1. بسم الله الرحمن الرحيم

2. Cardio-vascular Pharmacology
Professor Doctor:
Abd Al Rahman Abd Al Fattah Yassin
Professor and head of clinical pharmacology department
Mansura university

3. 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:

5. 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.

6. 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.

7. 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.

8. 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

9. Other groups of drugs Direct vasodilators e.g. hydralazine.
Centrally acting agents interfering with adrenergic function e.g. alphametyldopa, clonidine and guanfacine
Alpha adrenergic blockers e.g. prazocin.
Concurrent alpha and beta blockers e.g. labetalol, carvedilol.

10. 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.

11. DIURETICS Mechanisms 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.

12. 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

13. BETA BLOCKERS Indications 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.

14. 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.

15. 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.

16. 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.

17. These agents are bound to plasma proteins (70 to 98%)
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.

18. 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

19. 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.

20. They block tachycardia in calcium dependent cells, e. g
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.

21. 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.

22. 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.

23. Hypertrophic obstructive cardiomyopathy: because they produce:
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.

24. 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.

25. 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.

26. 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).

27. 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. 

28. 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.

29. 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.

30. Verapamil: 80-160 mg /8 hours orally
Dose and Preparations
 Verapamil: mg /8 hours orally
Nifedipine: mg/8 hour orally or S.L.
Diltiazem: mg/8 hours oral.

31. 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

32. There are two pathways for converting Angiotensin I to Angiotensin II, the first is the enzymatic pathway by Angiotensin converting enzyme (ACE) and the second is the non-ACE enzymes (Cathepsin, Chymase). So to prevent formation of Angiotensin II from Angiotensin I, these two pathways must be blocked.

33. 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.

34.  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.

35. 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.

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

37. Renal: C.N.S 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.

38. Its action on AT2 receptor produces the following:
Antiproliferation.
Apoptosis (normal cell death).
Vasodilatation and increase local bradykinin.

39. 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.

40. ACEIs inhibitors which contain phosphinate group e. g
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.

41. 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.

42. 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.

43. 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.

44. 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.

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

46. 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.

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

48. 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.

49. 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.

50. 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.

51. 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.

52. 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.

53. VASODILATORS Classifications
Arteriolar 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.

54. 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.

55. 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.

56. 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.

57. 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.

58. 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 mg rapidly. The dose can be repeated after 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. 

59. 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.

60. 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

61. Dosages: It is given by IV infusion in 5% dextrose
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).

62. 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.

63. 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.

64. 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.

65. Dose: mg/day orally.
Therapeutic uses
Moderate and severe hypertension mg twice/day
Prophylaxis in migraine 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.

66. 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.

67. ALPHA METHYL DOPA GUANFACINE
1-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.

68. ALPHA-ADRENERGIC BLOCKERS
 * Prazocin and trimazocin are selective alpha 1 blockers
 *Indoramine
Selective 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.

69. 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.

70. 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.

71. KETANSERIN Side effects: Dizziness, fatigue and polyuria.
 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 uses
Orally: hypertension and peripheral vascular diseases.
I.V.: asthmatic attack, thrombophlebitis, and pulmonary emboli.
 Effective dose: 20 mg 2-3 times/day

72. 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).

73. 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 g/kg/min.