No Slide Title · • Celotni upor žilja ('periferni upor') – s tem v veliki meri določen arterijski pritisk • Upor v določenih področjih žilja – pomen pri porazdelitvi

Inštitut za farmakologijo in eksperimentalno toksikologijo, Medicinska fakulteta, Univerza v Ljubljani

Zdravila pri angini pectoris in hipertenziji

Lovro Stanovnik

Inštitut za farmakologijo in eksperimentalno toksikologijo Medicinska fakulteta, Univerza v Ljubljani


Lastnosti žilja in njihov pomen

• Celotni upor žilja ('periferni upor') – s tem v veliki meri določen arterijski pritisk

• Upor v določenih področjih žilja – pomen pri porazdelitvi pretoka krvi v različnih organih. Pomembno pri: – Zdravljenju angine pectoris – Raynaudovem fenomenu – Pljučni hipertenziji – Cirkulatornem šoku

• Podajnost (compliance) aorte in odboj pulznega vala – pomen pri zdravljenju pešanja srca in angine pectoris

• Tonus ven in volumen krvi (napolnjenost cirkulacije) skupaj določata centralni venski pritisk – pomen pri zdravljenju pešanja srca in angine pectoris.

• Nastajanje ateromov in tromboza • Angiogeneza – pomen pri diabetični retinopatiji in pri zdravljenju

malignih obolenj


Regulacija tonusa žil • Kontrola mišic: mediatorji v simpatiku, žilni endotel, hormoni

• Kontrakcija ⇐ ⇑[Ca2+]i ⇒ aktivacija kinaze miozinskih lahkih verig ⇒ fosforilacija miozina, oz. sensitizacija miofilamentov na Ca2+ preko inhibicije miozinske fosfataze

• Kontrakcija gladkih mišic žilja – en ali več naslednjih mehanizmov: – Sproščanje intracelularnega Ca2+ preko inozitol trifosfata – Depolarizacija membrane ⇒ odprtje napetostno odvisnih kalcijevih

kanalov ⇒ vstop Ca2+ – Povečanje občutljivosti za Ca2+ z delovanjem na kinazo miozinskih

lahkih verig oz. na miozinsko fosfatazo

• Relaksacija:

– Inhibicija vstopa Ca2+ preko napetostno odvisnih kalcijevih kanalov bodisi direktno (npr. nifedipin) ali indirektno preko hiperpolarizacije membrane (npr. aktivatorji kalijevih kanalov – metabolit minoksidila)

– Povečanje koncentracije znotrajceličnega cAMP ali cGMP. • cAMP inaktivira kinazo lahkih miozinskih verig in facilitira iztok Ca2+, • cGMP preprečuje dvig [Ca2+]i , ki ga izzovejo razni agonisti


Endothelium-derived mediators. The schematic shows some of the more important endothelium-derived contracting and relaxing mediators; many (if not all) of the vasoconstrictors also cause smooth muscle mitogenesis, while vasodilators commonly inhibit mitogenesis. 5-HT, 5-

hydroxytryptamine; A, angiotensin; ACE, angiotensin-converting enzyme; ACh, acetylcholine; AT1, angiotensin AT1 receptor; BK, bradykinin; CNP, C-natriuretic peptide; DAG, diacylglycerol; EDHF, endothelium-derived hyperpolarising factor; EET, epoxyeicosatetraenoic acid; ET-1, endothelin-1; ETA/(B), endothelium A (and B) receptors; Gq, G-protein; IL-1, interleukin-1; IP, I prostanoid receptor; IP3, inosinol 1,4,5-trisphosphate; KIR, inward rectifying potassium channel; Na+/K+ ATPase, electrogenic pump; NPR, natriuretic peptide receptor; PG,

prostaglandin; TP, T prostanoid receptor. Downloaded from: StudentConsult (on 26 November 2013 08:31 PM)

© 2005 Elsevier


Direktno delujoči vazodilatatorji

• Kalcijevi antagonisti (blokatorji kalcijevih kanalov)

• Zdravila, ki aktivirajo kalijeve kanale (minoksidil, diazoksid)

• Zdravila, ki delujejo preko cikličnih nukleotidov (agonisti receptorjev β, NO, inhibitorji fosfodiesteraze, ….)


Mechanisms controlling smooth muscle contraction and relaxation. 1. G-protein-coupled receptors for excitatory agonists, mainly regulating inositol trisphosphate formation and calcium channel function. 2. Voltage-gated calcium channels. 3. P2x

receptor for ATP (ligand-gated cation channel). 4. Potassium channels. 5. G-protein-coupled receptors for inhibitory agonists, mainly regulating cAMP formation and potassium and calcium channel function. 6. Receptor for atrial natriuretic

peptide (ANP), coupled directly to guanylyl cyclase (GC). 7. Soluble guanylyl cyclase, activated by nitric oxide (NO). 8. Phosphodiesterase (PDE), the main route of inactivation of cAMP and cGMP. AC, adenylate cyclase; PKA, protein kinase

A; PKG, protein kinase G; PLC, phospholipase C. Downloaded from: StudentConsult (on 30 November 2013 08:01 PM)

© 2005 Elsevier


Classification of vasoactive drugs that act indirectly

Site Mechanism Examples

Vasoconstrictors

Sympathetic nerves Noradrenaline release Tyramine

Blocks noradrenaline reuptake Cocaine

Endothelium Endothelin release Angiotensin II (in part)

Vasodilators

Sympathetic nerves Inhibits noradrenaline release Prostaglandin E2 , guanethidine

Endothelium Nitric oxide release Acetylcholine, substance P

Central nervous sys tem Vasomotor inhibition Anaesthetics

Enzymes Angiotensin-converting enzyme inhibition

Captopril


Možnosti vpliva na oskrbo miokarda s kisikom

Pharmacological modification of the major determinants of myocardial O2 supply. When myocardial O2 requirements exceed O2 supply, an ischemic episode results. This figure shows the primary hemodynamic sites of actions of pharmacological agents that can reduce O2 demand (left side) or enhance O2 supply (right side). Some classes of agents have multiple effects. Stents, angioplasty, and coronary bypass surgery are mechanical interventions that increase O2 supply. Both pharmacotherapy and mechanotherapy attempt to restore a dynamic balance between O2 demand and O2 supply.

Presenter

Presentation Notes

Pharmacological modification of the major determinants of myocardial O2 supply. When myocardial O2 requirements exceed O2 supply, an ischemic episode results. This figure shows the primary hemodynamic sites of actions of pharmacological agents that can reduce O2 demand (left side) or enhance O2 supply (right side). Some classes of agents have multiple effects. Stents, angioplasty, and coronary bypass surgery are mechanical interventions that increase O2 supply. Both pharmacotherapy and mechanotherapy attempt to restore a dynamic balance between O2 demand and O2 supply.


Effects of myocardial ischaemia. This leads to cell death by one of two pathways: necrosis or apoptosis. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin AT1 receptor antagonist; ICE, interleukin-1-converting enzyme; PARP, poly-[ADP-ribose]-polymerase; TNF- alpha; tumour necrosis factor-alpha.

Downloaded from: StudentConsult (on 28 November 2013 01:37 PM) © 2005 Elsevier


Organski nitrati I • Predstavniki: Gliceril trinitrat (nitroglicerin), izosorbid mononitrat

• Vazodilatatorji: – delovanje na vene polnitev (preload) – arterije odboj pulznega vala obremenitev (afterload).

• Delovanje preko NO (njihov metabolit) NO tvorba cGMP aktivacija protein kinaze G vpliv na kontraktilne proteine (lahke verige miozina) in na regulacijo Ca2+.

• t½ – relativno kratek: – Gliceril trinitrat (nitroglicerin) – nekaj minut – Izosorbid dinitrat – cca 1 ura; t½ aktivnih metabolitov (izosorbid

mononitrat) – nekaj ur

• Vsi organski nitrati – metabolizem prvega prehoda (prirejen način aplikacije)


• Razvoj tolerance – klinično pomembna zaradi uporabe dolgo delujočih preparatov (prirejeno sproščanje).

• Terapevtski učinek pri angini pectoris: – Zmanjšana obremenitev srca – Dilatacija kolateralnih koronarnih žil ugodnejša

porazdelitev koronarnega pretoka

• Hudih stranskih učinkov ni veliko. – Začetek zdravljenja – glavobol, ortostatska

hipotenzija v začetku zdravljenja. – Pri predoziranju – methemoglobinemija (redko)

Organski nitrati II



Comparison of the effects of organic nitrates and an arteriolar vasodilator (dipyridamole) on the coronary circulation. [A] Control. [B] Nitrates dilate the collateral vessel, thus allowing more blood through to the underperfused region (mostly by diversion from the adequately perfused area). [C]

Dipyridamole dilates arterioles, increasing flow through the normal area at the expense of the ischaemic area (in which the arterioles are anyway fully dilated). CAD, coronary artery disease.



Kalcijevi antagonisti (blokatorji kalcijevih kanalov - Calcium Channel Blockers –

CCB)

• Delovanje na L-tip kalcijevih kanalov (napetostno odvisni kalcijevi kanali)

• Glede na kemijsko strukturo - 3 razredi: – fenilalkilamini (verapamil),

– dihidropiridini (nifedipine, amlodipine)

– benzotiazepini (diltiazem).


• Blokada vstopa Ca2+ preprečenje odpiranja napetostno odvisnih kalcijevih kanalov tipa L.

• Trije tipi – predstavniki verapamil, diltiazem in dihidropiridini (nifedipin).

• Delovanje na srce in gladke mišice ⇐ blokada vstopa Ca2+ ob depolarizaciji celice.

• Selektivnost za srce in gladko mišico različna: verapamil relativno kardioselektiven, nifedipin relativno selektiven za gladko mišico, diltiazem – vmes.

• Vazodilatatorno delovanje – v glavnem na uporovne žile (dihidropiridini) afterload. Dilatacija koronark ( pomen pri variantni angini).

• Vpliv na srce (verapamil, diltiazem): antidisritmično delovanje (atrijske tahikardije), moteno AV prevajanje; zmanjšana kontraktilnost

Kalcijevi antagonisti (blokatorji kalcijevih kanalov)



Kalcijevi antagonisti – klinična uporaba in stranski učinki

• Klinična uporaba: – Kot antidisritmiki (predvsem verapamil) – Pri angini pectoris (diltiazem) – Antihipertenzivi (predvsem dihidropiridini).

• Neželeni učinki: – Glavobol / ortostatska hipotenzija – Zaprtje (verapamil) – Otekanje gležnjev (dihidropiridini). – Verapamil in diltiazem – povečano tveganje za

odpoved srca ali srčni blok.


20 most frequent side effects of calcium channel blockers Adverse Reaction / Side Effect

Amlodipine Clevidipine Diltiazem HCl Felodipine Isradipine Nicardipine

HCl Nifedipine Nimodipine Nisoldipine Verapamil HCl

nausea 2.9% 4.8% 1.4% Reported 1.2 - 1.8% 1.9 - 7% 2 - 11% 1.2% 2% 0.9 - 2.7%

hypotension Reported Reported <4.3% Reported <1% 0.9 - 8% <5% 4.4 - 5% <1% 0.7 - 2.5%

headache 6.3% 4.6 - 5.4% 10.6 - 14.7% 13% 6.2 - 21% 1<23% 1.2% 22% 1.2 - 12.1%

peripheral edema

13.6 - 32.4% 2.6 - 4.6% Reported 7.2 - 15.2% 5.9 - 8% 4 - 30% Reported 7 - 29% 3.7%

dizziness 1.1 - 3.4% 3 - 3.5% 2.7 - 3.7% 4.7 - 7.3% 1.6 - 6.9% 4 - 27% <1% 3 - 7% 1.2 - 4.7%

flushing 0.7 - 4.5% 1.4 - 1.7% Reported 1.9 - 2.6% 9.7% <25% <1% 4% >0.6.8%

vomiting <1% 3.2% <1% Reported 1.1% 0.4 - 7% <1% <1%

palpitations 0.7 - 4.5% <1% 0.4 - 2.5% 1.2 - 4% 2.8 - 4.1% <7% <1% 3% Reported

diarrhea <1% <1% Reported 1.1% <3% 1 - 10% <1% <2.4%

heart failure <1% Reported <1% Reported 2 - 6.7% Reported Reported 1.8%

constipation <1% <1% Reported 1.7% 0.6% <3.3% 7.3 - 11.7%

angina Reported <1% 0.5 - 1.5% 2.4% 1 - 7% <1%

myocardial infarction Reported <1% <1% <1% 4 - 6.7% <1%

muscle cramps <2% <1% <8% <1% <2%

tremor <1% <1% 0.6% <8% <2%

weakness 1.2% 1<12%

pyrosis (heartburn) Reported 11% infection 1 - 10% Reported renal failure (unspecified) 9%

cough 0.8 - 1.7% <6%


Interakcije CCB • Metabolizem s citohromom P450

– Vsi kacijevi antagonisti (razen klevidipina) so substrati CYP3A4 • Digoksin

– Verapamil in diltiazem ⇒ ⇑ serumske koncentracije digoksina ⇐ ⇓ renalni in ekstrarenalni klirens digoksina

– verapamil and diltiazem ⇒ upočasnitev prevajanja v AV vozlu • Beta-blokatorji

– Aditivno hipotenzivno delovanje (terapevtsko zaželeno) – Beta-blokatorji skupaj z verapamilom in diltiazemom ⇒ ⇑ negativni inotropni

učinek – ⇑ blokada v AV vozlu ⇒ srčni blok, bradikardija, motnje prevajanja, podaljšan

PR interval. – Diltiazem ⇒ ⇑ koncentracije propranolola za 50% – Verapamil ⇒ ⇓ eliminacija metoprolola in propranolola.

• Ciklosporin – Verapamil, diltiazem, in nikardipin ⇒ ⇑ koncentracije ciklosporina (povečana

toksičnost) – Ciklosporin ⇒ ⇑ koncentracije nifedipina


Recommended Drug Therapy for Angina in Patients with Other Medical Conditions

Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O'Rourke RA, Schafer WP, Williams SV. ACC/AHA/ACP-ASIM: Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol 1999; 33:2092–197. Copyright © 1999 by the American College of Cardiology Foundation.


Recommended Drug Therapy for Angina in Patients with Other Medical Conditions I

CONDITION RECOMMENDED TREATMENT (AND ALTERNATIVES) FOR ANGINA

DRUGS TO AVOID

Medical Conditions

Systemic hypertension β receptor antagonists (Ca2+ channel antagonists

Migraine or vascular headaches

β receptor antagonists (Ca2+ channel antagonists)

Asthma or chronic obstructive pulmonary disease with bronchospasm

Verapamil or diltiazem β receptor antagonists

Hyperthyroidism β receptor antagonists

Raynaud's syndrome Long-acting, slow-release Ca2+ antagonists β receptor antagonists

Insulin-dependent diabetes mellitus

β receptor antagonists (particularly if prior MI) or long-acting, slow-release Ca2+ channel antagonists

Non-insulin-dependent diabetes mellitus

β receptor antagonists or long-acting, slow-release Ca2+ channel antagonists

Depression Long-acting, slow-release Ca2+ channel antagonists β receptor antagonists

Mild peripheral vascular disease

β receptor antagonists or Ca2+ channel antanogists

Severe peripheral vascular disease with rest ischemia

Ca2+ channel antagonists β receptor antagonists


Recommended Drug Therapy for Angina in Patients with Other Medical Conditions II


DRUGS TO AVOID

Cardiac Arrhythmias and Conduction Abnormalities

Sinus bradycardia Dihydropyridine Ca2+ channel antagonists

β receptor antagonists, diltiazem, verapamil

Sinus tachycardia (not due to heart failure)

β receptor antagonists

Supraventricular tachycardia Verapamil, diltiazem, or β receptor antagonists

Atrioventricular block Dihydropyridine Ca2+ channel antagonists

β receptor antagonists, diltiazem, verapamil

Rapid atrial fibrillation (with digitalis)

Verapamil, diltiazem, or β receptor antagonists

Ventricular arrhythmias β receptor antagonists


Recommended Drug Therapy for Angina in Patients with Other Medical Conditions III


DRUGS TO AVOID

Left Ventricular Dysfunction

Congestive heart failure

Mild (LVEF 40%) β receptor antagonists

Moderate to severe (LVEF <40%)

Amlodipine or felodipine (nitrates)

Left-sided valvular heart disease

Mild aortic stenosis β receptor antagonists

Aortic insufficiency Long-acting, slow-release dihydropyridines

Mitral regurgitation Long-acting, slow-release dihydropyridines

Mitral stenosis β receptor antagonists

Hypertrophic cardiomyopathy

β receptor antagonists, non-dihydropyridine Ca2+

channel antagonists

Nitrates, dihydropyridine Ca2+ channel antagonists


Diagram showing the main mechanisms involved in arterial blood pressure regulation (black lines), and the sites of action of antihypertensive drugs (hatched boxes + orange lines). ACE, angiotensin-converting enzyme; AI, angiotensin I; AII, angiotensin II; ET-1, endothelin-1; NA, noradrenaline; NO, nitric oxide.





Control of renin release and

formation, and action of angiotensin II. Sites of action of drugs that inhibit the cascade are shown. ACE, angiotensin-

converting enzyme; AT1, angiotensin II receptor subtype 1.



Formation of angiotensins I-IV from the N-terminal of the precursor protein angiotensinogen.



The active site of angiotensin-converting enzyme. [A] Binding of angiotensin I. [B] Binding of the inhibitor captopril, which is an analogue of the terminal dipeptide of

angiotensin I. Downloaded from: StudentConsult (on 26 November 2013 08:31 PM)

© 2005 Elsevier


Comparison of effects of angiotensin-converting enzyme inhibition and angiotensin receptor

blockade in the human forearm vasculature. [A] Effect of brachial artery infusion of angiotensin II

on forearm blood flow after oral administration of

placebo, enalapril (10 mg) or losartan (100 mg). [B] Effect of brachial artery

infusion of bradykinin, as in [A]. (From Cockcroft J R et

al. 1993 J Cardiovasc Pharmacol 22: 579-584.)




Common antihypertensive drugs and their adverse effects

Drug Adverse effects

Postural hypotension

Impotence Other

Thiazide diuretics (e.g. bendroflumethiazide) ± ++ Urinary frequency, gout, glucose

intolerance, hypokalemia, hyponatremia

ACE inhibitors (e.g. enalapril ) ± -

Cough, first-dose hypotension, teratogenicity, reversible renal dysfunction (in presence of renal artery stenosis)

AT1 antagonists (e.g. losartan) - - Teratogenicity, reversible renal dysfunction

(in presence of renal artery stenosis)

Ca 2+ antagonists (e.g. nifedipine) - ± Ankle oedema

β-adrenoceptor antagonists (e.g. metoprolol)

- + Bronchospasm, fatigue, cold hands and feet, bradycardia

α1 -adrenoceptor antagonists (e.g. doxazosin)

++ - First-dose hypotension


Simplified scheme showing the pathogenesis of heart failure, and the sites of action of some of the drugs used to treat it. The symptoms of heart failure are produced by reduced tissue perfusion, oedema and increased central venous pressure. ACE, angiotensin-converting enzyme.


Documents

No Slide Title · • Celotni upor žilja ('periferni upor') – s tem v veliki meri določen arterijski pritisk • Upor v določenih področjih žilja – pomen pri porazdelitvi