother with glucocorticoids reduces the incidence of respiratory distress syndrome in premature infants. when delivery is expected 34 weeks or before, betamethasone is used (good protein binding and placental metabolism allowing increased transfer across placenta into the fetus)
“Second Gas Effect”
Rapid uptake of N2O from alveolar gas serves to concentrate co-administered halogenated anesthetics, which speeds the induction of anesthesia (this is second gas effect)
On discontinuation of N2O, nitrous oxide gas can diffuse from blood to the alveoli, diluting O2 in the lung. This can produce diffusional hypoxia. To avoid, give 100% O2 rather than air following discontinuation of nitrous oxide
Piperacillin
A broad spectrum penicllin important for patients with gram-negative infections associated with bacteremias, pneumonias, infections following burns, and UTIs.
Main one that can treat P. aeuroinosa.
Often combined with tazobactam, a B-lactamase inhibitor
Ticarcillin
A penicillin similar to carbenicillin but is 2-3 times more active against P. aeruginosa.
Inferior to Piperacillin for infections caused by P. aeruginosa
Marketed in combination with clavulanate
Imipenem
B-lactam antibiotic that is resistant to most B-lactamses
Used against S. pneumoniae (penicillin resistant), enterococci, staphylococci, and Listeria species, especially hostpital acquired
Not absorbed orally
May cause nausea,vomitting, seizures, and hypersensitivity reactions
Used for UTI and lower respiratory tract infections, skin, soft tissue, bone, and joint, GYN, and intra abdominal infections.
Should not be used as monotherapy against P. aeruginosa because of risk of developing resistance.
Marketed in combination with cilastatin, which decreases imipenem degradation by the kidney
Meropenem
B-lactam antibiotic with some activity against imipenem resistant P. aeruginosa but less activity against gram positive cocci
derivative of thienamycin that does not require co-administration with cilastatin becaue it is not sensitive to renal dipeptidase
Less liklihood of causing seizures compared to Imipenem
Aztreonam
B-lactam antibiotic that induces the formation of long filamentous bacterial structures.
Resistant to many B-lactamases of gram-negative bacteria (has no effect against gram-positive bacteria)
Antimicrobial activity resembles that of an aminoglycoside
Acitivity is excellent against P. aeruginosa
Given IM or IV
well-tolerated (patients with hypersensitivity to penicillins often don’t react to this one)
Cephalosporins (General)
inhibit bacterial cell wall synthesis similar to B-lactams
Classified by arbitrary generations
None are effective against enterococci, MRSA, or listeria
Patients often show a positive Coombs test after large doses.
1st generation: good againts gram-positive and modest against gram-negative
2nd generation: increased activity against gram negative (oral administration for respiratory tract infections)
3rd: Substantial increase in activity against gram-negative bacteria, but much less so against gram-positives
4th: wide spectrum of positive and negative
Resistance: changing PBPs, destruction of the B-lactam ring
Cefuroxime
Second-Generation Cephalosporin
broader gram-negative activity against some Citrobacter and Enterobacter. Lacks activity against B. fragilis.
Effective in treating meningitis due to H. influenzae, N.meningitidis, and S. pneumoniae
Cefpodoxime proxetil
Orally administered third generation cephalosporin that is similar to fourth generation cefepime except that it is not more active against Enterobacter or Pseudomonas sp.
Cefotaxime
Third-Generation Cephalosporin
highly resistant to many B-lactamses and has good activity against many gram positive and gram negative bacteria. (but not B. fragilis)
Has been used effectively for meningitis caused by H. influenzae, * penicillin-sensitive *S. pneumoniae, and N. meningitides.
Ceftazidime
A Third Generation Cephalosporin with good activity against Pseudomonas.
Not as active as cefotaxime against gram-positive organisms.
Ceftriaxone
Similar activity as cefotazime and ceftizoxime.
A T1/2 of 8 hrs is the outstanding feature of this drug
Has been used for patients with meningitis, gonorrhea, et c with less doses than others
Cefepime
Fourth Generation Cephalosporin
Resistant to almost all B-lactamases, and is therefore effective against Enterobacteriaceae that are resistant to other cephalosporins
Has comparable activity to Ceftazidime in treatint Pseudomonas.
B-Lactamase Inhibitors
Most effective against plasmid encoded B-lactamases (inactive against the type I chromosomal B-lactamases)
Clavulanic Acid: suicide inhibitor that is well absorbed by mouth. Has been combined with amoxicillin and ticarcillin
Sulbactam: similar to clavulinic acid, given orally or parenterally
Tazobactam: penicillanic acid sulfone-B lactamase inhibitor that has poor activity against the Type I lactamases. Combined with piperacillin. May not be as effective as piperacillin alone when treating resistant P. aeruginosa
Erythromycin
Macrolide
Bacteriostatic (-cidal in large conc.) agent that binds to 50S subunit of bacterial ribosomes
Most active against aerobic gram-positive cocci and bacillus, inactive against most aerobic enteric gram-negative bacteria
Active against S pneumoniae, M. pneumoniae and a ton other
Stomach acid breaks it down, given in protective tablet; food delays absorption. Does not enter CNS
Oral administration of this can lead to epigastric distress (activates motility),
Can also lead to cholestatic hepatitis
Telithromycin
Ketolide similar to macrolides in MOA, but less susceptible to methylase mediated and efflux-mediated mechanisms of resistance than the Macrolides.
Similar activity as clarithromycin and azithromycin, often used for macrolide resistant S. aureus and S. pneumo
Same 50S ribosomal target as macrolides
No parenteral form
Contraindicated in Mysasthenia Gravis patients, also associated with loss of conscioiusness and visual disturbances
Clarithromycin
Slightly more active against strep and staph compared to Erythromycin
Activity against M. leprae, MAC complexes
Absorbed rapidly from GI tract, can be given with or without food
Resistant to methylation of the 50S, as it does not induce methylation of the 50S subunit (also not a substrate for efflux pump)
Azithromycin
Less active than erythromycin against gram-positive organisms, but more active against H. influenzae and Camplyobacter.
It and clarithromycin have enhanced activity against M. avium.
Rapidly absorbed and distributed (but not in CNS). Should not be administered with food
Can treat MAC complexes
Macrolides
Bind to 50S ribosomal subunit and inhibit translocation
Resistance: 1)drug efflux by an active pump mechanism (mrsA, mefA, or mefE)
2) ribosomal protection by inducible/constituitive methylase enzymes modifying ribosomal target (erm genes)
3) macrolide hydrolysis by esterases (Enterobacteriaceae)
4) chromosomal mutations that alter 50S subunit
All but azythromycin inhibit CYP3A4
Side Effects: hepatotoxicty (more so in erythromycin than in Clarithromycin or Azithromycin). All but azithromycin have been shown to cause cardiac arrhythmias (QT prolongation, bradycardia)
Quinolones
Target bacterial DNA gyrase (more for gram-negatives) and topoisomerase IV (more for gram-positives)
Potent against E. coli, Salmonella, Shigella, Enterobacter, Campylobacter, and Neisseria.
Can be used against multidrug resistant TB, M. avium, and atypical mycobacterial infections
Resistance: mutations in gyrase or Topo IV or by active transport out of the cell (no quinolone modifications)
Well absorbed following oral administration; cleared by kidney (watch for kidney problems)
Well tolerated; some GI discomfort; may cause joint problems in children
Use with caution in pateints on class III and class IA antiarrhythmics
Levofloxin
A quinolone that is useful against streptococci
the antibiotic of choice for L. pneumophila
Moxifloxacin
A quinolone that is useful against streptococci
Cleared by the liver (watch for hepatic failure)
Gatifloxacin
A quinolone that is useful against streptococci
Associated with both hypo- and hyperglycemia in older adults
No longer on the market because of these problems
Trimethoprim-Sulfamethoxazole
Trimethoprim inihibits bacterial DHFR
Sulfamethoxazole inhibits incorporation of PABA into folic acid
Used to treat S.pneumoniae along with a ton more
Resistance is through a plasmid encoded altered DHFR
Effective for acute exacerbations of chronic bronchitis. It should not be used to treat strep pharyngitis. Also effective for acute otitis media in children and acute maxillary sinusitits in adults caused by H. influenzae and S. pneumoniae.
Also useful to treat Pneumocystis jiroveci and used prophylatically for patients with neutropenia.
Relatively well tolerated, but may induce folate deficiency in patient’s already suffering from low folate
Amphotericin B
Polyene
MOA: forms pores by binding to ergosterol in fungi cell membranes
Four formulations: conventional (DOC or C-AMP), liposomal, lipid complex (most expensive), and colloidal dispersion
GI absorption is negligible
Works against Candida, Crytococcus, Blastomyces, Histoplamsa, Sporothrix, Coccidiodes, Paracoccidioides, Aspergillus, and the agents of mucormycosis
Aspergillus terreus and nidulans may be more resistant than other Aspergillus species. Resistance is by replacing ergosterol with other precursor sterols
Side Effects: fever and chills, nephrotoxicity (least with the lipid formulation). Tachypnea and respiratory stridor or modest hypotension may also occur, but these effects are short lived (30-45 minutes). Azotemia occurs in 80% of patients with C-AMB. Anemia may also occur due to decreased production of erythropoietin
Flucytosine
Fluorinated pyrimidine that is deaminated to fluorouracil, formed into FUMP, and incorporated into RNA or formed into FdUMP which blocks thymidylate synthetase.
MOA: DNA synthesis is impaired
Used against Cryptococcus, Candida, and the agents of chromoblastomycosis
Resistance: occurs often when used as monotherapy; either loses permease needed for cytosine transport or decreases activity of enzymes needed for metabolism.
Absorbed well from GI tract (reduce doses in patients with renal problems)
Used in combination with amphotericin B
Side Effects: may depress bone marrow, rash, nausea, vomiting, diarrhea, enterocolitis (all more frequent in AIDS patients)
Azoles (General)
MOA: 14 alpha-lanosterol demethylase inhibitors that serve to inhibit ergosterol synthesis
Resistance: mutations in gene for demethylase, increased azole efflux via an ABC, increased production of the demethylase
Interact with hepatic CYPs
Ketoconazole
Imidazole
Largely replaced by itraconazole except when cost is prohibitive
Administered orally, also available for topical use
Has some effect on corticosteroid suppression, can be used in Cushing’s
Lots of hepatotoxicity
Itraconazole
Synthetic triazole
Can be taken orally, is a substrate and inhibitor of CYP3A4 (watch for quinidine, halfantrine, levomethadyl)
Use for indolent, nonmeningeal infections due to B. dermatitidis, H. capsulatum, P. brasiliensis, and C. immitis (as well as some indolent invasive aspergillosis)
Not recommended for cryptococcal infections in AIDS patients due to high relapse ratios
Side Effects: potential hepatotoxicity, congestive heart failure in patients with impaired ventricular function, GI complaints, rash
Fluconazole
Triazole
Completely absorbed in the GI tract, enters the CSF well; it is an inhibitor of CYP3A4
Used especially in candidiasis and crytococcosis (meningitis in AIDS patients), coccidiodal meningitis
No activity against histo, blasto, aspergillus, mucomycosis or sporotrichosis
Side Effects: nausea, headache, potentially teratogenic
Voriconazole
Triazole
Orally available, genetic polymorphisms in population can affect metabolism
Better than amphotericin B for invasive aspergillosis, also used for candidiasis. Also for pneumocystis jiroveci
Side Effects: contraindicated in pregnancy, causes occasional hepatotoxicity, prolongation of QT interval, visual side effects.
Posaconazole
Triazole
Good against mucormycosis
Bioavailability enhanced by taking with food/increased gastric acid; metabolized by UDP glucuronidation
As good as fluconazole for candidiasis
Inhibits CYP3A4
Good safety profile with nausea, vomiting, diarrhea, abdominal pain, and headache most common side effects
Amantadine and Rimantadine
Anti-Influenza Agents
Rimantadine is a derivative of amantadine
MOA: inhibit viral uncoating and alter hemagglutinin processing on the influenza A (only) virus M2 protein
Well absorbed after oral administration (elderly need less of a dose).
Side Effects: dose-related CNS (nervousness, light headedness, insomnia) and GI side (effectsloss of appetite or nausea)
Can be used prophylactically
Effective if used within 2 days of onset of symptoms
Resistance is prevalent due to a mutation in the M2 protein
Oseltamivir
Anti-influenza Agent
Transition-state analog of sialic acid that is a potent selective inhibitor of influenza A and B virus neuramidases
Inhibits viral release from host cells
Mutations in neuramidase lead to resistance (seasonal flu is 100% resistant, H1N1 is susceptible)
Given orally
Side Effects: nausea, abdominal discomfort, emesis (preventable with administration with food)
Tuberculosis Treatment
Combination therapy in practice is isoniazid, rifampin, and pyrazinamide for two months (initiation phase) followed by intermittent rifampin and isoniazid (continuation phase)
Zanamivir
Nasally inhaled dry powder
Binds to neuramidase like oseltamivir
Used against A, B and H1N1
MOR: mutations in neuramidase or hemagglutinase
Well tolerated, but don’t use with patients with respiratory diseases like asthma
Bosentan
ET-1 antagonist (endothelin)
Used to treat pulmonary arterial hypertension, decreasing pulmonary vascular resistance
Methacholine
Muscarinic receptor agonist
Used in asthma challenge test
N-acetylcysteine
Mucolytic- can loosen mucous plugs in CF patients
Antidote for acetaminophen overdose
