Cockroft - Gault

• gold standard to estimate CrCl (glomerular filtration)
• CrCL= [140-age) x wt(kg)]/ (72 x SCr)
• x 0.85 for females
• dosage adjustments of drugs eliminated renally is based on an estimation of renal function using the cockroft gault equation

Rectal Drug Absorption

• works well in children who are vomiting or seizing
• occurs by passive diffusion
• works well for lipohilic/nonionic drugs
• if absorbed from lower aspect of rectum, bypass portal circulation and first pass metabolism of liver

Warfarin 

• anticoagulant
• metabolized (inact) by CYP2C9
• inhibits VKORC1
• can have SNP in either of these

P-glycoprotein

• phase III drug metabolism
• active transport of drugs out of the cell using ATP dependent drug efflux pump
• shares substrates w/ many CYPS
• inc intestinal expression = low bioavailability (keeps drugs out of system)
• dec brain expression linked to drug resistant epilepsy

Quantal Dose-Effect

• % of people that exhibit the pharm effect (yes/no)
• population data curve made
• Median effective dose (ED50)
• Median lethal dose (LD50)
• Therapeutic index = LD50/ED50
• warfarin has narrow therapeutic index and penicillin has a wide one

Gompertzian Model

• cancer growth model
• MAximum growth rate is at approx 1/3 of maximal tumor volume and slows to a plateau near lethal tumor volume
• this is more consistent with the sense that tumors appear to grow more quickly once detected

Cell cycle Phase Nonspecific Agents 

(CCNS)

• classic alkylating agents
• nitrosoureases
• non classic alkylating agents
• platinum analogs

Alkylating Agents (Cell Cycle non-specific)

• bis amines, nitrosoureases (-ustine), aziridines, alkylsufonate
• forms a storng electrophile through formation of carbonium ion intermediates
• transfer of alkyl groups to nucleic acid and proteins
• cross linking btw two DNA strands or btw two bases in the same strand
• inhibits DNA replication
• greatest effect on rapidly dividing cells
• inhibits all rapidly dividing tissues: toxic side effects are bone marrow depression and nausea and vomiting when given IV

Classic Alkylating Agents

• cyclophosphamide, ifosfamide
• must be activated by CYP
• major adverse effects: leukopenia, thrombocytopenie, and hemorrhagic cystitis (bladder inflam)
• MESNA protects urinary tract from urotoxic metabolites of cyclophosphamide and ifosfamide

Nitrosoureases

• highly lipid soluble, able to cross BBB (brain tumors)
• bifunctional alkylating agent 
• splits into two metabolites
• carbonium ion acts as a tpiacl alkylating agent
• isothiocyanate may interact with proteins and account for some 

Non Classic Alkylating agents 

• procarbazine, dacarbazine
• highest carcinogenic potential for alkylating agents

Platinum Analogs

• cisplatin, carboplatin, oxaliplatin
• forms cross links within DNA strands
• not really alkylating agents
• useful in solid tumors: lung, esophageal and gastric cancers, head and neck, testicular ovary and bladder
• adverse effects: nausea and vomiting, nephrotoxicity (urinary excretion)

Pyrimidine Antagonists

(antimetabolites)

• 5-Fluorouracil, interferes with thymidylate synthesis
• Cytarabine (cytosine): inhibits DNA pol and is for hematologic malignancies (not solid tumors)
• Gemcitabine (cytosine): inh DNApol and lung, pancreatic and bladder chancers
• high intracellular conc and prolonged half life

Purine antagonists

• 6 mercaptopurine, thioguanine
• inhibits enzymes for purine nucleotide biosynthesis
• inhibits glycoprotein synthesis and formation of DNA and RNA
• useful in acute leukemia

Methotrexate

• folic acid antagonist 
• inhibits dihydrofolate reductase (DHFR), which interferes with the synthesis of thymidylate, purine nucleotides, serine, methionine
• Leucovorin is a rescue for MTX induced bone marrow suprresion (folinic acid and unaffected by inh of DHFR)
• premetrexed inhibits Thymidylate synthase and DHFR

Vinca Alkaloids

• cell cycle specific -M phase
• vincristine, vinblastine, vinorelbine
• binds to tubulin
• mitotic inh or spindle poisons
• inhibits tubulin polymerization
• disrupts microtubule asemble 

Taxane Plant Alkaloids 

• Paclitaxel, docetaxel, and cabazitaxel
• mitotic spindle inh or spindle poisons
• bind to tubulin
• promotes tubuline polymerization and promotes microtubule assembly
• retards microtuble dissasembly
• hypersens observed in som patients (lung cancer)
• premedication with corticosteroids and antihistamines

Epipodophyllotoxins

• G-1 through s phase
• etoposide and teniposide
• mech of action: inhibitor of topoisomerase II; produce DNA damage (strand breaks)

Camptothecins 

• cell cycle nonspecific
• topotecan, irinotecan
• inhibit topoisomerase I ((enzyme responsible for cutting and religating single DNA strands; induced DNA damage

Anthracyclines

• antitumor antibiotics (cell cycle nonspecific)
• microbial producs
• intercalating topo inhibs that insert btw DNA base pairs
• interfere with DNA and RNA synthesis
• produce single strand breaks and free radicals
• cardiotoxiciity
• erythema and desquamation of skin sites prior radiation

Bleomycin 

• G2 - M phase
• mech of action: free radical formation, DNA-bleomycin-iron II complex
• single and double stand breaks
• pulmonary toxicity 

Tamoxifen

• selective estrogen rec modulator (SERM)
• competitive partial agonist - inh of estrogen
• early and metastatic ER positive breast cancer
• preventitive application of women with high risk
• menopausal smptoms and edema

Flutamide, bicalutamide

• anti androgen
• early stage and metastic prostate cancer
• nausea, mild hepatoxicity

Imatinib

• inh of tyrosine kinase domain of the Bcr-abl oncoprotein
• Bcr-abl gene philadalphia chrom - t(9:22)
• CML
• inh tyrosine kinases for PDGFR, stem cell factor and C-kit
• dasatinib, nilotinib

Bevacizumab

• VEGFR inhibitor 
• recombinant humanized monoclonal Ab
• targets all form of VEGF-A
• sorafenib, suntinib, pazopanib: hepatocellular
• bleeding and wound healing complications
• bloody or tarry stools

Phenylalanine to Epinephrine

• Ph is converted to tyrosine in the liver by phenylalanine hydroxylase
• tyrosine enters cell and converted to DOPA by tyrosine hydroxylase (rate limit)
• Dopa converted to dopamine by AAADC
• Dopamine enters vescicle by VMAT
• dopamine converted to NE by dopamine beta hydroxylase
• levers vesicle and converted to Epi by PNMT

Alpha adrenergic Receptors

• alpha 1: vasoconstriction and constriction of GI and GU sphincters
• Alpha 2: decrease sypmathetic outflow; decrease NE release (peripheral and central); can be automodulators

Beta Adrenoceptors

• beta1: increased heart funciton and increased renin secrtion
• Beta2: vasodilation and bronchoidlation
• Beta3: lipolysis

Metabolism of NE and Epi

• MOA: cytoplasmic pool, liver, kidney, gut other tissues (mitochondrial)
• COMT: specific for catecholamines, in liver, kidney and brain
• both metabolisms lead to VMA

Clonidine

• alpha 2 rec agonist
• activates presynaptic alpha 2 rec: decreases NE release
• inhibition of Ca influx
• used to treat hypertension, withdrawal, and glaucoma(dec aqueous humor production)
• Adverse: sedation, CNS depression, dry mouth, tolerance, hypotension

Adrenergic Reuptake Inhibitors

• cocaine and TC antidepressants
• inhibits NE transporter on cemm membrane (NET)
• increase NE sympathomimetic effects (HR, BP, sweating, ect)
• can inhibit indirectly acting amines (tyramine)

MAO inhibitors

• tranylcypromine and selegiline
• may enhance NE effect
• used as anti=depressants and to treat parkinsons
• increased response to indirecly acting sympathomimetics (tyramine)
• risk of hypertensive crisis)

COMT

• entacapone and tolcapone
• inhibit metabolism of levodopa (L-Dopa)
• Tx-parkinsonism

Phenylephrine

(sudafed)

• Alpha 1 agonist: along with midorine, methoxamine, ect
• used to treat nasal congestion, hypotension, paroxysmal tachycardia
• causes mydriasisi (pupil dilaiton), nasal vasoconstriction, smooth muscle contraction, arterial and veno constriciton, and bladder internals sphincter constriction
• inverse effects are rebound nasal congestion, hypertension, headahce, bladder urinary retension

Albuterol

• beta2 agonist
• smooth muslce relaxation (broncho and vasodilation)m glucogenolysis and gluconeogensis
• inc insulin secretion
• therapeutic uses: asthma, COPD, bronchospasm
• adverse effects: tremors, tachycardia, tolerance, nervousness, hperglycemia, lactic acidosis

Dobutamine

• Beta one selectivea gonist
• increase heart contractility, automaticity and conduction velocity
• increased secretion of renin
• increased lipolysisi which leads to increased FFA
• used for acute heart failure or cardiogenic shock

Ephedrine

• agonists of alpha and beta receptors
• resistant to MAO, and COMT metabolism
• vasoconstriction, slight inc in HRm CNS stimulation (inc allertness)
• used as decongestant, prophylactic Tx -bronchospasms, and orthostatic hypotension
• advrese effects: hypertension, insomnia, anxiety, tachycardia and arrhythmias

Phenoxybenzamine (PBZ)

• non specific alpha rec antagonist (alpha1 > alpha 2)
• irreversible noncompetitive inhibitor (unlike PHN)
• causes vasodilation, dec TPR, and dec BP
• Inc HR and CO from reflex
• uses: phechromocytoma (beta blocker), hypertension/hypertensive crises
• adverse effects: orthostatic hypotension, tachycardia, myocardial ischemia

Phentolamine (PHN)

• inhibits alpha 1 = alpha 2
• competitive, reversible inbibitor
• similar to PBZ
• vasodilation causes dec TPR and dec BP
• more prominent reflex in HR and CO (alpha 2 inh)
• used in hypertensive crisis, and pheochromocytoma (beta blocker)
• faster onset than PBZ and shorter duration
• adverse effect:hypotension, tachycardia, nasal congestion

Prazosin, Tramsulosin

• alpha 1 selective antagonist
• vasodilaiton (both arterial and venous)
• dec in TPR and dec  in BP
• smooth muscle relaxation (prostate)
• therapeutic uses: hypertension, benign prostatic hyperplasia (tamsulosin)
• drug interactinos: PDE5 and antihypertensives
• adverse effects: dizziness, orthostatic hypotensino, "first dose syncope"

Yohimbine

• alpha 2 receptor selective antagonist
• inc sympathetic outlfow from CNS, inc BP, inc HR
• Tx not fully established: sexual dysfunction and hypotension

Propranolol

• non selective Beta receptor antagonist
• long term dec in BP, CO, dec in CO and renin release
• bronchoconstriction, inh of Epi induced glycogenolysis, dec in lipolysis, and dec HDL
• uses: hypertension, angina, post MI, arrhythmia and migraine
• adverse effects: bary cardia, hypotenison, bronchoconstriction, sexual dysfunction
• timolol and nadolol effec is similar but lower CNS effects

Beta 1 selective antagonists

• metoprolol, bisoprolol, atenolol, esmolol
• used angina, hypertension, post MI, and HF (metoprolol)
• esmolol used for tachycardia and hypertension

Pindolol, acebutolol, carteolol, penbutolol

• beta blockers with ISA
• partial agonists (less efficacy than full agonists (effects lower than antagonists
• advantages over other beta blockers: dec TPR, dec HR and contractility; less bronchoconstriction, less cold extremeties ect
• uses: hyperteion, arrhtythmias, not effectve tx angina

Labetalol and Carvedilol

• non-specific beta block and specific alpha 1 block
• antioxidant activity (carvedilol)
• effects: usual beta blocker effects plus dec TPR (alpha 1) and inc HDL (alpha1)
• uses: heart failure (c), LV dysfunction (C) and hyperension
• adverse effects: orthostatic hypotension, bradycardia, AV block, raynaud's depression, hepatotoxcity (L)

Muscarinic Receptor Types

• M1 in CNS
• M2 in heart
• M3 in smooth muscle and gland secretion
• activates IP3 and also Gi to inhibit A/C
• also opens potassium channels, hyperpolarization of cardic cell membrane
• muscarinic rec in eye cause ciliary muscles to help get rid of aqueous humor and control the sphincter (M) for focus

Bethanechol

• muscarinic agonist, negligible effect at nicotinic receptors
• negligible susceptibility to AChE, significantly resistant to hydrolysis
• longer duration of action 
• clinical use: most widely used, post op and pos partum urinary retention (SC), to inc GI motility postoperatively (orally)

Carbachol

• non-selective muscarinic and nicotinic agonist 
• not hydrolysed by AChE, similar to betanechol
• topical, ocular and intraocular
• clinical use: glaucoma and miosis in ophthalmic surgery

pilocarpine

• salagen (plant)
• partial agonist (like bethanechol), greater affinity for muscarinic than nicotinic
• not hydrolyzed by AChE, topical, ocular and oral administration
• clinical use: glaucoma, sjogrens syndrome (to increase salivary secretions)

Cevimeline

• synthetic muscarinic agonist similar to pilocarpine
• not hydrolyzed by cholinesterase
• oral
• clinical use: xerostomia or dry mouth assoc w/ sjogren's syndrome

Edrophonium

• reversibly bind to active site of AChE
• prevent ACh ascess
• enzyme inhibitor complex relatively unstable, short lived (2-10 mins)
• Neostigmine, physostigmine (carbamates) has longer duration of action (30min-6h)

Muscarinic Antagonists

• Atropine: highly seletive, ocular, mydriasis of visual exam, treatment of bradycardia, and tremors from parkinsons
• Scopolamine: competitive muscarinic blocker, goes to CNS, transdermal patch for motion sickness
• Hyoscyamine: decrease intestinal spasms
• Ipratropium, benztropine: treatment of emphysema and chronic bronchhitis, asthma, parkinsons 
• Oxybutynin: treatment for hyperactive bladder 

Ganglionic blocker agents

• anti nicotinc drugs
• Hexamethonium:occupy sites on nicotinic ion channesl, used in hyprension
• EA: short duration
• Trimethaphan: short acting, used in hypertensive emergencies
• Mecamylamine: adjunct with transdermal nicotine patch

Tubocurarine

• non depolarizing NMJ blocker
• competitive inh
• reversed b cholinesterase inhibitors
• inhibits skeletal muscle contraction
• no CNS effects
• flacid paralysis
• can result in systemic histamine release leading to hypotension
• large doses lead to dec BP 

SuccinylCholine

• depolarizing NMJ inhibitor
• Two phases (irreversible and then competitive inh)
• fasciculations then flaccid paralysis
• adverse effects: inc intraocular pressure, malignant hyperthermia (inc in heat production), inc intragastric pressure, and muscle pain or myalgia
• when in phase two anticholinesterases can recovery (neostigmine and physostigime)

Horner Syndrome

• caused by pancoast tumor (interruption of left sympathetic nerve chian)
• ptosis (drooping eye)
• miosis (constriction of pupil)
• anhidrosis (loss of sweating)
• cause by an compression of the brachial plexus

Systemic Chemotherapy for NSCLC

• platinum agents: cisplatin, carboplatin (crosslinks within DNA)
• Taxans: paclitaxel, docetaxel (promotes tubulin polym)
• gemcitabine (pyrimidine/cytosine analog)
• pemetrexed (anti folate (inh thymidylate synthase)
• vinorelbine (vinca alkaloid, inhibit tuulin polym)
• Etoposide (epipodophyllotoxins/ top II inh)

Systemic Targeted Lung Cancer Therapy

• Bevacizumab: anti VEGF
• EGFR antagonists: erlotinib, afatinib, cetuximab)
• ALK(anaplastic lymphoma kinase) positive: crizotinib

Selective Long Acting Beta 2 receptor

Agonists

• salmeterol, formoterol, indaceterol
• onset: 5mins for formoterol and indaceterol but 20 mins fo salmeterol
• not for acute bronchospasms
• bronchopretective
• indaceterol, arformoterol and vilanterol used for COPD

Asthma and COPD 

Anticholinergics

• Ipratropium (SAMA) - onset 5 mins and for acute bronchospasms
• Tiotropium, Umeclidinium, aclidinium (LAMA): long acting and only used as first line therapy in COPD
• Adverse effects: dry mouth, blurred vission, exacerbatino of glaucoma, and rare reports of urinary retention in adults

Theophyline

• non specific phosphodiesterase inh and antagonizes Adenosine (a bronchoconstrictor)
• metabolized by CYP1A2
• narrow therapeutic index
• Uses: IV for severe acute asthma exacerbation or for asthma and COPD if disease refractory to other meds
• Adverse: 

Leukotriene Modifiers

• zafirlukas, montelukast: compet antagon of cys-LT1 rec, adverse (Z inhibts CYP2C9 and CYP3A4 so dont use with warfarin)
• Ziluton: sel inh of 5lipoxygenase (turns AA into LTA4), causes liver enzyme elevation
• Long term control of asthma in adults, efficacy inferior compared to corticosteroids, prohylaxis of exercise induced asthma

Nodular ILD

• small focal lesions
• silicosis
• coal workers pneumoconiosis
• sarcoidosis
• lymphangitic carcinomatosis

Reticular ILD

• irregular linear opacification
• chronic interstitial pneumonias
• collagen vascular diseases
• asbestosis
• lymphangitic carcinomatosis

Cystic ILD

• honeycombing (end stage processs): end stage pneumothorax 
• Lung cysts: lymphangioleiomyomatosis
• cavitary nodules: histocytosis

Ground Glass opacification ILD

• CT delineation
• amorphous increase in attenuation
• alveolar proteinosis
• DIP
• hypersensitivity pneumonitis
• pulmonary edema or hemorrhage
• pneumocystis carinii
• Respiratory distress syndrome (bilateral and symetrical)

Parenchymal opacification ILD

• often a component of diffuse infiltrating process, even though airspace/alveolar opacificatino exists
• pulmonary vasculate is opacified
• air bronchograms exist: chronic eosinophic pneumonia, bronchoalveolar carcinoma, lymphoma, cryptogenic organizing pneumonia/bronchiolitis obliterans wiht organizing pneumonia

Lofgren Syndrome

• erythema nodosum
• polyarthritis
• bilateral hilar lymphadenopathy (BHL)
• predicts an excellent prognosis and is associated with
• prognosis of spontaneous sarcoidosis remission 80%

Congenital Pulmonary Airway malformatin

• CPAM type O: tracheal very rare and fatal
• Bronchus (1): Large cyst, most common, good prognosis
• Brochiole (2): 10-15% of cases with poorer prognosis, and assoc with other anomalies
• Alveolar Duct (3): rare and high mortalite, involves entire lobe and even entire lung (small cysts)
• Alveolus (4): aprox 10-15% of cases assoc with pleuropulmonary blastoma; cyss lined with type I and II pneumocytes

CF in Lungs

• decrease H2O in mucus secretions
• most severely effects pancrease and then lungs
• lungs have increased IL-8 which attracts increased neutrophils and increased proteases
• Upper airways: nasopharyngeal inflam poyps, neutrophils and plasma cells
• Lower airway: include bronchiectasis with inc resp infectinos
• mutation deltaF508
• Geater than or equal 60mmol/L is diagnosis

Meconium Aspiration

• pulmonary hypertension with history of meconium staining
• imaging: inc aeration, patchy abnormalities, air trapping
• treatment: prevention and ECMO
• ECMO: venous blood removed from RA, membrane oxygenated, oxygenated blood returend to aorta, transient delivery of oxygenated blood to infant, like an artificial lung

Acute Laryngotracheobronchitis

• croup
• most common disease for subglottic area or disease of upper airways
• whooping cough or barking cough
• subglottic area is elongated and narrowed symmetrically
• proximal 1cm of trachea
• dilation (ballooning) of hypopharynx

Bronchopulmonary Dysplasia

• chronic lung disease of infancy (oxygen dependent at 4 wks of age)
• lung injury: barotrauma, oxidant injury, inflam med
• consequences: airway obstruction, decreased alveolar SA, hypoxemia, increased pulmonary arterial muscularizaiion (fails to go away at birth), increased work of breathing and poor growth
• treatment: support somatic growth, minimize work of breathing (diuretics to dry lung), prevent secondary infection/inflam

PE CXR Findings

• consolidation, pleural effusion, atelectasis, and prominent central pulmonary artery
• Hamptons hump (represents infarcted lung; does triangle pattern)
• Westmark's sign (lack blood flow: indicates a lack of vascular markings distal to the pulmonary embolic obstruction 

Clinical Features Suggesting Vasculitis

• multisystem inflammatino, rapidly progressive organ dysfunctnio
• constitutional symptoms (fever, weight loss)
• High ESR, severe anemia, throbocytosis
• In kidneys: active urinary sediment
• in lungs: hemoptysis, dyspnea
• skin: palpable purpura/hemorrhage
• acute neurologic changes: footdrop, altered metnal status

Endothelin-1

• elevated levels are seen in PAH patients
• levels correlate to severity of the disease
• fibrosis (inc fibroblast proliferation)
• hypertrophy (cardiac/vascular)
• cell proliferatino (vasc smooth muscle and fibroblast)
• inflammation (inc vasc permeability and neutrophil/mast cell act)
• vasoconstriction (direct or via renin)
• endothelin receptor antagonist can block there effects
• people with PAH also have impaired prostacyclin and Nitric Oxide Production

Metal Chelators

• EDTA: lead and cadmium
• BAL: lead, mercury, arsenic, cadmium
• DMSA (less toxic than BAL): lead, mercury, arsenic, cadmium
• Penicillamine: lead, mercury, arsenic and copper (major use for copper/wilson's disease)
• Trientine: detox of copper in wilson's (for patients w/ penicillin allergy)
• Deferoxamine: iron chelation only

Asthma

• Curschmann' spirals (whorls of shed epi) and charcot leyden crystals (MB proteins)
• wheezing, dyspnea and cough
• thickened basement membranes and eosinophils in sputum
• edema and inflamation
• smooth muscle hypertrophy
• Drug induced asthma inhibition of the cyclo-oxygenase pathway of the AA metabolism without affecting the lipoxygenase route (shifts ballance toward leukotrients that cause bronchial spasm)