Pharmacology of the heart and cardiovascular system

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Dr. Lenka Katila

For Health-Care Unit, Kemi Polytechnic school

Luleå, 1999-11-28

Pharmacology of the heart and cardiovascular system

Pharmacology of the heart

• 
  High mortality due to the cardiovascular diseases leads to high interest to treat it
  
• 
  Except primary prevention (healthy life style, motion, low-energy food…) is necessary also a good and sufficient therapy and so called secondary prevention, i.e. early therapy of cardiovascular disease and prevention of the complications.
  
• 
  Development of the new drugs for this area is really large and every year comes minimally 10 – 20 new products – drugs.
  

Effects of cardiovascular drugs:

1. 
   To quality of the hearth muscle – contractility, inothropy
   
2. 
   To the hearth rhythmus and frequency – against arhytmias
   
3. 
   To the metabolism of the myocard and the quality of the supplementation of the heart with the blood. (Low flow of blood in the coronary arteries is causing f.ex. angina pectoris.
   

1. 
   Contractility
   

• 
  Function of the heart as a pump
  
• 
  Necessary is presence of the Ca²⁺ in the cells for myocard-contraction
  
• 
  Drugs, which are increasing the concentration of the Ca2+ in the cells are increasing the contractility of the myocard (Cardiac failure)
  
• 
  They are called cardiotonics (according to the function)or cardioglykosids( according to the chemical structure)
  
• 
  They block Na+K+ATPas in the celular membrane of the myocardial cells and so the slow down exchange of Ca2+ and Na+. Intracelular Ca2+concentration increases and myocard contract more powerful
  
• 
  They slow down the rhythmus and conduction on the cardiac conduction pathway and may lead to the arhytmias, but on the other hand is used to therapy of some arhytmias – atrial fibrillation.
  
• 
  Side effects: vomiting, dizziness, yellow colored vision, disorientation
  
• 
  Low concentration of K+ in the blood can lead to easy overdosing, higher to the toxicity and therefore it is necessary to monitorate the level of the cardioglykosids in plasma
  
• 
  Typical drugs:
  

• 
  Digoxin, Digoxin, Lanacrist, Lanoxin (p.o., i.v.)
  
• 
  Medigoxin: Lanitop (p.o.)
  
• 
  Digitoxin: Digitrin (p.o.)
  
• 
  Oubain: Strophantin G (i.v.)
  

New cardiotonics, which effect is due to the inhibition of phosphodiestherase we use in the failing of the classics therapy

• 
  Amrinon: Inocor, Milrinon :Corotrop (i.v.)
  

Calcium

Natrium

Kalium

Na

K Na


DIG

Calcium

Natrium

Kalium


2. Antiarhytmics, antidysrhytmics
The complex of mistakes in the cardiac conduction pathway (SA, AV., Hiss, LBB, RBB, and Purkynje f.) causes arrhythmia

• 
  Most often due to the ischemia of myocard, AIM, ion dysbalance, action of some drugs
  
• 
  There are 4 main groups of Antiarhytmics
  

1. 
   Na –channels blockers on the cellmembrane:
   

• 
  Ia
  
• 
  Chinidin (Kinidin Duretter, Kinilentin)
  
• 
  prokainamid (Apo-procainamide, Procainamid)
  
• 
  disopyramid (Dirytmin,Norpace,Durbis)
  
• 
  ajmalin (Gilurytmal)
  
• 
  prajmalin (Neo-Gilurytmal)
  
• 
  detajmil (Tachmacolor)
  
• 
  IB
  
• 
  Lidocain – Xylocard
  
• 
  Mexiletin – Mexitil
  
• 
  Tokainid – Tonocard
  
• 
  Fenytoin – Epanutin, Phenytoin
  
• 
  IC
  
• 
  Propafenon – Rytmonorm
  
• 
  Flecainid – Tambocor
  
• 
  Lorkainid – Remivox
  

2. 
   Beta-sympatholytics – protection against abnormal action of the sympaticus and katecholamins ( see chapter autonomic nerves system)
   

3. 
   Drugs prolonging the action potential
   

• 
  Amiodaron – Cordarone,Sedacoron
  
• 
  Bretylium - Bretylate
  
• 
  Sotalol – Darob, Sotahexal, Sotalex
  

4. 
   Ca-channel blockers
   

• 
  Diltiazem – Cardizem, Coramil, Diltelan, Entrydil
  
• 
  Verapamil -Isoptin
  

Side effects: arhytmias, headache, and palpitations

Therapy: monitoring

Benign arhytmias: slow increasing the doses until the arrhythmia is over

Malign arhytmias: immediate quick therapy according to the arrhythmia
Exceptional arhytmias:

Ventricular fibrillation: defibrillation

Bradycardia: Atropine

Supraventricular arhytmias: Chinidin, Verapamil, beta-blockers, digoxin, and adenosine

Ventricular arhytmias: lidocain, mexiletin, Fenytoin, Amiodaron
3. Therapy of angina pectoris (AP)

• 
  Therapy of the acute attack of AP
  
• 
  Prevention of the attacks of AP
  

They do not have analgesic effect. The pain relief is caused by vasodilatation in the coronary arteries and higher delivery of O₂ to the heart.

Acute attack therapy

• 
  Nitroglycerin –causing vasodilatation in the venous system, but also in the coronary area
  
• 
  Application as a sublingual tablet or bucal spray.
  
• 
  It should not be swollen and inspired, because than the effect is prolonged.
  
• 
  Right after the pain is stopping the tablet should be spited out. This is preventing the development of tachyphylaxi
  
• 
  Nitroglycerin is evaporating and the tablets should be kept outside of the heating sources and used just to the expiry date.
  

Preventive drugs

1. 
   Nitrates
   

• 
  Similar action like Nitroglycerin
  
• 
  Isosorbid mononitrat -Monoket,Fem Mono, Ismo,
  
• 
  Isosorbiddinitrat-Sorbangil
  
• 
  Because of the possible developement of tachyphylaxe, the dosing is mostly big dose in the morning and no evening dose.
  
• 
  Side effects: headache
  

2. 
   Beta-blockers – not with vasospastic AP and with the signs of cardiac failure
   
3. 
   Ca-channels blockers – dilatation of the arterioles
   

Schema of the therapy AP

Lower venous return to Lower periphery

resistance

the heart

relaxing the contraction

Venous system

Lower workout

4. Antihypertensiva

• 
  Hypertension – repeatedly measured BP over 160/95 torr
  
• 
  20% of population
  
• 
  Serious risk factor for developement of other diseases – AIM, stroke…
  
• 
  myocard must work against higher peripheral resistance
  

Drugs:

1. 
   drugs regulating the water and ions balance – diuretics
   
2. 
   drugs regulating the sympatic action – Beta- blockers
   
3. 
   central Antihypertensiva
   
4. 
   Alfa-blockers
   
5. 
   vasodilatancia
   

1. 
   arterial system –dihydralazin, minoxil, Ca- blockers
   
2. 
   venous system – nitrates – not for treatement of hypertension
   
3. 
   both systems – ACE – inhibitors
   

Some antihypertensives can cause orthosthatic hypotensim – collapse.

Schema of the antihypertensive therapy

Arterial resistence

Plasma volume

Diuretics

Increase the amount of urine and the amount of K in urine

Decrease of plasma volume and secondary dilatation

Side effects: Loosing of the K, worse glucose tolerance, hyperlipidemia, and hyperurikemia

(Details in the homework)

ACE inhibitors

• 
  Inhibitors of the renin-angiotensin system through the inhibition of angiotensin converting enzyme.
  
• 
  Inactivation of vasodilatation kinins – decrease or peripheral resistance
  
• 
  Kaptopril – Capoten,Captopril
  
• 
  Enalapril – Renitec
  
• 
  Lisinopril – Vivatec
  
• 
  Ramipril – Pramace
  
• 
  Trandolapril - Gopten
  

 - Blockers

• 
  Their action is not very clear, probably optimalisation of the cardiac workout
  
• 
  Nonselective, without ISA – metiprondol
  
• 
  Nonselective, with ISA - Pindolol,(Visken), Sotalol-Darob
  
• 
  Selective with ISA – acebutol
  
• 
  Selective without ISA – atenolol(tenormin), betaxolol, metoprolol(Seloken)
  

Ca-channels blockers

• 
  Through peripheral resistance decrease, myocardial frequence AV conduction
  
• 
  Nifedipin, Dilthiazem
  

Centrally acting antihypertensives

• 
  Acting directly in the CNS by decreasing the tonus of the symphaticus
  
• 
  Alfamethyldopa- Aldomet,Dopagen
  
• 
  Klonidin – Catapressan, Haemiton
  
• 
  Guanfacin - Estulic
  
• 
  Urapidil - Ebrantil
  

-Blockers

• 
  for serious types of hypertension
  
• 
  prazosin
  
• 
  doxazosiln – Alfadil
  

Drugs effecting the muscular layer of the capillary wall

• 
  For serious types of hypertension
  
• 
  Minoxidil – Loniten
  
• 
  Diazoxid ->Hyperstat
  
• 
  Natrium nitroprusid – Nipride
  

Drugs effecting sympaticus and parasympaticus
Autonomic (vegetative) nerve system is participating importantly on the regulation organism´s functions, which are out of the voluntary control.
Schema of the system:

Drugs, which are effecting those systems, are called:

1. 
   Sympatomimetic d.
   
2. 
   Sympatolytic d.
   
3. 
   Parasympatomimetic d.– cholinergica
   
4. 
   Parasympatholytic d.– anticholinergica
   
5. 
   Ganglioplegica
   

1. 
   Sympatomimetic drugs
   

• 
  Activation of the adrenergic receptors
  
• 
  Directly or by releasing NADR from the postganglionic neuron
  
• 
  Basically the effect is called alpha () and beta ().
  
• 
  1 effect: vasoconstriction, mydriasis
  
• 
  2 effect: releasing of NADR lead to the decrease of production of cAMP and thus to decrease of NADR relief, so it is a control mechanism
  
• 
  1 effect:  pulse,  contractility of myocard,  consumption of oxygen,  arythmogenity,  metabolisation ( glycogenglucose, feat tissuefeatty acids)
  
• 
  2 effect: contractions of the smooth muscles of bronchi, uterus, intestines and vessels
  
• 
  3 receptors are on the adipocytes and they might be answer to the therapy of obesity
  

Using of those effects:

• 
  1: prolongation of the effect of the local anesthetics, decongestion of the mucous in the nose, increasing of the blood pressure if seriously decreased, mydriasis
  
• 
  2: antihypertensiva
  
• 
  1:rarely – some types of blocks of the cardiac conduction pathway
  
• 
  2: bronchodialatation with asthma, tocolytics – obstetrics
  

Adrenaline (epinephrine)

• 
  direct  and  effect
  
• 
  impossible to give per oss
  
• 
  extremely high  effect on the heart, in the low doses vasodilatation, in the high doses vasoconstriction
  
• 
  bronchodilatation
  
• 
  increasing glycemia
  
• 
   O₂ consumption
  
• 
  indication: CPR, antialergicum, additional substance to the local anesthetics
  

Noradrenaline

• 
  mostly 1 effect, the effect on the myocard might be different
  
• 
  indication: extreme hypotension, rarely with the shock
  

Dopamine

• 
  Effect: vasodilatation,  myocard contractility,  cardiac output
  
• 
  Indication: sudden renal or cardiovascular failure
  

Isoprenalin

• 
  Just  effect
  
• 
  Indication: bronchial asthma, bradycardia or AV block
  

Ephedrine

• 
  Gently effect on the bronchi, stimulation of the heart and  peripheral resistance
  
• 
  Psychostimulans!!!
  

Amphetamine

Metamfetamin

Phenmetrazin

• 
  Psychostimulancia, anorectic
  

Clonidin

• 
  2 effect
  
• 
  decreasing the tonus of the sympaticus
  
• 
  indication: hypertension, therapy of the morphinist
  

 - Sympatomimetic effect

• 
  special group of the drugs, which are used in the therapy of asthma for bronchodilatation or as a tocolytics for relaxing the contractions of the uterus
  
• 
  mostly inhalation
  
• 
  fenoterol – Berotec ( asthma), Partusisten (obstetrics)
  
• 
  salbutamol – Ventolin
  
• 
  terbutalin – Bricantyl
  

Sympatolytica

Direct effect – on the receptor

Indirect effect – block neurotransmitters releasing
- Blockers

• 
  effect: dilatace of the vessels and hypotension
  
• 
  indication: arteriosclerosis, benign prostate hyperplasy, rarely as a antihypertensiva
  
• 
  prazosin – antihypertensivum
  
• 
  alfuzosin, doxazosin – BPH
  
• 
  fentolamin – feochromocytom
  
• 
  ergometrin, ergotamin, metylergometrin – uterotonika, antimigrenotika
  
• 
  dihydroergotamin, antimigrenotikum
  
• 
  dihydroergotoxin – arterosclerosis
  

 - blockers

• 
  block of the  - receptors
  
• 
  see the book and homework
  

Parasympatolytic and cholinergic drugs – see homework

Analgesics

• 
  Pain is very often symptom of the diseases; it is as well very unpleasant feeling of discomfort, provocation stress at the organism.
  
• 
  Some pain can be treated by the solving of the original problem , especially inflammations, but some must be treated by special drugs, called analgesics
  
• 
  There are two groups of those drugs according to the pharmacological effect:
  
• 
  Narcotic group – Opioids drugs, anodyne
  
• 
  Non – narcotic group – analgesics, antipyretics
  

Opioids

• 
  All the drugs, which effect is similar as morphine’s effect
  
• 
  Opium – drug ( see drug abusing chapter)
  

Morphine

• 
  Effects: against cough, pain, diarrhea, breathing depressions, miosis, euphoria, dysforie, developing of tolerance
  
• 
  Mostly iv, im, sc, but there are also per oss forms
  
• 
  Morphine, Dolcontin, MST Continuous, Vendal retard
  

Codeine

• 
  Antitusicum, analgeticum
  
• 
  Citodon, Panocod
  

Petidin – Dolsin, Dolcontral, Petidin

Analgeticum, im. , iv
Piritramid - Dipidolor

Fentanyl, Sufentanyl, Remifentanyl – i.v. i.m. – Very strong Opioids for anesthetic use

Tilidin – Valoron

Buprenorfin – Temgesic

Nalbufin – Nubain

Tramadol – Nobligan, Tiparol, Tradolan
Naloxon – Narcanti, Naloxone, Intrenon – antagonistic effect

Indication: intoxication, diagnostic use in suspicion for morphinism, end of the anesthesia

Non-narcotic analgesics

They can not even in the high dose provoce the narcotic status

Effects:

• 
  Analgesia
  
• 
  Antipyretic effect
  
• 
  Intiflogistic effect - prostaglandin and other mediators of the inflammation
  

Acetylsalicylic acid

• 
  Used over 100 years
  
• 
  Another effect: antiagregans – against aggregation of the platelets
  
• 
  Negative effect to the gastric mucous – irritations, bleeding
  
• 
  Can provoke allergic reaction
  
• 
  Can provoke Rey syndrome at the neonates, who has the metabolism disturbances
  
• 
  Albyl, Barnalbyl per os, tbl., effervescent tbl, Magnecyl, Dispryl, Aspirin
  

Acetaminophein – Paracetamol

• 
  Low antiinflamational effect
  
• 
  Mostly antipyretic and analgeticum
  
• 
  Good tolerance at the GIT and no risk for Rey sy
  
• 
  Panadol, Alvedon, Panodil, Citodon, Panocod
  

Chynin

• 
  Antimalarikum
  
• 
  Rarely as a analgeticum
  

Analgesics mixtures

• 
  Mostly several types of the analgesics
  
• 
  T.ex. Coldrex, , Alka-Seltzer,Magnecyl-Cofein,…
  

Ibuprofen

• 
  Gently for the stomach
  
• 
  Strong antiinflamatory effect
  
• 
  Brufen, Ibuprofen, Ipren, Ibutop,…
  

Cells

Special pharmacology

Dr. Lenka Katila

For Health-Care Unit, Kemi Polytechnic,

Luleå, 1999-11-28