Pharma Drug Tables - 1st Shifting

Monique · Wine · Jamie · Juria · Lenard PHARMACOLOGY: COMPREHENSIVE TABLE OF DRUGS (1st Shifting Period) | Page 1 of 29Section 2D – Batch 2014

COMPREHENSIVE TABLE OF DRUGS1st Shifting Period

NOTE: Should there be any discrepancies between this table and what’s written in the transes, please consult KATZUNG for confirmation and go instead with what’s indicated in the textbook. Thank you!CHOLINERGIC AGONISTS (PARASYMPATHOMIMETICS)

A. CHOLINORECEPTOR-ACTIVATINGMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

AcetylcholineBinds to and activates muscarinic or nicotinic receptors.

2 Major mechanisms:

1) Ach release activates muscarinic receptors on effector cells & alters organ function directly.

2) Ach Release interacts with the muscarinic receptors on nerve terminals to inhibit release of neurotransmitter.

Eyes Miosis Accommodation for near vision Contraction of both the smooth

muscles of the iris and the ciliary muscles facilitate aqueous humor outflow into the canal of Schlemm, draining the anterior chamber and thus helping in the treatment of glaucoma.

Cardiovascular System (-) inotropic, chronotropic,

dromotropic effects Reduction in peripheral vascular

resistance Vasodilation Decreased BP

reflex increase in heart rate Direct cardiac actions of

muscarinic stimulants are mediated by M2 receptors while vasodilation arises from activation of M3 receptors.

Respiratory System Bronchoconstriction Stimulation of bronchial gland

secretions Gastrointestinal System

Increased motility Relaxation of sphincters Stimulation of gastric secretions,

but less stimulation in pancreatic and intestinal secretions

The M3 receptor is required for direct activation of smooth muscle contraction while the M2 receptor reduces cAMP formation and relaxation caused by adrenergic agonists.

Genitourinary System Stimulation of detrusor muscle and

relaxation of trigone and bladder muscles increased voiding

Glands Increased secretion of sweat,

salivary, lacrimal, and nasopharyngeal secretions.

Central Nervous System The brain has more muscarinic

very rapidly hydrolyzes, therefore needing a large amount given in IV to take effect (but only lasts 5-20 seconds)

Methacoline more resistant to hydrolysis

Carbachol

more resistant to hydrolysis and has longer duration of actionBethanecol

post-op ileus, reflux esopahagitis, urinary retention


receptors, the spinal cord has more nicotinic receptors.

Chronic exposure to nicotine increases high-affinity agonist binding, permitting greater release of dopamine in the mesolimbic system mild alerting action and addictive property of nicotine from tobacco

B. CHOLINESTERASE INHIBITORSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

SIMPLE ALCOHOLEdrophonium

Hydrolyzes acetylcholine to choline and acetic acid.

Increases the endogenous acetylcholine concentration in synaptic clefts & neuroeffector junctions (amplifiers).

Some can also inhibit butyrylcholinesterase (pseudocholinesterase), but has little significance because this enzyme is not important in the physiologic termination of synaptic acetylcholine action.

Same as cholinoreceptor activating

Myasthenia Gravis, Ileus, Arrhythmias

Short acting (2-10 minutes) Heavily bound by H-bond to AChE

CARBAMATESNeostigmine Myasthenia Gravis, Ileus Poorly absorbed in the conjunctiva, skin, and

lungs because their permanent charge renders them lipid-insoluble. This warrants larger doses in oral administration than when they are given through parenteral means.

Pyridostigmine Myasthenia Gravis

Physostigmine

Myasthenia Gravis

Glaucoma & Accommodative eotopia

Anti muscarinic drug intoxication (atropine, TCA,

anti depressants)

Well-absorbed from all sites and distributed well in the CNS, but more toxic than other carbamates.

ORGANOPHOSPHATES:Echothiophate

are well-absorbed in the skin, lung, GIT, and conjunctiva, thus making them dangerous.

highly polar and more stable than other organophosphates.

Parathion CNS toxicity are lipid soluble and readily absorbed in all routes, even in the CNSMalathion

Pilocarpine Glaucoma

CevimelineDry mouth with Sjogren’s

syndrome, radiation damage of salivary gland

Donepezil, Galantamine, Rivastigmine Alzheimer’s disease

CHOLINERGIC ANTAGONISTS (PARASYMPATHOLYTICS)A. ANTI – MUSACRINIC DRUGS

Mechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes


Atropine

Reversible blockade of actions of cholinomimetics at muscarinic receptors (competitive binding and inhibition).

How do acetylcholine and anti-muscarinic drugs bind to muscarinic receptors? Aspartate in the third transmembrane segment of the muscarinic receptors forms a nitrogen bond with the nitrogen ion of acetylcholine and the anti-muscarinic drugs, which explains their competitive binding.

When atropine binds to the muscarinic receptor, it prevents two mechanisms: the release of IP3 and the inhibition of adenylyl cyclase.

Since the blockade produced by these drugs is reversible, their effects can be overcome by increased concentrations of acetylcholine or other muscarinic agonists.

Because they do not block nicotinic receptors, these drugs have little to no action at skeletal neuromuscular junctions or autonomic ganglia.

Muscarinic receptors are constitutively active, and drugs that block the actions of acetylcholine are inverse agonists that shift the equilibrium of the receptor to its inactive state.

Most sensitive in salivary, bronchial, and sweat glands.

Least sensitive in gastric parietal cells.

Atropine more effectively blocks exogenously-administered cholinoceptor agonists than endogenously-released acetylcholine.

Central Nervous System Atropine has minimal stimulant

effects on the CNS (especially the parasympathetic medullary centers) and a slow, long-lasting sedative effect on the brain.

Scopolamine has more marked central effects: drowsiness and amnesia; can also cause excitement, agitation, hallucinations, and coma in toxic doses.

Reduction of tremors in Parkinson’s disease. Parkinsonian tremors are caused by a relative excess of cholinergic activity because of a deficiency of dopaminergic activity in the basal ganglia-striatum system.

Motion sickness appears to involve muscarinic cholinergic transmission. Best alleviated by scopolamine.

Eyes The pupillary constrictor muscle

depends on muscarinic cholinergic activation. This activation is blocked by anti-muscarinic drugs and results in mydriasis (pupillary dilation).

Cyclopegia – weakening the contraction of the ciliary muscle, resulting in the loss of the ability to accommodate and thus cannot focus on near vision.

Decreased lacrimal secretion Cardiovascular System

Tachycardia due to sensitivity of the sinoatrial node to muscarinic receptor blockade (particularly the prejunctional M1 receptors) that results in vagal slowing. Lower doses sometimes produce initial bradycardia before tachycardia manifests.

Reduced PR interval in the ECG – due to blocking of muscarinic receptors in AV node

Constriction of coronary arteries and skeletal muscle vessels; can also cause cutaneous vasodilation in upper parts of the body in toxic doses.

Has little effect on blood pressure. Respiratory System

Bronchodilation

Mydriasis Cycloplegia Atropine poisoning: dry

mouth, mydriasis, hot and flushed skin, agitation, delirium for as long as one week. Remember: “Dry as a bone, blind as a bat, red as a beet, mad as a hatter.”

Hyperthermia, especially in children

anti-diarrheal, anti-sialogogic, antidote to muscarinic poisoning

for bradycardia in acute myocardial infarction

for routine pre-operative medications to counter the increase in airway secretions and laryngospasms induced by anesthetics

Angle-closure glaucoma Benign Prostatic

Hyperplasia Gastric ulcer (because of

slowing of gastric emptying time, causing increased gastric secretions and possible aggravation of gastric ulcer)

Scopolamine

anti-spasmodic, anti-motion sickness

for reduced amnesia associated with surgical or obstetric delivery

for routine pre-operative medications to counter the increase in airway secretions and laryngospasms induced by anesthetics

rapidly and widely distributed in the CNS, where it has a greater effect there than other anti-muscarinic drugs.

Dicyclomine anti-spasmodicBenzropine Anti - parkinsonism

Homatropine

mydriatic, cycloplegic

for synechia (adhesion in uveitis and iritis)

Also used for complete ophthalmologic examination through induction of temporary ciliary paralysis

IpratropiumTiotropium


Reduced tracehobronchial secretions

The effectiveness of non-selective anti-muscarinic drugs are not as useful in treating COPD because the blockade of M2 receptors on postganglionic parasympathetic nerves can oppose the bronchodilation caused by block of M3 receptors.

Gastrointestinal System Blockade of muscarinic receptors

cannot totally abolish GI activity because of influences from local hormones and non-cholinergic neurons in the enteric nervous system.

Decreased volume of pepsin, acid, and mucin secretion but only in large doses of atropine.

Decreased motility from stomach to the colon

Intestinal paralysis caused by anti-muscarinic drugs is temporary; peristalsis is usually restored after 1-3 days of anti-muscarinic therapy.

Anti-muscarinic drugs have a


Oxybutynin

for bladder spasm after urologic surgery and reducing urinary incontinence with neurologic diseases; this drug is selective for M3

receptors.

Propiverineis also used to reduce incontinence and has lesser CNS toxicity.

B. ANTI –NICOTINIC DRUGS/ GANGLION BLOCKERSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Tetraethylammonium (TEA)

Reversibly blocks acetylcholine action at nicotinic receptors of both parasympathetic and sympathetic ganglia. Some can also block the ion channel gated by nicotinic cholinoceptor.

Subject to both depolarizing and non-depolarizing blockade, but most ganglion blockers now are classified as non-depolarizing competitive antagonists.

Hexamethonium – produces blockade by occupying sites in or on the nicotinic ion channel, not the nicotinic receptor itself.

Trimethaphan – blocks the receptor, not the ion channel.

Since their blockades are reversible, their effects can be counteracted by increasing the concentration of acetylcholine or other agonists.

Central Nervous System (Mecamylamine) Readily crosses the blood-brain

barrier to enter the CNS Sedation Tremor Choreiform movements Mental aberrations

Eyes Cycloplegia Loss of accommodation (ciliary

muscle loses innervations from PNS)

Moderate dilation of pupil Cardiovascular System

Vasodilation Hypotension (especially orthostatic

hypotension) d/t decreased peripheral resistance and venous return and blocked postural reflexes that prevent venous pooling

Marked decrease in arteriolar and venomotor tone

Diminished cardiac contractility (negative inotropic effect)

Moderate tachycardia Gastrointestinal System

Reduced secretion, but not enough to effectively treat peptic ulcer disease

Profound inhibition of motility constipation

Genitourinary System Hesitancy in urination Urinary retention in men with BPH Erection and ejaculation may be

prevented by moderate doses Reduced thermoregulatory

sweating

hypertension very short duration of action

Hexamethonium (C6) hypertension introduced clinically as the first drug effective for management of hypertension

Mecamylamine

Possible adjunct with transdermal nicotine patches to reduce nicotinic cravings in patients attempting to quit smoking

Malignant hypertension

a secondary amine developed to improve the degree and extent of absorption in the GI tract

since quaternary amine ganglion-blocking compounds are poorly and erratically absorbed

after oral administration.

Blocks central nicotinic receptors

Trimethaphan

Treatment of hypertensive emergencies

Dissecting aortic aneurysm

Producing hypotension to reduce bleeding in neurosurgeries

Treatment of patients undergoing electroconvulsive therapy

Malignant hypertension

short-acting; inactive orally, therefore given through IV.


ADRENERGIC AGONISTSMechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notes

Phenylephrine

Direct Agonist – directly bind and activate receptors

Indirect Agonists – displace stored NE from nerve endings (eg. Tyramine) or

inhibit reuptake of release NE (ex. Cocaine and tricyclic antidepressants)

α1 – increases DAG, IP3 thus activates protein kinases

α2 – inhibits adenylcyclase thus decreases CAMP

β1,2,3 – stimulates adenylyl cyclase, increases ATP to CAMP conversion, increases Ca influx inside myocardial cells, promotes relaxation of smooth

muscle

D1 – stimulates adenylcyclase, vasodilation

D2 – inhibits adenylyl cyclase, opens K channels, decreases Cainfux

Eyes – mydriasis, cyclopegia, decrease aqueous humor production

Cardiovascular System – vasoconstriction, (+) inotropy and

chronotropy

Respiratory System – bronchodilation

Gastrointestinal Tract – decrease motility and secretion

GUT – slow voiding and urinary retention

Glands – decrease sweat, lacrimal, nasopharyngeal constriction

CNS - stimulant

Endocrine -

Beta - increase lipolysis, glycogenolysis, insulin

Alpha - inhibit or opposite alpha

Nasal congestionChronic orthostatic hypotension Alpha agonist

Milodrine Hypotension Alpha 1 agonist

Clonidine Hypertension

Alpha 2 agonistAlso found effective in treatment of diarrhea in diabetics with autonomic

neuropathyMethyldopa Hypertension Alpha 2 agonist

Norepinephrine Acute hypotensionPhenylephrine Acute hypotensionMethoxamine Acute hypotension

Epinephrine Cardiac arrest and complete heart block

Isoproterenol Cardiac arrest and complete heart block

Albuterol Bronchial asthma Beta 2 selectiveMetaproterenol Bronchial asthma Beta 2 selective

Terbutaline Bronchial asthma Beta 2 selectiveIsoproterenol Bronchial asthma Beta selectiveEpinephrine Anaphylactic

Phenylephrine MydriaticApraclonidine GlaucomaBrimonidine Glaucoma

Ritodrine Suppressing premature laborTerbutaline Suppressing premature laborEphedrine Stress incontinence

Psuedoephrine Stress incontinenceAmphetamine Euphoriant

Methylphenidate ADHD

Dexmedetomidine For sedation under intensive care situations and during anaesthesia

Modafinil narcolepsyMitodrine Chronic orthostatic hypotensionEphedrine Chronic orthostatic hypotension

ADRENERGIC ANTAGONISTSMechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notes

Alpha receptor Antagonists Blockade of peripheral dopamine receptors – minor clinical importance at

present

Blockade of CNS dopamine receptors – clinically significant

α1 receptor antagonist drugs vasodilation and tachycardia

α1 receptor antagonist drugs acts on receptors on vascular smooth muscle decreased arteriolar and venous tone

Eyes - contraction of iris sphincter, ciliary muscle

Cardiovascular System – vasodilation, (-) inotropy and chronotrophy

Respiratory System – bronchoconstriction, increase T-B

secretion

Gastrointestinal Tract – increase motility and secretion

α antagonist drugs as stated in mechanism of action may cause

orthostatic hypertension, vasodilation leading to tachycardia

Eyes – blockade of receptors in other tissues leading to miosis

Gut – blockade of α1 receptors in base of bladder and prostate leading to resistance to urine flow and urinary

retention

Phentolamine Pheochromocytoma, erectile dysfunction Reversible antagonist

Prazosin Chronic hypertension, peripheral vascular disease, urinary obstruction

Reversible antagonist

Labetalol Hypertensive emergencies Reversible antagonist

Phenoxybenzamine Pheochromocytoma, peripheral vascular disease Irreversible antagonist

Terazosin Chronic hypertension, urinary obstruction

Doxazosin Chronic hypertension, urinary obstruction

Indoramin Chronic hypertension


decreased peripheral vascular resistance and blood pressure vasodilation

increased venous pooling in the periphery cannot maintain BP in the upright position orthostatic hypotension

α1 receptor antagonist drugs prevent pressor effects of usual doses of

α agonists

α1 selective antagonist drugs – convert a pressor to a depressor, response of

agonists with both α and β effects (eg. epinephrine)

B receptor antagonist drugs – HPN, ischemic heart disease, arrhythmias,

endocrinologic and neurologic disorders,

GUT – increase voiding

Glands – increase sweat, lacrimal and nasopharyngeal secretion

CNS – decrease migraine and tremors

Endocrine – inhibit lipolysis glycogenolysis, T4-T3 and increase

VLDL

Urapidil Chronic hypertension, urinary obstruction

Chlorpromazine Chronic hypertensionHaloperidol Chronic hypertensionTamsulosin Urinary obstructionAlfuzosin Urinary obstructionUrapidil Urinary obstruction

Beta Receptor AntagonistsPropranolol Hypertension Non-selectiveMetoprolol Hypertension Selective, non partial agonist

Atenolol Hypertension Selective, non partial agonistBisoprolol Hypertension Selective, non partial agonistPindolol Hypertension Selective, partial agonist

Metoprolol CHFBisoprolol CHFCarvediol CHFTimolol Glaucoma

Betaxolol GlaucomaLabetalolol Hypertension

Timolol Ischemic heart disease, glaucoma, neurologic disorders

Propranolol Ischemic heart disease, hyperthyroidism, neurologic disorders

Metoprolol Ischemic heart disease, heart failure, neurologic disorders

Sotalol Cardiac arrythmiaBisoprolol Heart failureCarvediol Heart failureBetaxolol GlaucomaCarteolol Glaucoma

Levobunolol GlaucomaMetipranolol Glaucoma

Atenolol Neurologic disordersNadol Neurologic disorders

INOTROPIC CARDIOTONICSA. ADRENOCEPTOR & DOPAMINE RECEPTOR AGONISTSẞ

Mechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notes

Dobutamine

Stimulation of cardiac β1 adrenoceptor→↑inotrophy>↑chronotrophy

Peripheral vasodilation ↑ myocardial oxygen demand ↑ CO ↓ ventricular filling

CVS: hypotension due to β receptor stimulation Tachycardia, Arrhythmia, Angina Acute Heart failure Synthetic analog of Dopamine

Dopamine

Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors

Splanchnic and renal vasodilation

Tachycardia, arrhythmia, peripheral vasoconstriction Acute heart failure

B. α-ß NON-SELECTIVE


Epinephrine

Sympathetic agonist Physiologic antagonist of Histamine-1

receptorsDrug of choice in anaphylactic shock

Norephinephrine Stimulates heart and blood vessels Does not act on β2 receptors (cannot be used in asthma)

C. BYPIRIDINES (PHOSPHODIESTERASE INHIBITORS)

MILRINONE (drug of choice)Levosimendan Inhibits phosphodiesterase III

(PDEIII)→↑cAMP→ vasodilation→ inotropic effect

Less toxic than Inamrinone

Ventricular Arrhythmia Half-life: 3-6 hoursExcretion: 10-40% urine

Inamrinone Toxic for bone marrow and liver

D. CARDIAC GLYCOSIDES (DIGITALIS)

Digoxin

Inhibits Na-K ATPase (channel receptor antagonist)

Works in tandem with the Na-Ca exchange channel: inhibition of Na-K ATPase increase in intracellular Na (sodium retention) increase in intracellular Ca (calcium retention) ↑ binding of Ca (sequestered from SR) with troponin C ↑ excitation-contraction coupling through the sliding mechanism of actin and myosin filaments ↑ myocardial contractility

Digitalis-induced arrhythmia (V Arrhythmia)

Acute Congestive Heart Failure

Less mortality than digitoxinFormer primary drug

Very narrow PIFAB ANTIBODY- Antidote to adv

effectHalf-life:36-40 hours

DigitoxinLonger-acting

NON-INOTROPIC CARDIOTONICSA. VASODILATORS

Mechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notesIsosorbide Dinitrate (ISDN)

Isosorbide Mononitrate (ISMN)

Venodilation → reduction in preload Releases nitric oxide Activates guanylylcyclase

Severe headache due to vasodilation (Monday Disease)

Venodilator

Hydralazine

Arteriolar dilatation→ reduction in afterload

Reduces blood pressure and afterload Results in increased cardiac output

SLE (sue to acetylating property in Phase II metabolism either fast or

slow)

Arteriodilator

Sodium Nitroprusside Releases NO spontaneously Activates guanylylcyclase Cyanide Poisoning

B. ANGIOTENSIN-CONVERTING ENZYMES INHIBITORS (ACE INHIBITORS)CAPTOPRILENALAPRILLISINOPRIL

PERINDOPRILQUINAPRILRAMIPRIL

Reduce aldosterone secretion reducing salt and water retention reducing preload

Reduce peripheral resitance reducing afterload

Reduction in tissue angiotensin levels reduce sympathetic activity (diminution of angiotensin’s presynaptic effects)

Reduces long term remodeling of the

Dry CoughAngioedema

Heart Failure (with diuretics) Pregnant women (fetal nephrotoxicity)


heart and vessels reduction in mortality and morbidity

C. ANGIOTENSIN II BLOCKERSLOSARTAN

VALSARTANEPROSARTANOLMESARTAN

CANDESARTAN

Same CI as that of ACE inhibitors

EPROSARTAN – long-acting; given once a day

D. DIURETICS (See page 15 for more comprehensive information on diuretics)LOOP DIURETICS

Furosemide

Reduction of facilitation of sympathetic nervous system

Preload reduction: reduction of excess plasma volume and edema fluid

Afterload reduction: lowered blood pressure

POTASSIUM-SPARING DIURETICS

SpironolactoneAct on the collecting tubule→ blocks the release of aldosterone

Genitourinary: antiandrogenicEplerenone No antiandrogenic effect

Ethacrynic acidLowering of electrolyte

HyperuricemiaAutotoxicity leading to deafness

E. β ADRENOCEPTOR BLOCKERSBisoprololCarvedilolMetropolol

Propanolol (PO/IM)Esmolol (IO)

Reduction in damaging the sympathetic influences in the heart (Tachycardia, arrhythmias)

Inhibition of renin release Carvedilol: Peripheral vasodilation via

α-adrenoceptor blockade

Bradycardia, precipitate decompensation of cardiac function Chronic Heart Failure

ANTI-ARRHYTHMICSA. CLASS 1 – Sodium-Channel Blocking

Mechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notesSubgroup 1A

Procainamide Slows down upstroke of action potential and conduction

Prolongs QRS duration and action potential

Ganglion Blocker: ↓ peripheral vascular resistance

Torsade de pointes arrhythmia, syncope, SLE-like syndrome

Atrial and Ventricular ArrhythmiasQuinidine

Torsade de pointes, Syncope, Cinchonism (headache, dizziness and

tinnitus), Nausea, Vomiting

Rarely used because of cardiac and extracardiac adverse effects

DisopyramideSame as quinidine, may precipitate heart failure, atropine-like activity,

worsening of pre-existing glaucomaSupraventricular Arrhythmias Heart failure, glaucoma Cardiac antimuscarininc effects even

more marked than those of quinidine

Subgroup 1B

LidocaineBlocks activated and inactivated sodium

channels with rapid kineticsHypotension, Asystole, malignant HPN (rare), CNS manifestations

Ventricular tachycardiaVentricular fibrillation Local anesthetic

Phenytoin

Alters Na, K, Ca conductance, membrane potentials and the concentration of amino

acids and nuerotransmitters: (NE, Ach, GABA)

Nystagmus, ataxia, drowsiness, Gingival hyperplasia, Peripheral

neuropathyDigitalis Induced Arrhythmias

Ventricular ArrhythmiaAntiseizure

Orally administered

Mexiletine Similar to lidocaine Hypotension and CNS symptoms Ventricular Arrhythmias Increased metabolism: phenytoin,


phenobarbital, rifampinDecreased: cimetidine

Subgroup 1C

Flecainide

Potent blocker of Na and K channels with slow unblocking kinetics

(-) chronotrophic effect

May cause severe exacerbation of arrhythmia, Brugada Syndrome

Supraventricular Arrhythmia, SV Tachycardia, VT, Wolff-Parkinsons-

White Arrhythmias

Increased metabolism: propranolol, quinidine. amiodarone

Propafenone

Similar to quinidine but does not prolong AP

(-) chronotrophic effect

Metallic taste, constipation,arrhythmia exacerbation

Increased metabolism: Warfarin, digoxin, metropolol

Moricizine Potent sodium channel blocker that does not prolong AP Ventricular Arrhythmia Withdrawn from market

Phenothiazine derivativeB. CLASS 2 – ß-ADRENOCEPTOR-BLOCKING DRUGS

Propranolol (non-selective)Timolol

MetropololEsmolol (Intraoperative Arrhythmia, IV)

Acetabulol (oral)

Inhibit catecholamine binding at beta-receptors

Direct membrane stabilizing property (-) inotropic, chronotrophic effects

Hypotension, bradycardia, CHF, Wheezes, Raynaud’s, Depression,

Hypoglycemia, Insomnia, Decreased libido

C. CLASS 3 – K-Channel Blockers

AmiodaroneMultiple actions: Class IV- ↑AV nodal conduction Class I- depresses Vmax Class II- noncompetitively blocks α

and β

Bradycardia, Hypo/Hyperthyroidism, asymptomatic corneal deposits, dose-related pulmonary toxicity (pulmonary

fibrosis) Ventricular ArrhythmiaSupraventricular Arrhythmia (low

doses)Ventricular Tachycardia

Bioavailability: 35-65%

Dronedarone Similar with amiodarone without the thyroid and pulmonary toxicity

Structural analog of amiodaroneLacks iodine atoms

1st antiarrhythmic drug to demonstrate a reduction in

mortality/hospitalization in patients with AF

Vernakalant

Multi-channel blocker Prolongs atrial effective refractory

period Slows conduction over AV node Does not change QT interval

Dysgeusia (disturbance of taste), sneezing, paresthesia, cough,

hypotensionAtrial Fibrillation New Class III drug

Sotalol

Non-specific β-adrenergic receptor-blocker (class 2)

Action potential (repolarization) prolonging (class 3)

Dose-related incidence of Torsade de pointes Ventricular Arrhythmias 100% bioavailability

excretion: kidneys

IbutilideDofetilide

Ibutilide: activate slow inward sodium current QT Prolongation SVT

IV for IbutilideDofetilide: PO, 100% bioavailability

D. CLASS 4 – Calcium Channel Blocking Drugs

Verapamil

Reduces the plateau height of the action potential, slightly shortens action potential, and slightly prolongs total Purkinje fiber AP

Peripheral vasodilation→transient hypotension

(-) inotropic effects

Dose-related cardiotoxic effects, can induce AV block in large dosages,

constipation, lassitude, nervousness, peripheral edema

SVTReduction of ventricular rate in AF and

flutter

PrototypeBioavailability: 20%

PO dosage>IV dosage because of 1st pass effect

Adenosine

Inhibits the AV node by acting with α1 receptors that opens the adenosine

sensitive K channel to hyperpolarize and inhibit AV node and indirectly inhibit

calcium channel opening

Flushing, dyspnea, chest pressure Drug of choice for prompt conversion of paroxysmal SVT to sinus rhythm

Contraindicated in the presence of Methylxanthines due to inhibition of

action

Naturally occurs in the bodyT ½: 1 to 6 secs

DigoxinSlowing sinus node discharge rate,

shortening atrial refractoriness, prolonging AV nodal refractoriness

See cardiotonics


ANTIHYPERLIPIDEMICSA. COMPETITIVE INHIBITORS OF HMG-COA REDUCTASE (REDUCTASE INHIBITORS) – “STATINS”


Pravastatin Inhibits HMG-CoA

Reductasepreventing the formation of mevalonate (rate limiting step of sterol synthesis)

Induces an increase in high affinity LDL receptors on hepatocytes

Increases both fractional catabolic rate of LDL and liver’s extraction of LDL precursors (VLDL remnants) from the blood→↓ LDL

Interfere with the synthesis of lipid intermediates with important biological effects

May ↑ HDL cholesterol by preventing the geranylation of Rho A and phosphorylation of peroxisome proliferator-activated receptor (PPARa)- factor that regulates APO A1 transcription

Myopathy – cessation upon removal of therapy

Hepatic toxicityCataract

PancreatitisHeadacheDizzinessInsomnia

Blurred visionDysgeusiaSkin rashes

Drugs used to lower lipid levels in the body (e.g. cholesterol, LDL)

Pregnant and lactating women and those likely to become pregnant,

hepatic and renal impairment, porphyria, untreated

hypothyroidism

Most effective in reducing LDL together

Decrease oxidative stress Decrease vascular inflammation Increases stability of

atherosclerotic lesion Has an open active lactone ring

Lovastatin Inactive lactone prodrug Hydrolyzed in the GIT→ β

hydroxyl derivatives

Simvastatin Same as Lovastatin More potent than lovastatin

Fluvastatin

Most effective in reducing LDL together

Decrease oxidative stress Decrease vascular inflammation Increases stability of

atherosclerotic lesion Fluorine containing Almost completely absorbed

Rosuvastatin Fluorine containing 19 hours (long lasting)

Atorvastatin Same as rosuvastatin but only lasts for 14 hours

B. FIBRIC ACID DERIVATIVES (FIBRATES) – LIPOPROTEIN LIPASE STIMULANTSFenofibrateGemfibrozilBezafibrateCiprofibrate

Increases peripheral clearance of lipoproteins

Peroxisome proliferator-activated receptor α agonist

Effects on plasma levels of Lipoprotein: ↓VLDL and chylomicron ↓or↑ LDL Mosly only modest ↓ in

LDL Others, especially with

combined hyperlipidemia, LDL often ↑

Moderate ↑ in HDL

Effects on plasma levels of lipids: ↓TG ↓Cholesterol

Cholesterol gallstones- reflecting ↑ in cholesterol content of bile

Hepatotoxicity – ↑ aminotransferases or alkaline phosphatases

Myositis, myopathy, rhabdomyolysis, myoglobinuria, renal failure

GIT – anorexia, nausea, GI discomfort

Skin rashes, urticarial, hair loss

Fatigue, headache, impotence

Anemia, leucopenia

Hypokalemia, arrhythmias

↓ WBC or Hct

Hypertriglyceridemia with ↑ VLDL or chylomicrons

Hypertriglyceridemia- Type I, IV, V

Familial combined hyperlipidemi (Type IIb), VLDL is ↑

Familial dysbetalipoproteinemia (Type III)

Hypertriglyceridemia d/t treatment with viral protease inhibitors

General: Absorption: >90% with meal Plasma protein binding: >95% Excretion: Predominantly as

glucoronide conjugates Conjugates: 80-90% in urine; smaller amounts

in feces;(Katzung) 60% in urine as

glucoronide conjugates; 25% in feces

Monitor: Serum levels of creatine kinase,

aminotransferases, and plasma proteins

Renal function tests Thyroid status


T ½: Fenofibrate- 20 hrsGemfibrozil- 1.5 hrsClofibrate- 15 hrs.

C. STEROL ABSORPTION INHIBITOR

Ezetimibe

Blocks sterol transporter NPC1L1 in intestine brush border→ inhibits reabsorption of cholesterol excreted in bile: ↓ LDL and phytosterols

Selective inhibitor of intestinal absorption of cholesterol & phytosterols

Inhibit absorption of cholesterol both in diet and in bile

Actions: ↓ LDL, minimal ↑ in HDL cholesterol

Synergistic with statin

Familial combined hyperlipidemia when LDL is increased

Familial hypercholesterolemia (heterozygous, homozygous)

Readily absorbed Conjugated in intestine to an

active glucoronide Enterohepatic circulation T ½ of active metabolite: 22 hrs 80% excreted in the feces

Drug interactions:- ↑ with fibrates- ↓ with cholestyramine

NIACIN – VLDL SECRETION INHIBITORS

Nicotinic Acid (Vit. B3) and derivativesDecreases catabolism of apoA1; reduces VLDL secretion from liver→↑ HDL, ↓ LDL and TG

Effect on plasma levels of lipoproteins: ↓VLDL, IDL, LDL, Lp(a), ↑ HDL Most effective agent for

increasing levels of HDL Only antihyperlipidemic

drug that decreases Lp(a) significantly

Estrogen and Neomycin also decreases Lp(a) significantly

Effect on plasma levels of lipids: ↓ TG ↓ Cholesterol

Other effects: ↓ Fibrinogen ↑ Tissue plasminogen activator

Skin and mucous membrane:o Harmless cutaneous

vasodilator (flush), uncomfortable sensation of wamth and pruritus

o Rashes, dry skin, dry mucous membranes

o Acanthosisnigricans

GITo Hepatotoxicityo Myopathyo Metabolic: Hyperglycemia,

Hyperuricemia

CVS: Arrhythmia, hypotension Ocular toxicity: Amblyopia

(reversible)- reduced vision in an eye not correctable by a manifest refraction; Maculopathy

AcanthosisnigricansPeptic ulcer/severe pepric disease

Hepatic diseaseDiabetes mellitus

GoutPregnancy

Patients on hypertensive therapy

Monitor serum levels of: glucose, aminotransferase, uric acid, albumin, CK

Pharmacokinetics:Absorption – almost completeMetabolism – extensiveExcretion – urine mostly as metabolites;Doses – daily vitamin requirement as antihyperlipideicT ½ - 60 mins.

BILE ACID BINDING RESINS

ColestipolCholestyramine

Colesevelan

Binds bile acids in gut preventing reabsorption, increases cholesterol catabolism, up regulates receptors →↓ LDL

Enhanced conversion of cholesterol to bile acid

GI: constipation, sensation of fullness, discomfort

↓ absorption of- Folic acid- Drugs- Fat soluble vitamins

Hypoprothrombonemia

Increase bleeding tendency

Increase effects of anticoagulants

Hypertriglyceridemia

HypertriglyceridemiaDiverticulitisHemorrhoids

Biliary obstruction

Large polymeric cationic exchange resins and insoluble in water

ANTI-HYPERTENSIVES


DRUGS THAT ALTER SNS FUNCTION A. Centrally acting Sympathoplegic drugs rarely used - Methyldopa - Clonidine -Reduce sympathetic outflow from vasomotor center in brain -increase sensitivity

to baroreceptor center Central α adrenoceptor stimulation -Decrease TPR, HR, CO -Decrease renal vascular resistance

-only used for HPN in pregnancy -Dry mouth -sedation -depression -Lactation > prolactin secretion (Methyldopa) -HPN crisis > inc SNS activity (Clonidine withdrawal)

B. Ganglion- Blocking drugs Trimetaphan - Block nicotinic receptors on postganglionic neurons of SNS and PNS - Not used Severe hypotension Sexual dysfunction Constipation Urinary retention Glaucoma

C. Adrenergic Neuron Blocking Drugs - Guanethidine - Guanadrel >do not enter CNS - Reserpine -Inhibit release of NE from sympathetic nerves transported by NET -interferes

with VMAT >depletes NE, dopamine, 5HT in central and peripheral nerve endings

Postural hypotension Sedation Depression Extrapyramidal s/sx GI sx

D. Adrenoceptor Antagonists 1. Beta Blockers - Decrease CO, TPR, HR - Propranolol Cardioselective: - Metoprolol - Atenolol - Nadolol - Betaxolol - Bisoprolol Partial Agonists: - Pindolol - Acebutolol With α blocker: - Labetalol - Carvedilol

- depress RAAS by blocking the intrarenal & extrarenal B-receptors involved in renin secretion - same as propranolol in B1 blockade but less potent B2 - less CO & HR depression than other B blockers

- most widely used - long half lives > OD administration - useful in pt with bradycardia & Peripheral Vasc Disease - tx of HPN in pt with pheochromocytoma and HPN crisis - tx ofpt with HF & HPN

Bradycardia DM Peripheral vascular insufficiency

2. α1 Blockers Selective: - Prazosin - Terazosin - Doxazosin Non-selective: - Phentolamine Phenoxybenzamine

-Blocks α1 receptors in arterioles, venules -Vasodilation - tx of BPH & HPN - dx & tx of pheochromocytoma

1st dose effect > occurs in salt & H2O depleted pt > reduce 1st dose & administer at h.s. Dizziness Headache Lassitude

II. DIRECT VASODILATORS A. Arteriolar - HPN emergencies Tachycardia flushing Hypertrichosis HA

- Hydralazine - Minoxidil - Diazoxide - Fenoldopam

B. Arteriovenous Sodium Nitroprusside Activates guanylyl cyclase > inc intracellular cGMP > relaxed smooth muscle Cyanide AccumulationCalcium Channel BlockersDihydropyridine: - Nifedipine - Amlodipine - Nicardipine - Nisoldipine > More selective vasodilator > Less cardiac depressant than - Verapamil & - Diltiazem - Nimodipine: cerebral blood vessels

-bind to L-type Ca++ channel (heart smooth muscle) -decrease trans-membrane Ca++ current -smooth muscle relaxation

-Decrease myocardial contractile force - decrease myocardial O2 requirement - decrease HR (Verapamil, Diltiazem) -relief vasospasm in coronary artery RX: Angina pectoris -Decrease AV node conduction RX: - Supraventricular tachycardia - AF

Peripheral vasodilator RX: - HPN - Raynaud’s phenomenon

Nicardipine RX: Severe HPN – thru IV

Cardiac depression peripheral edema flushing dizziness

III. ANGIOTENSIN INHIBITORS 1. ACE inhibitors


Excreted in kidneys except Fosinopril - Enalapril - Lisinopril - Benazepril - Perindopril - Quinapril - Ramipril - Trandolapril

- Inhibits peptidyl transferase and inactivates bradykinin - ---- Reduced SNS stimulation - Low Na+ delivery - Low Na+ distal renal tubule - Low renal arterial Pressure

- Tx in pt with chronic kidney disease and DM - Tx of HF - reduced incidence of DM in pt with MI

Acute renal failure Hyperkalemia Dry cough Angioedema CI for pregnant pt

2. Angiotensin Receptor Blocker - Valsartan - Candesartan - Eprosartan - Irbesartan - Telmisartan - Olmesartan

- No effect on bradykinin Metabolism > more selective blocker of angiotensin effects than ACE inh

- pt with HF and chronic kidney disease - can be given to DM nephropathy

Same with ACE inh except for the cough and angioedema

3. Renin blockers Clonidine (central SNS) β blockers (renal, extrarenal) Aliskiren Reduces plasma renin activity, angiotensin I, II, aldosterone Greater anti HPN

effect

ANTI-HYPERTENSIVES: DIURETICSA. CARBONIC ANHYDRASE INHIBITORS


Acetazolamide

Acts on the proximal convoluted tubules where reabsorption of sodium bicarbonate occurs

Sodium bicarbonate will be absorbed through the sodium-hydrogen exchanger Na ions will be reabsorbed into the interstitium of the kidneys while H will be secreted to the tubular lumen

H ions will combine with bicarbonate to form carbonic acid

Carbonic acid will dissociate to H2O and CO2 by the enzyme carbonic anhydrase

Acetazolamide inhibits this enzyme No sodium ion will be reabsorbed due to the decreased ability to exchange Na with H ions Blocks sodium bicarbonate rabsorption

Inhibition of bicarbonate reabsorption in the proximal convoluted tubule

depletion of bicarbonate increased NaCl reabsorption in the rest of the renal

tubules

Hyperchloremic metabolic acidosis Renal stones: decreased citrate

excretion, Ca++ salt precipitation d/t presence of alkaline pH

Renal potassium wasting Drowsiness Paresthesias Nervous system toxicity (seen in

patients with renal failure) Allergic reactions

Glaucoma (Dorsolamide, Brinzolamide – topical or eyedrop forms for organ selectivity) decreased formation of aqueous humor

Metabolic alkalosis decreased bicarbonate reabsorption

Acute mountain sickness decreased production of CSF

Urinary alkalinization: decreased bicarbonate reabsorption increased urinary pH enhanced excretion of weak acids

Adjuvants in treatment of epilepsy, hypokalemic periodic paralysis, and in increasing urinary phosphate excretion during severe hypophosphatemia.

Hepatic encephalopathy/hepatic coma/impaired liver function –

alkaline pH decreases urinary NH4

excretion

Prototype drugWell-absorbed after oral administration Excretion of the drug is by secretion

in the proximal tubule S2 segment Onset of action: 30 minutes to 2

hours Duration: 12 hours 85% of the bicarbonate reabsorptive

capacity of the proximal convoluted tubule is inhibited.

Diuretic efficacy of acetazolamide decreases significantly with use over several days.

B. LOOP DIURETICSFurosemide 20/40 mg tab; 20mg amp –

prototype drugButenamide (Lasix) 1mg tab; 0.5mg amp

Torsemide (not available locally)Ethacrynic Acid (not available locally)

Acts on the Loop of Henle, particularly in the thick ascending limb

Inhibits Na-K-2Cl transporter in the thick ascending limb decreased NaCl, Mg, Ca reabsorption

Increases renal blood flow useful for patients with decreased urine output

Also shown to induce expression of COX-2 increased synthesis of prostaglandins (PGE2) from arachidonic acid inhibits salt

Hypokalemia/Hypokalemic Metabolic Acidosis

Hypomagnesemia Ototoxicity (reversible) Hyperuricemia, gout (d/t increased

reabsorption of uric acid in renal tubules secondary to hypervolemia)

Allergic reaction (loop diuretics are sulfonamides)

Severe dehydration (d/t excessive urine output)

Pulmonary edema Acute hypercalcemia (inhibits

Ca++ reabsorption) Hyperkalemia (inhibits K+

reabsorption) Acute renal failure (increase rate

of urine flow by increasing renal blood flow; increased K+ excretion)

Allergic reaction Liver cirrhosis Borderline renal failure

Most effective type of diuretics because of the large sodium chloride absorptive capacity of the thick ascending limb effect is not diminuted by acidosis, unlike other types of diuretics

Onset: 2-3 hours (furosemide); 1 hour (torsemide)

Duration: 2-3 hours (furosemide); 4-6 hours (torsemide)

Rapidly absorbed Eliminated by the kidney by

glomerular filtration and tubular secretion


transport in the thick ascending limb (this can be blocked by NSAIDs)

Diuretic activity of loop diuretics correlates with their secretion by the proximal tubule.

C. THIAZIDES

ChlorothiazideHydrochlorothiazide (12.5/25 mg tab)

Indapamide (1.5mg tab)

Blocks NaCl transporter in the distal convoluted tubule inhibits NaCl reabsorption, but increases Ca reabsorption

Increase in calcium reabsorption is postulated to result from effects in both the proximal and distal convoluted tubules: PCT: thiazide-induced

volume depletion enhanced Na+ and passive Ca++ reabsorption

DCT: thiazide-induced blockade of Na entry decreased intracellular Na enhances Na-Ca exchange in the basolateral membrane increased Ca reabsorption

Metabolic alkalosis Hyperuricemia Hyperglycemia (d/t impaired

insulin release and decreased glucose utilization)

Hyperlipidemia Dilutional hyponatremia (d/t ADH

production secondary to hypovolemia)

Allergy

Hypertension Congestive Heart Failure Hypercalciuria Nephrogenic diabetes insipidus

Hydrocholorthiazide: prototype drugAll thiazides can be administered orally

but there are differences in their metabolism: Chlorothiazide is not very lipid soluble and must be given in large doses; this is the only thiazide available for parenteral administration.

All thiazides are secreted by the organic acid secretory system in the proximal convoluted tubule and compete with the secretion of uric acid by that system thiazides may blunt uric acid secretion and elevate serum uric acid level.

Usually combined with other drugs, such as beta blockers, ARBs, and ACE inhibitors to potentiate the effects of controlling blood pressure. There are drugs available that already have combined beta blocker/ARB/ACE inhibitor and diuretic effects.

However, if diuretics are to be given with calcium channel-blockers, they should be given separately.

D. POTASSIUM-SPARING DIURETICSSpironolactone

EplerenoneAmiloride

Triamterene

K-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone at the late distal and cortical collecting tubules.

Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene)

Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity. Amiloride and triamterene do not block aldosterone, but instead directly interfere with Na+ entry through the epithelial Na+ channels (ENaC) in the apical membrane of the collecting tubule. Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective potassium-sparing

Hyperkalemia Metabolic acidosis Gynecomastia, impotence –

Spirinolactone ARF – Triamterene + Indomethacin Renal stones – Triamterene

Hyperaldosteronism Primary – Conn’s

syndrome Secondary – CHF, liver

cirrhosis, nephrotic syndrome

Acute Renal Failure Hyperkalemia Liver disease

Direct Antagonists of Aldosterone Receptors Spironolactone

Synthetic steroid that acts as a competitive antagonist to aldosterone

Substantial inactivation of spironolactone occurs in the liver

Rather slow onset of action, requiring several days before full therapeutic effect is achieved

Eplerenone More selective: less

active on androgen, progesterone receptors

Spironolactone analog with much greater selectivity for the mineralocorticoid receptor


diuretics

Several hundred-fold less active on androgen and progesterone receptors than spironolactone

Fewer adverse effects Inhibitors of Na+ influx through

ion channels in luminal membrane Amiloride Triamterene

Metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites

Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized)

Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT (cortical collecting tubule).

E. OSMOTIC DIURETICS

Mannitol

Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle's loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule.

Prevents the normal absorption of water by interposing a countervailing osmotic force resulting to increased urine volume.

Increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ as well as water reabsorption.

Decreases intracranial pressure Decreases intraocular pressure

Congestive heart failure Increased ECF volume Hyponatremia Dehydration

Mannitol – prototypic drug; the only osmotic diuretic available

Mannitol is poorly absorbed by the GI tract, and when administered orally it causes osmotic diarrhea. For systemic effect, mannitol must be given parenterally.

F. ADH AGONISTSVasopresin

Desmopresin

Renal action appears to be mediated primarily via V2 receptors although V1a

receptors may also be involved.Central Diabetes Insipidus

G. ADH RECEPTOR ANTAGONISTSConivaptan (only drug approved for use)

LixivaptanTolvaptan

ADH antagonists inhibit the effects of ADH in the collecting tubule

Both lithium and demeclocycline appear to reduce the formation of cyclic adenosine monophosphate

Nephrogenic Diabetes Insipidus Syndrome of Inappropriate Diuretic Hormone (SIADH)

Congestive Heart Failure


(cAMP) in response to ADH

ANTI-ANGINAA. NITRATES


NitroglycerinIsosorbide Dinitrate (ISDN)

Isosorbide Mononitrate (ISMN)

Nitrates will be removed of its nitrate group by Gluthatione S-Transferase

which will release the free nitrate. The free nitrate will then be converted to nitric oxide. The nitric oxide causes activation of guanylylcyclase and an

increase in cGMP which, in turn, would cause smooth muscle relaxation as

stated in the previous mode of action.

dilation of veins – decreased preload (venous return)

dilation of arteries – decreased LV volume and wall tension (decrease afterload)

Hypotension because it is not only the coronary vessels that are dilated but also the other blood vessels (peripheral blood vessels)

Tachycardia Severe headache (due to

vasodilation of cerebral vessels)

Angina Increased intracranial pressure

Nitroglycerin considered as the

prototype of the group not sensitive to sunlight

but may lose its potency due to volatilization and adsorption to plastic surfaces, therefore it should be kept in a tightly closed glass containers

Isosorbide dinitrate/mononitrate sublingual administration

to prevent first pass effect in the liver

can also be given transdermally by placing a patch on any part of the chest or even in the abdomen; will be absorbed in the skin mucous membrane and will produce the therapeutic effect

Onset: 1-3 minutes Duration: 15-30 minutes Types of Administration: SL,

Transdermal, SR 1-3 minutes of administration would

provide immediate relief of the chest pain. If the chest pain is not relieved, wait for another 15 minutes then administer again (duration of action: 15-30 minutes). If the chest pain is not yet relieved by this, the patient must have a probable MI and should be admitted immediately to an ICU.

Slow Release tablets: used as maintenance given once a day

B. SILDENAFIL, TADANAFIL, VARDENAFILSildenafilTadanafilVardenafil

Sildenafil is a drug used for the treatment of impotence or erectile

dysfunction which blocks the action of phosphodiesterase. By blocking PDE,

there will be an increase in cGMP

Sexual impotenceErectile dysfunction

Patients taking nitrates


which will result to relaxation. This mode of action can also aggravate the

hypotensive effects of the nitrates.C. NEW DRUGS FOR ANGINA

Nicorandil

Activate cardiac potassium channels thereby hyperpolarizing the smooth muscle membrane therefore decreasing heart rate (myocardial protection)

Can also release nitric oxide in the endothelium thereby dilating the coronary vessels

Decreased HRDilation of coronary vessels

Better than the nitrates Available in 5, 10, 20 mg doses

and is given twice a day every 12 hours

A nicotinamide nitrate ester

TrimetazidineInhibit oxidation of fatty acids in the myocardium thereby improving the

metabolic status of ischemic tissues

20 mg (given 3x a day) 35 mg (every 12 hrs)

RanolizineBlocks the late Na current also blocking the calcium causing decrease myocardial contractility

Decreased myocardial contractility

IvabradineInhibits hyperpolarization by the activated Na channels in the SA node thereby decreasing heart rate

Decreased HROther effects similar to calcium channel

blockers

MUCOKINETICS (EXPECTORANTS)A. DIRECTLY-ACTING


Guaiphenesin/Guaifenesin

Decrease sputum viscosity and increase sputum volume thereby

decreasing difficulty in expectorationNausea, gastric disturbances,

drowsiness and rashProductive cough Hypersensitivity

Na+, K+ citrate/acetate Increase bronchial secretion by salt

action ↑ Na content→↑ H2O content

Productive cough

B. REFLEXLY-ACTING

Ammonium chloride

Cause irritative action on bronchial mucosa resulting to production of excess respiratory tract fluid w/c is easier to cough

Nausea and vomitingProductive cough Irritant to gastric mucosa

Potassium Iodide Productive coughC. MUCOLYTIC

Bromhexine

Depolymerizes polysaccharide directly as well as by liberating lysosomal

enzymes w/c breaks down the fiber network in the tenacious sputum

Rhinorrhea, lacrimation, gastric irritation Productive cough

Hypersensitivity

Ambroxol

Makes the phlegm in the airway thinner and less sticky by increasing

the body’s natural production of surfactant (anti-glue)

Mild GI effects and allergic reactionProductive cough

Hypersensitivity, epileptic patients Metabolite of Bromhexine

Acetylcysteine Splits disulphide bonds linking proteins in the mucus thereby reducing mucus

viscosityProductive cough Hypersensitivity Also used in management of

paracetamol poisoning

Carbocisteine Liquefies viscid sputum Nausea, gastric discomfort, GI bleeding, skin rash Productive cough Hypersensitivity, Active peptic ulcer,

children under 2 years old


ANTITUSSIVESA. NARCOTIC ANTITUSSIVE


Codeine Directly suppresses cough center by binding to distinct receptors in medulla

(TD)Sedations, nausea, constipationHigher dose: respiratory depression,

drowsinessDry cough Asthmatic px, px with diminished

respiratory reserves

Pholcodeine- has similar efficacy as codeine with longer duration

(12hrs) with no analgesic or addictive property

B. NON-NARCOTIC ANTITUSSIVESDextromethorpan Depress cough center in medulla and

increasing the threshold for coughStupor, ataxia, respiratory depression,

convulsion in children Spasmodic cough children below 6 yrs., px taking MOA inhibitors A synthetic compound

Noscapine Depress coughHeadache and Nausea Spasmodic cough *Asthmatic patients

Equally antitussive as codeineNo narcotic, analgesic or dependance properties

C. ANTI-HISTAMINICS

ChlorpheniramineDiphenhydramine

PromethazineSedative and anti-cholinergic action Urinary retention

Blurred vision

DrowsinessNauseaVomiting

ConstipationHeadache

Lack selectivity for cough centersNo efficacy in asthma

ANTI-ASTHMA(BRONCHODILATOR RELIEVERS AND CONTROLLERS)

A. ß2 AGONISTSMechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notes

TerbutalineAlbuterol

SalbutamolFenoterol Promotes bronchodilation

Activate G protein→↑ cAMP→↓ intracellular Ca

Throbbing headache, Tremors, tachycardia, palpitation Asthma

R isomer activate beta receptorS isomer causes inflammation

FormoterolSalmeterol

Long actingNo anti-inflammatory property

B. SYMPATHOMIMETICEpinephrine Bronchodilation CV: vasoconstriction Tachycardia, arryhtmia, worsening of

angina pectoris Status asthmaticus Onset- 15 mins.Duration- 60-90 mins.

C. MUSCARINIC ANTAGONISTSAtropine

Inhibit the effect of acetylcholine at muscarinic receptors

Treatment of asthma

Prototype drug

IpratropiumOnly have partial reversible property

for COPDInhibits M3 receptors

Tiotropium Dizziness, ↑ intraocular pressure, tachycardia

Approved as treatment for COPD

D. METHYLXANTHINES

Theophylline

Uncertain: phosphodiesterase inhibition, adenosine receptor

antagonist (Katzung)

Res: bronchodilationCV: cardiac stimulation

Musculoskeletal: increased skeletal muscle strength (diaphragm)

Anorexia, nausea, vomiting, abdominal discomfort, anxiety, headache, seizures, arrhythmias, insomnia Asthma, COPD Narrow therapeutic window

Aminophylline IV Competitive nonselective PDE inhibitor


Non selective adenosine receptor antagonist

Res: bronchodilation Bronchial asthma Less potent and shorter acting than theophylline

ANTI-ASTHMA(ANTI-INFLAMMATORY CONTROLLERS)

A. CORTICOSTEROIDSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

ORAL:

Prednisone , Methyprednisolone (dose depend on severity)INHALED: Budesonide, Fluticasone (Long Acting q 12 hrs)

Reduce airway reactivity Increase airway diameter Inhibit lymphocytic,

eosinophilic airway mucosal inflammation

Reduce frequency of asthma attacks

Potentiate effects of β2

agonists

Oropharyngeal candidiasis – inhaled give spacer devices

Hoarseness – advise to drink H20 or gurgle after inhaler

Adrenal insufficiency – best time 8am to mimic diurnal variation

Slow growth rate – children

Osteoperosis - cataract

effective in improving all indices of asthma control—severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life

Corticosteroid + LABA (Long Acting β2 Agonist) ( inhaled)

Budesonide + Formeterol Fluticasone + Salmeterol

(Seretide)

B. ANTI-LEUKOTRIENES

5 – lipoxygenase inhibitor ( not available ) ZileutonLTD4 – receptor Antagonist Montelukast, Zafirlukast (available in market)

liver toxicity

prevent Leukotriene synthesis Prevent LT action Bronchoconstriction, bronchial reactivity,

mucosal edema, mucus hypersecretion

C. MAST CELL STABILIZERS

INHALED:Na Cromoglycate

– inhibits degranulation of mast cell (inhibits histamine & serotonin)

Aspirin-induced asthma

Cromolyn, Nedocromil Inhibit antigen, exercise- induced asthma, slightly bronchial reactivityInhibit mast cell degranulation Produces an alteration in the function of delayed chloride channels in the cell membrane, inhibiting cell activation. This action on airway nerves is thought to be responsible for nedocromil's inhibition of cough; on mast cells, for inhibition of the early response to antigen challenge; and on eosinophils, for inhibition of the inflammatory

are minor and are localized to the sites of deposition.

throat irritation cough mouth dryness rarely, chest

tightness, and wheezing

can be prevented by inhaling a 2-adrenoceptor agonist before cromolyn or nedocromil

allergic rhinoconjunctivitisApplying the solution by nasal spray or eye drops several times a day is effective in about 75% of patient

Cromolyn - poorly absorbed from the gastrointestinal tract and must be inhaled as a microfine powder or aerosolized solution. Nedocromil also has a very low bioavailability and is available only in metered-dose aerosol form.


response to inhalation of allergens

treatment Serious adverse

effects are rare Reversible

dermatitis, myositis, or gastroenteritis

D. METHYLXANTHINES

Theophylline, theobromine, caffeine

Inhibit phosphodiesterase, increase CAMP ( relax smooth muscle, cardiac stimulation, bronchodilation) in some tissues including CGMPPDE4 appears to be the most directly involved in actions of methylxanthines on airway smooth muscle and on inflammatory cells. The inhibition of PDE4 in inflammatory cells reduces their release of cytokines and chemokines, which in turn results in a decrease in immune cell migration and activation Another proposed mechanism is inhibition of cell-surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) may be potent in inhibiting bronchoconstriction in asthmatic subjects.-research suggests that the efficacy of theophyllines may be due to a third mechanism of action: enhancement of histone deacetylation. Acetylation of core histones is necessary for activation of inflammatory gene transcription. Corticosteroids act, at least in part, by recruiting histone deacetylases to the site of inflammatory gene transcription, an action enhanced by low-dose theophylline.

CNS: nervousness, tremors, arousalCVS: + chronotropy, inotropy GIT: stimulate acid, enzyme secretion ( give after meals)Kidneys: Increase GFR, Reduce tubular Na reabsorption ( weak diuretics)Respiratory: relax musclesSkeletal muscles: improve contraction of diaphragm

Pentoxyfylline – decrease blood viscosity ( for Reynaud or stroke due to thrombosis)Their major source is beverages (tea, cocoa, and coffee, respectively)The importance of theophylline as a therapeutic agent in the treatment of asthma has waned as the greater effectiveness of inhaled adrenoceptor agents for acute asthma and of inhaled anti-inflammatory agents for chronic asthma has been established, but theophylline's very low cost is an important advantage for economically disadvantaged patients in societies in which health care resources are limited.

E. ANTI – IgE MONOCLONAL ANTIBODIESOmalizumab inhibits binding of IgE to mast

cellsFor chronic severe asthma

decreases frequency & severity of asthma exacerbations


inadequate control by high dose inhaled steroid + LABA

with IgE mediated sensitivity

AUTACOIDSRole MOA Organ System Effects Antagonists

1. HISTAMINE Found in skin, GI

mucosa, lungs, liver, placenta, brain

Mediator of immediate allergic & inflammatory reactions

Gastric acid secretion

Binds with membrane receptors:H1*smooth muscle *endothelium

H2*gastric mucosa *cardiac muscle *brain *immune cells

H3*pre-synaptic brain *myenteric plexus

H4*eosinophils *neutrophils *CD4T cells

CNS*stimulate sensory nerve endings (pain, itch) CVS *vasodilatation* (+) inotropy * (-) chronotropy *fluid transudation

RS *bronchoconstriction (H1)

GIT*increased intestinal motility* increased gastric acid* increased pepsin *Intrinsic Factor secretion

I. Physiologic Antagonist EpinephrineII. Inhibitors of Histamine ReleaseCromolyn, Nedocromil, β2 agonists inhibits degranulation of mast cells III. Histamine Receptor AntagonistA. H1 Receptor Antagonists (1st Generation) for hypersensitivity reactions1. Sedation (1st generation, side effect) Highly sedative

Diphenhydramineq6-8Dimhenhydrinateq8Promethazine (parenteral)Hydroxyzine (itarax) LA

Moderately SedativeBuclizine (appetite stimulant)Cinnarizine (vertigo/motion sickness)Meclizine PheniramineCyproheptadine

Mild SedativeChlorpheniramineClemastine LADimethidineMethdilazine NAMepyramine NATriprolidine NACyclizine NA

2.Anti-emetic, anti-nausea (Meniere’s syndrome) Rx: Scopolamine (not available)Promethazine (IM) DimenhydrinateCyclizine Meclizine (Bonamine)BetahistineCenarizine

3.Anti-Parkinsonism suppress extra-pyramidal symptoms

Rx: Diphenhydramine

4.Anti-cholinergic urinary retention, blurred vision (side effects)

High anti-cholinergic actionPromethazineDiphenhydramine (Benadryl)DimenhydrinatePheniramineCyproheptadine

Low anti-cholinergic actionChlorpheniramineHydroxyzine


CyclizineMeclizine

Minimal/ absent anti-cholinergic actionClemastineTerfenadine (arrhythmia effect)AstemizoleLoratidine (Alerta)EbastineCetirizine

5.Adrenoceptor-blocking (α) orthostatic hypotension

Rx: Promethazine (should be in supine postion)

6. Serotonin blocking Cyproheptadine (appetite stimulant)

7.Allergy Urticaria, Allergic rhinitisSide Effects/ToxicitySedation, decreased alertness & concentration, motor incoordination, light-headedness, dryness of mouth, urinary hesitancy, blurring of visionCyclizine, Meclizine teratogenicB. H1 Blockers (2nd generation) Higher H1 selectivity No anti-cholinergic side effects no CNS depressant property (Do not potentiate

alcohol, benzodiazepine) Inhibit late phase allergic reaction by acting on

LT, anti-platelet activating effect Poor anti-pruritic, anti-emetic, anti-tussive

properties Used for: Allergic rhinitis, conjunctivitis, hay

fever, urticaria, atopic eczema, acute allergic reactions

LoratadineDesloratadine Cetirizine inhibits H release & cytotoxic mediators from platelets & eosinophil chemotaxis AzelastineEbastine Terfenadine blocks cardiac K+ channels (overdose); Torsades de pointes Fexofenadine no arrhthymogenic potential

C. H1 Blockers (3rd generation)Levocetirizine

D. H2 Blockers Anti-ulcer Cimetidine Cytochrome P450 inhibitor, anti-androgen effects

RanitidineFamotidineNizatidine

SEROTONIN Major source in

intestines (90%) Platelets Brainstem (mood,

sleep, appetite, pain perception, temperature & BP regulation, vomiting)

Synthesized from tryptophan

Degraded by MAO 5HT1,2,3,4,5,6,7

receptors

CNS*Vomiting*Pain*Itch*Bezold-Jarisch reflex (5HT3) *chemoreceptor reflex – marked outflow of vagal stimulation to the heart bradycardia

CVS *vasoconstriction (5HT2) except skeletal muscle, heart *platelet aggregation

RS *bronchoconstriction (5HT2)

GIT *increases motility thru ACh (5HT4)

I. Serotonin (5-HT) AgonistsA. 5HT1A ReceptorBuspirone (anxiolytic)B. 5HT1D ReceptorAmlotriptan NASumatriptan Zolmitriptan (constrict cerebral vessel)(migraine headache)C. 5HT4-Cisapride(toxic)Tegaserod (partial agonist) irritable bowel syndromeII. Serotonin (5-HT) Antagonists1. 5HT1-5HT2 Methysergide

2. 5HT2 Ketanserin blocks platelet aggregation for stroke Ritanserindecreases thromboxane formation for stroke

3. 5HT2, H1 Cyproheptadin for cold-induced urticaria for carcinoid syndrome4. 5HT3 Ondansetron chemotherapy-induced nausea & vomitingTherapeutic Uses


Skeletal muscles *serotonin syndrome (5HT2) – *hyperthermia

1. controls S/S carcinoid, post-gastrectomy dumping syndrome Cyproheptadine sedative, stimulates appetite, good anti-pruritic

2. Raynaud’s disease Ketanserin blocks platelet aggregation for stroke Ritanserindecreases thromboxane formation for stroke

3. Anti-emetic (anti-cancer, radiotherapy) Ondansetron

4. Migraine prophylaxis, Carcinoid,post-gastrectomy dumping syndrome

Methysergide

5. Migraine (better tolerated) SumatriptanZolmitriptan

6. Schizophrenia RisperidineClozapine

ERGOT ALKALOIDSMechanism of Action Organ System Effect Adverse Effects Indications Contraindications Other notes

Amine Alkaloids Ergometrine Ergonomine

Amino Acid/Peptide Alkaloids Ergotamine Regotoxine

Semi-Synthetic Alkaloids Ergometrine Ergonomine

agonist, partial agonist, antagonist at α receptors, serotonin receptors, CNS

dopamine receptors

CNS – powerful hallucinogen (Lysergic Acid Diethylamide or LSD)

Bromocriptine inhibits prolactin CVS – vasoconstriction d/t partial

agonist effects at α adrenoceptors

Nausea, vomiting (high dose) Prolonged vasospasm

gangrene, bowel infarction Drowsiness, hallucinations

Ergotamine, Ergonovine, Methysergide – migraine headache (partial agonist α & 5HT2)

Uterus – postpartum hemorrhage, induces labor

Ergonovine, Oxytocin (parenteral), Methylergometrine (Methergine) parenteral or oral

EICOSANOIDSMechanism of Action Organ System Effect Adverse

EffectsIndications Contraindications Other notes

Arachidonic AcidProstaglandins

Arachidonic Acid Oxygenated by 4 routes:

Lipoxygenase: HETEs, leukotrienes, lipoxins

Cytochrome P450 (epoxygenase) – EETs, vasodilator

Icoeicosanoid: Isoprostane, vasoconstrictor

Cyclooxygenase: PG, prostacyclin, thromboxane

PGH synthase-1 (COX-1): gastric epithelial protection

PGH synthase-2 (COX-2): source in inflammation

ProstaglandinBind to receptors on cell surface

CVS TXA2, PGF2α – vasoconstriction,

bronchoconstriction, contraction of uterus

PGI2/prostacyclin, PGE1 – vasodilatation, bronchodila, relaxes uterus

Epoprostenol (PGI2) – pulmonary HPN

Alprostadil (PGE1) – patency of DA COX inhibitor (Indomethacin) –

closes ductus arteriosus GIT

Misoprostol/cytotec (PGE1) – for peptic ulcer (NSAID- induced), for abortion

Enprostil NA (PGE) – inhibit HCl secretion

Respiratory System PGE2, PGI2 – bronchodilatation

Lipid-derived autacoids Oxygenation products of polyunsaturated long chain fatty acids Plant & fish oil precursors Arachidonic Acid – most important precursor

Eicosanoid Inhibitors Corticosteroids: inhibits all pathways by stimulating synthesis of

inhibitory protein, inhibit phospholipase A prevent arachidonic acid release

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): blocks prostaglandin & thromboxane formation by inhibiting cyclooxygenase activity

Aspirin (Acetylsalicylic Acid) – irreversible acetylation of platelet cyclooxygenase (other drugs not irreversible); inhibits TXA2 synthesis

Mechanism of action: irreversibly inhibits platelet COX1 (8-10 days)

Indications: transient ischemic attack (TIA), CAD (coronary artery disease)

Adverse Effects: Gastric/duodenal ulcer


PGD2, TXA2 – bronchoconstriction PGF2α, LT – bronchoconstriction

Platelet aggregation PGD2, PGE2, PGI2 – inhibit TXA2 – stimulate Aspirin – inhibits platelet COX1

Kidney PGE2, PGI2 – vasodilatation TXA2 – vasoconstriction

Reproductive system PGF2α, PGE2- uterine contraction,

soften cervix Dinoprostone, Misoprostol,

Carboprost PGE2, PGF2α – SE dysmenorrhea

(take NSAIDs) Alprostadil (PGE1) – relax smooth

muscle of corpora cavernosa for erectile dysfunction

Effects of lipooxygenase, cytochrome P450 metabolites: CVS

12Hydroxyeicosatetraenoic (HETE) – chemoattractant for smooth muscles

LTC4, LTD4 – myocardial depressant, constriction of coronary arteries

GIT LTB4 – chemoattractant for PMNs

Respiratory LTC4, LTD4 – bronchoconstriction,

mucus secretion, plasma exudation Blood

LTB4 – chemoattractant for T cell, eosinophils, monocytes, mast cells

Renal System 20 HETE – vasoconstriction EET – vasodilatation, natriuresis

Hepatotoxic Allergy (most common)

Non-selective COX inhibitors – blocks prostaglandin, TXA2 synthesis

Pyrazone – Phenylbutazone, Oxybutazone Indole – Indomethacin, Sulindac Propionic acid – Ibuprofen, Naproxen, ketoprofen Anthranilic acid – Mefenamic acid Aryl-acetic acid – Diclofenac Oxicam – Piroxicam, Tenoxicam Pyrolopyrole – Ketorolac

COX-2 Selective Inhibitors Mechanism of action: bind to and block active site of

COX2 enzyme (reversible) Less GI effects, no platelet effect Adverse Effects:

Fluid retention Hypertension Hepatotoxic Nephrotoxic Rashes

VASOACTIVE PEPTIDESANGIOTENSIN RECEPTOR ANTAGONISTS


Valsartan Selective competitive antagonist of angiotensin AT1 receptors

Arteriolar dilationdecreased aldosterone secretionincreased sodium and water excretion

Hypertension Eprosartan, irbesartan, candesartan, olmesartan, telmisarta - similar to valsartan

CONVERTING ENZYME INHIBITORSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

EnalaprilInhibits conversion of angiotensin I to angiotensin II

Arteriolar dilationdecreased aldosterone secretionincreased sodium and water excretion

Hypertension heart failure Captopril and many others -similar to enalapril


RENIN INHIBITORSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Aliskiren Inhibits catalytic activity of reninArteriolar dilationdecreased aldosterone secretionincreased sodium and water excretion

Hypertension

KININ ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

IcatibantSelective antagonist of kinin B2

receptorsBlocks effects of kinins on pain, hyperalgesia, and inflammation

Potential use for inflammatory pain and inflammation

VASOPRESSIN AGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Arginine vasopressinAgonist of vasopressin V1 (and V2) receptors Vasoconstriction Vasodilatory shock Terlipressin - more selective for V1 receptor

VASOPRESSIN ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Conivaptan Antagonist of vasopressin V1 (and V2) receptors

VasodilationPotential use in hypertension and heart failure hyponatremia

Relcovaptan – increased selectivity for V1

receptor

NATRIURETIC PEPTIDESMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Nesiritide Agonist of natriuretic peptide receptors Increased sodium and water excretionvasodilation Heart failure

VASOPEPTIDASE INHIBITORSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

OmapatrilatDecreases metabolism of natriuretic peptides and formation of angiotensin II Vasodilation

increased sodium and water excretion Hypertension heart failure

ENDOTHELIN ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

BosentanNonselective antagonist of endothelin ETA and ETB receptors Vasodilation Pulmonary arterial

hypertension Sitaxsentan, Ambrisentan - selective for ETA

receptors

VASOACTIVE INTESTINAL PEPTIDE AGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Under developmentSelective and nonselective agonists of VPAC1 and VPAC2 receptors

VasodilationMultiple metabolic, endocrine, and other effects

Type 2 diabetes chronic obstructive pulmonary disease

SUBSTANCE P ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

AprepitantSelective antagonist of tachykinin NK1

receptorsBlocks several central nervous system effects of substance P

Prevention of chemotherapy-induced nausea and vomiting


NEUROTENSIN AGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

PD149163 Agonist of central neurotensin receptors Interacts with central dopamine systems

Potential for treatment of schizophrenia and Parkinson's disease

NEUROTENSIN ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

MeclinertantAntagonist of central and peripheral neurotensin receptors

Blocks some central and peripheral (vasodilator) actions of neurotensin None identified

CALCITONIN GENE-RELATED PEPTIDE ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

BIBN4096BSAntagonist of calcitonin gene-related peptide (CGRP)

Blocks some central and peripheral (vasodilator) actions of CGRP Migraine

NEUROPEPTIDE Y ANTAGONISTSMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

BIBP3226Selective antagonist of neuropeptide Y1

receptorsBlocks vasoconstrictor response to neurotensin

None identified

Urotensin AntagonistsMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

PalosuranPeptide antagonist of urotensin receptors

Blocks potent vasoconstrictor action of endothelin Diabetic renal failure

NITRIC OXIDEMechanism of Action Organ System Effects Adverse Effects Indications Contraindications Other Notes

Nitric Oxide

NO activates soluble guanylyl cyclase to elevate cGMP levels in vascular

smooth muscle

1. blood vessels vasodilator inhibits PMN adhesion to endothelium

2. respiratory system relax smooth muscles for pulmonary hypertension and ARDS

3. platelets inhibits platelet adhesion, aggregation,

enhance fibrinolysis4. CNS

modifies NT release, learning & brain development

Methemoglobinemia

Hypoxic respiratory failure and pulmonary hypertension Inhaled gas

Documents

Pharma Drug Tables - 1st Shifting