Principles of antihypertensive therapy Arterial BP Physiology: ! Determinants – BP regulation !! BP = CO x PVR

" Moment to moment regulation

# Peripheral vascular resistance: " vessel tone !! arterioles, postcapillary venules (capacitance)

• smooth muscle • sympathetic nervous system • vascular compliance – stiffness

" blood volume # CO:

" contractility, " preload

Therapy: ! Non pharmacological

# Weight loss # Restrict Na intake # Increase aerobic exercise # Moderate alcohol consumption

! Pharmacological # Considerations:

" Genetic polymorphism – variable response " Long term administration effects

# Classification by primary site or mechanism of action:

" Diuretics # Thiazides # Loop diuretics # K sparing agents

" Sympatholytic # Beta adrenergic antagonists # Alfa adrenergic antagonists # Mixed alfa – beta antagonists # Centrally acting agents # Adrenergic neuron blocking agents

" Ca Channel Blockers " Renin – angiotensin system

# ACEI (Angiotensin converting enzyme inhibitors) # ARB (Angiotensin II receptor blockers)

" Vasodilators # Arterial # Arterial and venous

Common uses of diuretics in Intensive Care

o Maintain or adjust fluid balance o Hyperkalemia o Renal failure

• Renal mechanisms o Almost all diuretics act on apical membrane, but spironolactone

$ require transport into the luminal delivery by filtration and secretion

• Other drugs with diuretic effects o Dopamine 1 receptor agonists $ poor diuretics

" Dopamine ( 1 – 3 mcg/kg/min) • # renal blood flow and GFR • AMPc inhibition of Na/H exchanger (proximal tubule)

" Fenoldopam mesylate • More selective (less cardiac effects)

o Aminophylline $ weak diuretics " # AMPc by phosphodiesterase inhibition

Site Mechanism Process Diuretic action Glomerular capillaries$ Bowman’s space$ Proximal tubule

Hydraulic pressure generates the ultrafiltrate

• Na movement accompanied by water

• Osmotic diuretics (freely filtrated – poorly reabsorbed)

Na-K ATPase pump • Active transport Na out to the ultrafiltrate with Cl, HCO3, water

Proximal tubule

Carbonic anhydrase (CA) (extracellular and intracellular)

• 60-70% Na filtrated reabsorbed as NaHCO3 • CA converts carbonic

acid to water and carbon dioxide o Depends on

secretion of H by Na/H exchanger

• Carbonic anhydrase inhibitors • NSAID organic acid

transport (including loop and thiazide transport)

Na – K – 2Cl pump (related to the countercurrent generation of medullary concentration gradient)

• Na K Cl water reabsorption

• Loop diuretics o Depends on

secretion into the tubule

o NSAIDs decrease responsiveness

Thick ascending limb

Macula densa (yuxtaglomerular apparatus)

• Na reabsorption (distal Na delivery)

•

Na – K exchanger Thiazide

Carbonic anhydrase (small amount)

HCO3 reabsorption Acid secretion

Distal convoluted tubule

Ammonium ion transport into urine

Distal tubule

Connecting duct

Na channel – K/H transport linked (controlled by aldosterone)

Na reabsorption (and passively Cl and water)

o K and H secretion

Triamtirene Amiloride

Diuretic Indications Effects Side effects

Acetazolamide • Chloride unresponsive metabolic acidosis • $ ocular fluid production (glaucoma) • Altitude sickness (metabolic acidosis $ # O2 delivery)

• Prevents H secretion and HCO3 reabsorption • # Na and HCO3 delivery to distal segment • Inhibits organic acids secretion

• Metabolic acidosis • Unmask primary respiratory acidosis • # ammonium retention (exacerbation of encephalopathy) • # nephrolithiasis

Mannitol • # ICP – cerebral oedema • Controversial

o Renal failure and AAA repair

o Rhabdomyolysis

• Volume depletion • HyperNa • Hyperosmolarity ( # osmolar GAP ) • Renal failure $ fluid overload

Loop diuretics • Frusemide • Ethacrynic acid (> ototoxicity – used allergy to sulphonamide)

• Fluid overload • Continuous infusion

o better haemodynamic tolerance

o Less [ ] dependent ototoxicity

• Systemic vasodilatation (particularly venous)

• Metabolic alkalosis • Volume depletion • Hypo: K, Na, Cl, Mg, Ca • Ototoxicity ( [ ] dependant) • Chronic use $resistance and dependence o # expression Na/K

exchanger (distal tubule)

o Tubular hypertrophy o hyperaldosteronism

Thiazide diuretics • hydrochlorothiazide • metolazone • chlorothiazide (PO and IV)

• $ Na reabsorption (distal) • # reabsorption:

o Ca o Uric acid

• Hypok • hypoNa • volume depletion $ hyperreninemic hyperaldosteronism $ thiazide resistance and dependence • exacerbate

o HyperCa o Gout

• Insulin resistance + $ insulin release (2ry to hypokalemia)

Potassium – Sparing diuretics • **Spironolactone • Amiloride • Triamtirene

• **Liver dysfunction • Diuretic resistance or dependence to thiazide diuretics • K sparing

• **Competitive inhibition of intracellular aldosterone receptor o blocks ammonia

production • inhibition of luminal Na channel $ $ K and H secretion

• Hyperkalemia (particularly K supplement, NSAIDs, ACE I) • Metabolic acidosis

• Diuretic dependence and resistance mechanisms:

o Loop diuretics or thiazide " # Na delivered to distal segments $ compensatory # distal Na reabsorption $

offset action " $ Intravascular volume $ $ GFR $ # proximal tubular Na absorption $ $ Na

distal delivery " $ Intravascular volume $ # aldosterone and ADH $ $ diuretic effects " Prolonged exposure $ tubular remodeling and cellular hypertrophy $ #

expression of pumps and channels $ resistance and dependence

• ACUTE TOLERANCE $ acute adaptation to Na and Fluid depletion actions of diuretics

o Early brisk diuresis o Diuretic breaking in periods between doses $ in favour of

infusion

• DIURETIC RESISTANCE AND DEPENDANCE $ molecular and cellular remodeling in tubules and tubular cell hypertrophy in chronic administration

o Dependant even for basal conditions to maintain fluid and electrolyte balance

o Frusemide $ 1 month therapy

• PHARMACOKINETIC FACTORS OF RESISTANCE o Impaired luminal delivery (SITE OF ACTION)

" Amount of diuretic filtrated • $ renal perfusion - $ GFR

" Decreased transport • NSAIDs • Metabolic acidosis

o Hypoalbuminemia $ # distribution volume of protein bounded diuretics

o Proteinuria $ diuretic binding in the tubule $ $ effective [ ] at site of action

Diuretics Drugs PK PD Thiazides and related

(1)Hydrochlorothiazide (2)Benzothiadiazines: (chlorothiazide) (3)Thiazide class (Chlortalidone) (4)Metolazone

R: PO (4) retains effect with GFR <30ml/min

MA: (1-2-3) Thiazide sens Na-Cl coTP (1) Open Ca – activated K channels ! Hyperpolarize smooth muscle ! close Ca channels !! vasoconstriction (1) inhibits vascular carbonic anhydrase Eff: !Extracell volume ! ! CO Direct vasodilation Ido: enhance other antiHT – refractory HT to " 3 drugs SEff: K – Mg waste Inhib Uric secretion Erectile dysfunction – impotence HypoNa ! Ca excretion Change lipids and glucose tolerance Max eff: 4 – 12 weeks CIdo: Breast feeding

Loop diuretics Frusemide Bumetanide

Duration action: short SEff: Rapid Na uresis K – Mg waste

K sparing agents

Spironolactone [1] Amiloride Triamtirene

SEff: HyperK [1] Impotence, gynecomastia, Prostate hyperplasia CIdo (relative): Renal failure

R: Route E: Elimination M: Metabolites

MA: Mech action Eff: Effects SEff: Side Effects Ido: indication CIdo: Contraindication

PK PD Sympatho

litic Drugs

Route t1/2 T Elimin Metab Mech action Effects Ido Side Effects Propranolol (1) • Lipophilic • 90% prot bound • Active - enantiomer

PO IV

3-5 hrs

L: #1st pass

4-OH propranolol (less active)

(1) Non selective ß blocker

Atenolol (2) • Hydrophilic • Accumulates

renal dysf

PO IV

6 hrs (5-8)

24 hrs

K: No $

Metoprolol (3) PO IV

4-6 hrs

12 hrs (SR)

CYP2D6 #1st pass

Bisoprolol (4) Long (11-17hrs)

24 hrs

Liver K

(2-3) Modest selective ß1 blocker (2) Intrinsic activity and membrane stabilising

• ! Myocardial contractility – HR – CO • ! renin secretion • CNS: ! sympathetic vasoconstriction • # PG synthesis

• HT • IHD – ACS- angina • Prevent reflex tachycardia • Tachyarrhyt

hmias • (1)Tremor • (1) Portal

HT – variceal bleeding • LV systolic

dysfunction (# quality & ! mort) • LVH • Acute Ao

dissection

• Bradycardia - ! CO • Delay conduction • Asthma - # Airway resistance • Less bronchoconstriction (2,3) • Periph vasc insuff • Withdrawal syndrome • # IOP • Impair recovery after hypoglycaemia • Precipit heart failure (susceptible) • Fatigue, depression • Blunt recognition of ! BSL • Sexual dysfunction • Hyperthyroidism (1): !T4-T3 conversion • Migraine prophylaxis

Esmolol (5) ULTRA SHORT ACTING @ accumulates if prolog infusion

IV infusion

8-10 min

Load Infusion

RBC esterases hydrolysis

Carboxilic acid metab ( 4 hrs @)

Selective ß1 blocker

• HT Intra and postop • Emergency • Critically ill • SVT

Nevibolol (6) 10-12 hrs

24 hrs

(6) D-isomer: Most selective ß1 blocker L-isomer: Vasodilation (release endothelial NO)

ß adrenergic blockers

Carteolol, timolol (7) Betaxolol (8)

Topical (ocular)

12-24hrs effect

Non selective (7) Selective ß1 (8)

• !aquous humour production

• Glaucoma

PK PD Sympatho

litic Drugs

Route t1/2 T Elimin Metab

Mech action Effects Ido Side Effects

Labetalol (4 diastomeres) Different PK and PD of isomers

PO IV

8 hrs ( d isom 15 hrs)

• #1st pass (20-40% bioavailability) • L:

oxidation and glucuronidation

Reversible antagonist Racemic mixture 3:1 of ß:" • "1 selective antag • ß1 selective antag • ß2 partial agonist Inhib • Direct vasodilation

ß block 5-10 fold !!1 block

• ! Periph vasc resistance

• Pheochromocytoma • HT emergency

" and ß adrenergic blockers

Carvedilol • Lipophilic • 95% prot

bound

PO 7-10 hrs

• Liver: #1st pass CYP2C9 – CYP2D6 9STEREOSELECTIVE)

Racemic mixture 1:1 of ß:" • Non selective ß (1,2) • Selective "1 • Antioxidant, antiproliferative • Block ca channel

• Vasodilatation • Attenuates O2

radical free lipid peroxidation • Inhibits vascular

smooth muscle mitogenesis • Improves survival

in heart failure: COMET, COPERNICUS, CAPRICORN studies)

• Heart failure and HT

PK PD Sympatho

litic Drugs

Route t1/2 T Elimin

Metab

Mech action Effects Ido Side Effects

Prazosin PO 3-4 hrs

Terazosin

PO 12 hrs

24 hrs

Doxazosin 22 hrs

24 hrs

Selective "1 block ( arterioles – venules) Competitive Antag

• Dilatation resistance and capacitance vessels • ! reflex tachycardia (

Norad negative feedback "2 presynaptic)

• Combined diuretic or ß blocker • Prostate

hypertrophy • Bladder

obstruction

• Salt – water retention • Postural

hypotension (1st dose phenomenon) •

Phentolamine PO IV

Non selective " block Reversible Antag Antag 5-HT

• ! PVR – BP • Venodilatation

• Pheochromocytoma • Withdrawal

clonidine (with ß blocker) •

•

" adrenergic blockers

Phenoxibenzamine

PO IV

"1 >> "2 Irreversible Antag Antag Ach, 5-HT and histamine Block uptake 1&2

• ! PVR – BP • Venodilatation

• Pheochromocytoma

•

Methyldopa

PO 2 hrs

Renal

False transmitter periph neurons (minimal antiHT) Release " Methylnorepinephrine or Methyldopamine (" central agonist)

• ! sympathetic outflow • ! periph vas

resistance • ! renal vasc

resistance, maintaining renal flow

• HT pregnancy • #! HR - CO

"1 agonist – arterioles • Initial brief pressor effect

"2 agonist – medulla • ! sympathetic tone • # parasympathetic

tone

Centrally acting "2 > "1

Clonidine Imidazoline derivative

PO IV

8-12 hrs

Lipid sb

Imidazoline receptor agonist

• antiHT

• • !! HR • ! CO • Depression • Withdrawal

(protracted use)

PK PD Sympatholitic Drugs Route t1/2 T Elimi

n Metab

Mech action Effects Ido CIdo Side Effects

Ganglion blocking

Hexamethonium Trimethapahan

Competitive antag N cholinergic – postganglionic neurons

NO • Sympathoplegia (orthostatic hypotension, sexual dysf) • Parasympathoplegia

(constipation, urinary retention, precipitation glaucoma, blurred vision, dry mouth)

Guanetidine

5 days

Prevent release Norepinephrine – post ganglionic sympathetic neurons (uptake by NET - replaces norepinephrine)

• Pharmacologic sympathectomy: gradual (mx 1-2 weeks) • Effect prevented by

cocaine, amphetamine, TCA, phenothiazines, phenoxibenzamine)

RARE • Postural hypotension • Diarrhoea • Impaired ejaculation •

Adrenergic neuron blocking

Reserpine (alkaloid from root)

Irreversible block vesicles take up and store amines (vesicular membrane transporter): depletion norad, dopa, serotonin – central, periph, adrenal

• ! CO, periph vasc resistance

RARE • Sedation • Depression • Parkinsonism ( dopa

depletion) • Diarrhoea • GI cramps • # GI acid production •

PK PD Vasodilators Drugs Route t1/2 T Elimi

n Metab

Mech action Effects Ido CIdo Side Effects

Diltiazem [D] Verapamil [V]

PO IV

• Block voltage gated “L-Type” Ca channels %! Ca influx

• Vasodilatation %! PVR • ! Inotropic and

Chronotropic

• HT • Angina • SVT

• Cardiac depressant: !CO – HR: [V]>[D]

Ca Channel antagonists

Dihydropyridine (nife [Nf], amlo, felo, isra, nisol, nicar)

SR PO IV (Nimodipine - Nicardipine – clevidipine)

! Ca influx • ! PVR: more selective – less cardiac depressants

• HT • SAH

(nimodipine)

• Reflex tachycardia • [Nf] # risk MI –

mortality • Oedemas (pretibial) • Constipation

Hydralazine

IV PO

1.5 – 3 hrs

8-12 hrs

Liver 1st pass (acetylation–slow/fast)

Unknown Inositol triphosphate – Ca release from sarcoplasm reticulum

• Arteriolar dilatation (no veins)

• HT – short term (combination) • Heart

failure

• Tachyphilaxis • Reflex tachycardia -

angina • SLE-like syndrome

(reversible) • Headache • Nausea • Anorexia • Palpitations • Sweat – flushing • Periph neuropathy

Nicorandil KATP activation and NO donor

• • Refractory angina

•

Minoxidil PO Long acting

Minoxidil sulphate (active)

• Arteriolar dilatation (no veins)

• • Reflex tachycardia ++ • Palpitations • Angina • Oedema • Hypertrichosis

Diazoxide (struct related thiazides)

IV bolus or infusion

24 hrs

Opens K channels (antag intracellular ATP) Hyperpolarize smooth muscle membrane Switch off Voltage dependent Ca Channels

• Arteriolar dilatator • HT emergencies

• Reflex tachycardia (angina – ischaemia) • Hypotension ( stroke –

MI) • Inhibits insulin release

– hyperglycaemia • Na and water retention

PK PD Vasodilators Drugs Route

t1/2 T Elimin Metab Mech action Effects Ido CIdo Side Effects

Glyceryl trinitrate

IV SL TOP

L and smooth muscle: denitrated SL: avoids 1st pass

• Vasodilatation • ! Preload &

afterload

• Angina • APO

• Tolerance • Vasodilatation –

tachycardia • Orthostatic hypotension • Headache

Sodium Nitroprusside (complex iron – cyanide – nitroso miety) Sensitive to light Powder to make solution

IV infusion

1-10 min

Uptake red cells – liberation cyanide

Thiocyanate ! kidney

Denitration % Release nitric oxide from drug or endothelium ! activation guanylyl cyclase ! # cGMP ! dephosphorilation of myosin light chain phosphate ! smooth muscle relaxation

• Arterial and venous dilatation (! periph vasc resistance - ! venous return)

• HT emergency • Short term (

< 72 hrs)

• !BP - Intra arterial recording • Accumulation cyanide ! # cyanide (prolong admin – days pred if renal dysf) • weakness • disorientation • psychosis • muscle spasms • convulsions • confirmed: [] >10 mg/dl • delayed hypothyroid • Metab acidosis • Arrhythmias • MethHb

Organic Nitrates

Amyl nitrite Inhal 3-5 min

• • Cyanide intoxication

•

Sildenafil Inhibits Phosphodiesterase (PDE type 5) • Inhib breakdown

cGMP ! # cGMP

• Vasodilatation • Erectile dysfunction • Severe PHT

Synergistic with NO donors

• Hypotension

Bosentan Endothelin receptor antagonist

• • Severe PHT • Pregnancy

• Hypotension

Fenoldopam IV 10 min

Conjugation

Activation dopamine (D1) receptors

• Periph arteriolar vasodilatation • Na uresis

• HT emerg • Post op HT

•

PK PD Vasodilators

Inhibitors of angiotensin

Drugs Route t1/2 T Elimin Metab Mech action Effects Ido CIdo Side Effects

Captopril

Enalapril PO IV(enalaprilat)

11 hrs

24 – 12 hrs

Renal Hydrolysis –enalaprilat

Lisinopril (lysine derivative from enalaprilat)

PO 12 hrs

Renal

ACE Inhibitors

Prodrugs

Benazepril Fosinopril # Moexipril # Perindopril Quinapril Ramipril Trandolapril

Long acting

Renal (except #)

Hydrolysis – liver

Inhibits RAS system Stimulates Kallikrein – kinin system (bradykinin and Substance P *)

• No good correlation renin plasma activity and response

• Severe Hypotension • If hypovolaemic • 1st dose hypotension • ARF (specially id bilat

renal art stenosis) • # K ( specially

interactions K sparing diuretics and K supplements) • Dry cough *

(bradikinin) • Angioedema * • Altered taste • Skin rash • Drug fever

ARB (sartans)

Losartan Valsartan Candesartan Eprosartan Irbesartan Telmisartan Olmesartan

PO Competitive inhibitors of angiotensin and receptors (AT1) NO bradikinin activity

• ! periph vasc resistance • NO reflex

symapthetic activation (down reset baroreceptors or enhanced parasympathetic activity)

• HT • IHD • CCF • After MI

(specially if LV dysf) • DM

retinopathy • CRF - DM (!

proteinuria – stabilize renal function) • Progressive

renal insuf

2nd and 3rd trimester of pregnancy (anuria – ARF) 1st trimester (teratogenesis) Critical renal artery stenosis (bilateral)

• Less common cough and angioedema

Aliskrein PO Renin antagonist

Non peptide antagonists

Enalkiren PO Reduce plasma renin activity

Aldosterone receptor inhibitors

Spironolactone Eplerenone

! Renal cortex stimulation " Positive feedback:

• ! Renal art perfusion pressure • Sympathetic neural stimulation: ß agonist • PGI2 • ! [Na] distal renal tubule (macula densa)

" Negative feedback: • Angiotensin II

! Renin " Produced by yuxtaglomerular apparatus " Short t1/2 " Proteolysis angiotensinogen (inactive plasma globulin produced by liver) into

angiotensin I (inactive decapeptide – N terminal) " Antagonist: Enalkiren

! ACE " Endothelial ! membrane bound (predominantly rich vascular beds)

• " [ ]lung > heart, brain, striated muscle, kidney " Hydrolysis angiotensin I into angiotensin II (active octapeptide )

• Other enzyme forming angiot II: chymase ( not inhibited by ACEI) " AT 1 Receptors! G protein coupled receptor

# Vasoconstriction ( mostly efferent kidney arterioles) " 40 times more potent than noradrenaline

# " release Norad – sympathetic terminals # Stimulates Na reabsorption ( prox tubule) # Secretion aldosterone ( adrenal cortex) # Cell growth ( heart – arteries)

" AT 2 # Fetal expression # Brain adults # Inhib cardiovasc cell growth

" Inactivates bradykinin (vasodilatator: releases NO and prostacyclin) ! Adrenal gland

" Aminopeptidase A & N " Converts angiotensin II into III and IV

! Angiotensin " II and III ! Stimulate aldosterone release " III ! thirst " IV ! endothelium: release plasminogen activator inhibitor 1

! Parallel systems for angiotensin generation " Heart ! trophic changes – LVH