Cardio-vascular Pharmacology

Professor Doctor: Abd Al Rahman Abd Al

Fattah YassinProfessor and head of clinical

pharmacology departmentMansura university

HYPERTENSION•  Hypertension is a persistent elevation of blood 

pressure above 140/90 mm. Hg. • Classification of Hypertension According to etiology: essential and secondary 

(e.g. thyrotoxicosis).• According to type: systolic, diastolic and mixed 

(more dangerous).• According to degree:

N.B:•Borderline hypertension: Hypertensive cases with blood pressure always at the upper limits of normal.•Labile hypertension: In which blood pressure is only occasionally elevated. 

THERAPY OF HYPERTENSION A) Non-Drug Therapy• It  includes  decrease  sodium  intake, weight  reduction  in  obese,  stop smoking,  coffee  and  alcohol  drinking; exercise program and control diabetes mellitus and hyperlipideamia.

Avoid  agents  that  increase  blood  pressure  as Sympathomimetics.  Steroids.  NSAIDs. Carbenoxolone,oral contraceptives,cyclosporine,  recombinant human  erythropoietin,  and  products  that contain  large  quantities  of  sodium.  Such  as effervescent solutions.

B) Drug Therapy (Antihypertensives)  There  are  many  groups  of  drugs  available  for treatment of hypertension Commonly used drugs:•Angiotensin converting enzyme inhibitors.•Beta-blockers.•Calcium channel blockers.•Diuretics.N.B: Beta blockers nowadays restricted to the presence of other associated diseases (angina arrhthymia and thyrotoxicosis)because of their diabetogenic effect

Other groups of drugs 1. Direct vasodilators e.g. hydralazine.2. Centrally acting agents interfering with

adrenergic function e.g. alphametyldopa, clonidine and guanfacine

3. Alpha adrenergic blockers e.g. prazocin.4. Concurrent alpha and beta blockers e.g.

labetalol, carvedilol.

5.Adrenergic neurone blockers e.g. reserpine and alpha methyldopa.6.Serotonine antagonists e.g. ketanserine. 7.Ganglion blockers e.g. trimetaphan.8.Potassium channel openers e.g. cromakalim, pinacidil.9.Imidazoline receptors agonist e.g. moxonidine and rilminidine.

DIURETICSMechanisms of Diuretics as an Antihypertensive• Decrease peripheral vascular resistance due to

vasodilator action possibly through:• Direct vasodilator effect.• Decreased vascular receptor sensitivity to

vasopressin agents (adrenaline, angiotensin II by decreasing Na+ content in the cells of vascular wall.• Increase synthesize of the vasodilator PGs.• Diminished cardiac output due to decrease

blood volume by the diuretic action.

Indications of Diuretics in Hypertension

Thiazides: •Initial therapy in most hypertensive patients.•Part of most combined antihypertensive regimen.

Loop diuretics•Hypertensive crises.•Chronic renal failure.•Resistant hypertension where there is marked sodium retention due to other antihypertensives, cardiac failure or liver cirrhosis

Spironolactone: Primary hyperaldosteronism

BETA BLOCKERSIndications of beta-blockers in hypertension:•Hypertensive patient with stable angina, supraventricular or ventricular arrhythmias.•In patients with increased adrenergic activity e.g. younger age group, hyperkinetic circulation, alcohol withdrawal hypertension, with labile hypertension and palpitation.•Hyperrenenimic hypertension.•As a part of combined therapy. •N.B. Beta-blocker of choice in treatment of hypertension should be cardioselective 1 blocker and

with a long duration of action e.g. atenolol.

CALCIUM CHANNEL BLOCKER (C.C.Bs)

Definition: These are drugs, which block the slow calcium influx occurring during the terminal phase of depolarization and during the plateau phase of the action potential.

Classification according to the therapeutic effects:

• Calcium channel blockers with cardiac effects e.g. verapamil and diltiazem.• Calcium channel blockers with vascular

effects e.g. nifedipine, isradipine and clvedipine• Calcium channels blockers with tissue

protection: e.g. flunarizine, nifedipine.

Pharmacokinetics• Absorption of these agents is nearly complete

after oral administration. Their bioavailability is reduced in some cases because of the first pass hepatic metabolism. The effects of theses drugs are evident within 30 to 60 minutes of an oral dose, with the exception of the more slowly absorbed and longer acting agents e.g. amlodipine. Peak effects of verapamil occur within 15 minutes of its intravenous administration.

• These agents are bound to plasma proteins (70 to 98%). Their elimination half-lives are widely variable. Some of them have metabolites e.g. diltiazem, verapamil which have a vasodilator effect. The metabolites of the dihydropyridines are inactive or weakly active. • In patients with hepatic cirrhosis the

bioavailabilites and half-lives of the Ca2+ channel blockers may be increased and dosage should be decreased. The half-lives of these agents may also be longer in older patients.

Pharmacological Effects:Smooth muscle•They cause relaxation of vascular smooth muscle,  bronchiolar,  gastrointestinal,  and uterine  smooth  muscle.  In  the  vascular system  arterioles  appear  to  be  more sensitive  than  veins.  Dihydropoyridines have  a  greater  ratio  of  vascular  smooth muscle  effects  relative  to  cardiac  effects than do dilitazem and verapamil 

Cardiac muscle• These drugs reduce cardiac contractility in a

dose dependent fashion. This reduction in mechanical function is another mechanism by which the calcium channel blockers may reduce the oxygen requirement in patients with angina.• The calcium channel blockers have been

demonstrated to protect against the damaging effects of calcium.

They block tachycardia in calcium dependent cells, e.g. the atrioventricular node, more selectively than do the dihydropyridine. On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects; they are therefore less depressant on the heart than verapamil or diltiazem.

Other pharmacological effects• They may ↓ platelet aggregability.• They  interfere with stimulus secretion 

coupling  in  gland and nerve  terminals e.g. verapamil inhibits insulin release.• They  inhibit  calcium  influx  across 

nervous  membranes,  so  they  are effective  in  limiting  the  spread  of seizure activity.

Therapeutic Indications A) Cardio-selective CCBs are used in treatment of: •Ischemic heart disease: all types of angina and myocardial infarction. Mechanisms of action in Ischemic heart diseases•Decrease arterial blood pressure, contractility and heart rate so they decrease myocardial oxygen demand. •Decrease Coronary vascular resistance so increases blood flow to the myocardium.•Dilatation of epicardial coronary arteries•Decrease Ca++ load, which improve myocardial relaxation and decrease myocardial cell necrosis.

Cardiac arrhythmias e.g. paroxysmal supraventricular  tachycardia because  they  prolong intranodal  conduction  time  and  slow  AV  conduction and lengthen the ERP of the AVN.Hypertrophic obstructive cardiomyopathy: because they produce: •Reducing  contractile  force  during  systole,  this  leads to  decrease  O2  consumption  and  increase  exercise tolerance.•Enhance  relaxation  during  diastole  resulting  in improving coronary flow.Arterial hypertension: due to vasodilatation of the blood vessels.

B) Vascular selective CCBS are used in:• Arterial hypertension: due  to  vasodilatation 

of the blood vessels.• Cerebral vasospasm (nimodipine).• Peripheral vascular disease.• Chronic renal failure to minimize ischemia• Re-perfusion injury in the myocardium.• Migraine.

Adverse Effects• Aggravation of congestive heart failure (with verapamil or diltiazem). • A.V. block in-patients with pre-existing disease or when combined with beta-blockers (with verapamil or diltiazem).•Nausea, vomiting, constipation and reversible hepatotoxicity.

• Interference with normal glucose insulin-response and worsen diabetes mellitus.• Hypotension, flushing, nasal congestion, tinitus and occasional aggravation of angina (with nifedipine).• Ankle edema (with nifedipine or verapamil).

Drug Interactions• Verapamil  with  digitalis  or  with  beta-

blockers  may  cause  A-V  block  due  to additional  effect  on  conducting  system (nifedipine would be the drug of choice if B-blockers are to be used with CCBs).• CCBs and direct vasodilators may cause 

profound hypotension.

Contraindications and precautions• Verapamil should be used with

great caution in the presence of heart failure, unstable AV block, sick sinus syndrome, low blood pressure states e.g. cardiogenic shock & with beta blockers.

• Verapamil and diltiazem are contraindicated in Wolf-Parkinson-White syndrome complicated by A.F. & A. flutter.

• Nifedipine is contraindicated in idiopathic hypertrophic subaortic stenosis, severe myocardial depression and unstable angina.

Dose and Preparations

Verapamil:   80-160 mg /8 hours orallyNifedipine: 10-40  mg/8  hour orally or S.L.Diltiazem: 30-90 mg/8 hours oral.

RENNIN ANGIOTENSIN ALDESTERON SYSTEM

 RENIN • It is a proteolytic enzyme secreted by the kidney into the blood stream.•Kidney and blood contain also (inactive renin) i.e. pre-renin which is converted to active renin by tissue kallekrein.•It has a t½ 80 minutes 

RENIN ANGIOTENSIN SYSTEM • ACE inhibitors only block the ACE pathway

leaving the other pathway working to produce Angiotensin II. This may explain failure of these drugs to control some cases of hypertensive patients and necessitates addition of diuretics to ACE inhibitors in these cases.

•  Stimuli that increase renin secretion: Sodium depletion, diuretics, hypotension, hemorrhage, upright posture, dehydration, constriction of renal artery, heart failure and Cirrhosis• Inhibitors of renin secretion: Increased Cl- or Na+ reabsorption, angiotensin II, vasopressin and increased blood pressure.

Actions of Angiotensins• Angiotensin I (precursor of angiotensin II): It has 

no pharmacological action.

• Angiotensin II: It acts on two receptors; AT1 and AT2 

• Its action on AT1 receptor produces the following:

• CVS: • Arteriolar constriction leading to increase systolic and 

diastolic blood pressure (4-8 times as active as epinephrine).

• Angiotensin II produces positive inotropic and chronotropic effects which are primarily due to central and peripheral sympathetic stimulation. In addition, angiotensin II has a weak direct inotropic effect.

Endocrine: •Increase secretion and synthesis of aldosterone.•Facilitate catecholamine synthesis and release.•Increase pituitary vasopressin and ACTH.

Renal:• Suppress renin release• V.C  of  renal  efferent  arterioles, 

increases  proximal  tubular  Na+ reabsorption 

C.N.S• Increase  H2O  intake  and  vasopressin 

secretion.• Stimulate  central  sympathetic 

discharge.

Its action on AT2 receptor produces

the following:• Antiproliferation.• Apoptosis (normal cell death).• Vasodilatation  and  increase  local 

bradykinin.

Inhibitors of Renin Angiotensin System:• Inhibition of renin release: by beta-blockers, clonidine,

alpha methyl dopa and prostaglandin inhibitors e.g. indomethacin.

• Renin activity inhibitors e.g. enalakrine , pepstatin and aliskirin.

• Angiotensin converting enzyme inhibitors (ACEIs): • Sulph-hydryl containing ACEIs: e.g. Captopril, Alacepril,

Zofenopril• ACEIs without sulph-hydryl group: e.g. Enalapril,

Lisinopril, Prindopril, Ramipril, Cilazapril, Benzapril, Quinapril.

• ACEIs inhibitors which contain phosphinate group e.g. Fosinopril is the only ACE that contains a phosphinate group that binds to active site of ACE. It is a prodrug which is transformed to fosinoprilat, an ACE inhibitor which is more potent than captopril yet less potent than enalaprilat. It is metabolised and excreted into both the urine and bile. It is has a plasma half-life 11.5 hours. The oral dosage of fosinopril ranges form 10 to 80 mg. daily.

• Angiotensin II receptor blockers e.g. Saralasin, Losartan, Valsartan.

Mechanism of Action of ACEIs• Interrupt Renin-Angiotensin-Aldosterone pathway through 

inhibition  of  peptidyl  dipeptidase  enzyme  that  converts angiotensin  I  to angiotensin  II.  These drugs prevent ang-II formation in the tissues (heart, blood vessels).

• Prevent  inactivation  of  kinins  lead  to  increase  the concentration of bradykinins which is a potent vasodilator.

Pharmacokinetics of ACEIs• Captopril: is rapidly absorbed from GIT. It is 

distributed to most tissues except the CNS. The primary route of excretion is the kidney; 50% is eliminated as unchanged drug.• Enalapril: it is inactive. It undergoes hepatic 

hydrolysis to the active diacid form enalaprila it is more slowly absorbed and the active metabolite has a long half-life and duration of action. Thus, enalapril is given usually once daily.• Lisinopril: it is not a prodrug it is not metabolized 

by the liver it is given once daily.

Pharmacological Effects• They decrease peripheral resistance but little change in heart

rate, cardiac output or pulmonary wedge pressure.• Do not modify cardiovascular responses to autonomic

reflexes. And don’t cause tachycardia inspite of hypotension due to: reset of baroreceptors reflex sensitivity downward., Venodilatation offered by ACEIs. and modification parasympathetic activity.

• They increase renal blood flow; Cerebral and coronary blood flow are maintained even when systemic blood pressure is reduced.• In congestive heart failure, ACEIs increase the

cardiac output, cardiac index, and decrease the heart rate.• They decrease the left ventricular mass and wall

thickness and prevent ventricular enlargement after myocardial infraction.

Clinical Uses• Hypertension.• Heart failure.• Postinfarction ventricular remodeling.• Renal diseases in cases of Scleroderma.• Possible  new  uses:  Insulin  resistance  - 

Arteriosclerosis - Rheumatoid arthritis.

Adverse Effects• First dose hypotension specially in sodium

depleted person.• Cough and bronchospasm due to accumulation of

bradykinin and prostaglandin (treated by NSAIDs).• Angiedema: secondary to change in bradykinin

metabolism, it may cause respiratory arrest and death.• Proteinuria in patients with compromised renal

function.

•Neutropenia: especially in patient who have impaired renal function or serious autoimmune diseases.• Skin rashes.•Hyperkalaemia.• Temporary loss of taste.•Headache, dizziness and fatigue.

Contraindications• ypotension: systolic pressure less than 95 mm Hg.• Severe renal failure.• Hyperkalaemia.• Severe anaemia.• Bilateral renal artery stenosis or stenosis in a

solitary kidney because angiotensin II, by constricting the efferent arteriole, helps to maintain adequate glomerular filtration when renal perfusion pressure is low. Consequently inhibition of ACE can induce acute renal insufficiency.

• Immune problems, in particular due to collagen vascular, autoimmune disease or with immunosuppressive drugs.• Patients’ known to have neutropenia or

thrombocytopenia.• Pregnancy and breast-feeding because ACE

inhibitors can cause fetal pulmonary hypoplasia, fetal growth retardation and fetal death.

Precautions during Use of ACEIs

• Initial dose should be low.• Diuretic use with caution.• Measurement  of  blood  urea  and 

creatinine  before  and  one  week  after treatment then every 3 months.• Electrolyte assay specially potassium.

ANGIOTENSIN II RECEPTOR BLOCKERS

Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. More recently candesartan, eprosartan, irbesartan, and telmisartan have been released. They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors. 

• They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotenin II. The adverse effects are similar to those described for ACE inhibitors, including the hazard of use during pregnancy. Cough and angioedema can occur but are less common with angiotensin receptor blockers than with ACE inhibitors.

VASODILATORSClassificationsArteriolar vasodilators: e.g. nifedipine, hydralazine, minoxidil.Directly relaxes arteiolar smooth muscles and thus decrease peripheral vascular resistance and arterial blood pressure so they are used in systemic hypertension, forward congestive heart failure or in low C.O.P state.

Venodilators: e.g. nitrates.Chiefly used in congestive heart failure or in acute pulmonary edema.

Mixed arterio and venodilators: e.g. sodium nitroprusside, prazocin, ACEIs and Trimetaphan. They can be used in heart failure as they act on both pre-and afterload.

General Consideration as Regard Arteriolar V.D

• Beneficial  effect  on  peripheral  vascular resistance  can  be  partially  antagonized  by increased  reflex  sympathetic  activity  which can  result  in  increase  heart  rate,  stroke volume,  C.O.P.  and  plasma  renin  activity.  It can be counteracted by beta-blockers.• They  can  cause  salt  and  water  retention. Therefore they should be used in conjunction with diuretics.

• They preserve renal and cerebral blood flow.• They  almost  completely  devoided  of  CNS side effect.• They don't cause orthostatic hypotension or sexual dysfunction.• Best  indicated  in  hypertensive  heart  failure and renal hypertension. 

HYDRALAZINE• It directly relaxes small arteries and arterioles.• It decreases arterial blood pressure• It is absorbed from GIT, acetylated in the liver.Uses• Combination therapy for hypertension.• Primary pulmonary hypertension.Dose: 10 mg 2-3 times/day.Adverse effects• Systemic Lupus-like syndrome in slow acetylators.• Nasal congestion, flushing,  lacrimation, drug  fever, 

skin rash.• Headache,  palpitation,  tachycardia,  anginal  pain, 

anorexia, nausea, dizziness.

MINOXIDIL• It  is  arteriolar  vasodilator,  which  cause  activation  of 

potassium  channel  result  in  hyperpolariziation  of  the  cell membrane,  which  will  causes  relaxation  of  vascular  smooth muscle.

• It  is  absorbed  from  GIT,  metabolized  by  conjugation  with glucoronic acid in the liver, excreted in the urine.

• Uses• Severe hypertension in combination therapy.• Azotemic hypertensive patients.

DIAZOXIDE• It is related to chlorothiazide but produces sodium retention rather than

diuresis.• It has a direct vasodilator action on the arterioles through activation of

potassium channels.• The drug is 90% bound to plasma albumin.• Uses• Hypertensive emergencies e.g. hypertensive encephalopathy, and toxaemia

of pregnancy.• Hypoglycaemia due to hyperinsulinism.• Dosage: it is given by I.V. injection. Start with small dose 50-75 mg rapidly.

The dose can be repeated after 10-15 minutes intervals.• Adverse effects• Tachycardia which can precipitate angina.• Hyperglycaemia due to inhibition of insulin release.• Sodium and water retention.• Hyperuricemia.• Others: nausea, vomiting, constipation.

• Dose:  The  effective  dose  range  is  10-40  mg/day /orally.

• Adverse effects• Palpitation, tachycardia, anginal pain, headache.• Fluid retention and edema.• Hypertrichosis• Pericardial effusion.

SODIUM NITROPRUSSIDE• It has a vasodilator effect on the smooth muscle of the 

venoarteriolar beds, through activation of guanylate cyclase which bring about an increase in cGMP .

• It is rapidly metabolized in red cells to cyanide, which is then metabolized to thiocyanate prior to renal excretion.

• Uses• Hypertensive encephalopathy• Refractory cases of congestive heart failure 

Dosages: It is given by IV infusion in 5% dextrose. The  initial  dose  is  0.5 g/kg/minute  and may be increased  up  to  10  g/kg/min  as  necessary  to control blood pressure. Adverse effects•Nausea,  vomiting,  sweating,  restlessness headache,  palpitation  and  substernal  pain  and may  be  increased  up  to  10  g/kg/minute  as necessary to control blood pressure.•Prolonged  therapy may  lead  to accumulation of cyanide  (metabolic  acidosis,  arrhythmias,  death) or thiocyanate (delirium and psychosis).

Precautions•Infusion must not  stop abruptly  to avoid  rebound hypertension.•In  liver  disease,  cyanide  doesn’t  convert  to thiocyanate and hence more toxic.•Higher rates of infusion may result in toxicity.

CENTRALLY ACTING ANTIHYPERTENSIVES CLONIDINE

It is an agonist to central postsynaptic 2 adrenoceptors suppressing sympathetic outflow and reduces blood pressure. It has been postulated that they it is also partly due to effects of imidazoline receptors which act in CNS to reduce sympathetic outflow to the heart and vascular smooth muscles.It decreases synthesis of NE by decreasing dopamine - hydroxylase and N-methyl transferase enzymes.It acts on peripheral presynaptic 2 adrenoceptors inhibiting N.E release.

It reduces plasma renin activity, decrease renal vascular resistance and renal blood flow is maintained.

Reduction of cardiac output due to decrease heart rate.

Pressor effects of clonidine are not observed after ingestion of therapeutic dose but overdose may induce severe hypertension due to stimulation of postsynaptic adrenoceptors.

Dose: 0.2-1.2 mg/day orally. Therapeutic uses•Moderate and severe hypertension 0.1 - 0.2 mg twice/day•Prophylaxis in migraine 0.025 mg twice /day.•In opiate withdrawal to reduce signs of sympathetic overactivity.•Sedation and reduction of anxiety in preanaesthetic medication Adverse effects•Dry mouth and sedation.•Salt and water retention •Withdrawal syndrome leads to hypertensive crisis. It is treated with reinstitution of clonidine or administration of both alpha and beta-blockers. So clonidine withdrawal, if indicated, should be done gradually with substitution by other antihypertensive.

Drug interactions•Tricylic antidepressant may block the antihypertensive effect of clonidine •Beta-blockers may aggravate the hypertensive crises following sudden clonidine withdrawal.•CNS depressants may cause excessive drowsiness with clonidine.

ALPHA METHYL DOPA1-It stimulate central postsynaptic alpha 2 receptor so, decrease central sympathetic outflow.2-it inhibits renin release.3-it cause formation of false chemical transmitter.

*It can be used in treatment of hypertension with pregnancy.

GUANFACINE• Has a mechanism of action similar to clonidine. •Hypotensive effect is associated with a fall in peripheral resistance, HR and COP.•Most common side effects are dry mouth, somnolence, dizziness and asthenia.

ALPHA-ADRENERGIC BLOCKERS * Prazocin and trimazocin are selective alpha 1 blockers *IndoramineSelective blocker to postsynaptic 1receptors.First dose phenomenon does not occur. It causes sedation, lethargy, drowsiness and dizziness.Contraindicated in renal failure and depressive states.Dose 25 mg twice /day.

CONCURRENT ALPHA AND BETA ADRENOCEPTOR BLOCKERS

LABETALOL It  blocks  both  alpha  (selective  1  blocker)  and  beta-receptors (non-selective -blocker). It  lowers  blood  pressure  by  reducing  peripheral resistance without affecting cardiac output.It reduces plasma renin activity.It has a rapid onset of action as an antihypertensive.It  is  used  for  emergency  control  of  severe hypertension with  pheochromo-cytoma,  and  hypertensive  response during abrupt clonidine withdrawal.

Carvedilol

1-Block both alpha and beta receptors.2-Has vaodliator effect.3- Has antioxiodant effect.4- Can be used in treatment of heart failure. 

KETANSERIN It  is a selective antagonist of 5-HT2 receptors  in smooth muscles of 

arteries, bronchi and platelets. It also blocks alpha adrenoceptors.It  lowers  the BP without postural  hypotension or  reflex  tachycardia 

and the effect is greater on the diastolic blood pressure.It does not affect glomerular filteration rate or renal blood flow

Side effects: Dizziness, fatigue and polyuria.

Potential usesOrally: hypertension and peripheral vascular diseases.I.V.: asthmatic attack, thrombophlebitis, and pulmonary emboli.

Effective dose: 20 mg 2-3 times/day 

Dopamine (D1) receptor agonist e.g. Fenoldopam• Pharmacokinetics:• Given by continuous intravenous administration.• Metabolized in the liver by conjugation (t 1/2 10 minutes).

• Pharmacological Effects:• ++  Dl   receptors  in peripheral  arteries  leading to  arterio-

dilatation  & natriuresis.

• Therapeutic uses:• Treatment of hypertensive emergency.• Treatment of post-operative hypertension.

• Adverse effects:• Reflex tachycardia, headache & flushing.• ↑ IOP (avoided in patient with glaucoma).

HYPERTENSIVE EMERGENCIES• These  include  hypertensive  encephalopathy,  cerebral  stroke,  acute  left 

ventricular failure, aortic dissection, epistaxis, and severe renal failure.• Patient should be hospitalised.• Reduction of blood pressure should be in hours and not in minutes.• Sublingual nifedipine or captopril may be effective in reducing blood pressure.• Parenteral therapy:• Diuretics (frusemide, Bumetanide) I.V.• Reserpine 1-2 mg I.M (never I.V.)• Diazoxid 300 mg I.V. very rapidly• Sodium nitroprusside infusion 2-5 g/kg/min. according to blood pressure• Hydralazine 20 mg I.V. slowly diluted.• Beta blocker (Propranolol) 1-2 mg I.V. slowly diluted.• Methyl dopa I.V. diluted• Nifedipine I.V., diluted.• Nitroglycerin I.V. 1-10 g/kg/min.