1111012053 ika yulia rizki

Cardiovascular

Drugs:

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Calcium Channel- Blocking

Agents

Digilatis

β Adrenergic Antagonists



Calcium Channel-Blocking Agentsv Calcium channel blockers (CCBs) were initially introduced forus

ein the

UnitedStates in 1981,

and extended-releaseformulations were available 10 years

later.

v Indications for

arrhythmias,

prophylaxis.

use of

these

drugs are angina, hypertension,subarachnoi

dhemorrhage

and migraine



Calcium Channel-Blocking

Agents

v Structure

1- Phenylalkylamines: Verapamil

2- Benzothiazepines: Diltiazem

3- Dihydropyridines: Nifedipine, Amlodipine,…

4- Diarylaminopropylethers: Bepridil

5- Tertraline Derivatives: Mibefradil



Pharmacology

v The CCB currently available act on

L-Type

channel

of cardiacand vascula

rsmooth

muscle

cells.

5 6 IIIII

IVI

56III IV



Pharmacologyv Antagonisms of L-Type channels results primarily in

effects

onthe heart

and peripheral vascular smooth muscle.

v Negative chronotropy (decreased heart rate)

v Negative inotropy (decreased cardiac contractility)

v Decrease cardiac out put and Hypotension



Pharmacokinetics

Absorption(%)

Volume ofDistribution(L/Kg)

Protein Bonding(%)

Terminalhalf-life (h)

Verapamil

>90 4.7 90 3-7

Diltiazem

>90 5.3 80-90 4

Nifedipine >90 0.8-1.4 90 5

Amlodipin

100 21.4 >95 35



Toxicityv Acute toxicity

Case reports describing Overdose of S-R Preparearions

describe

a delayin symptoms by as long( Verapamil, Diltiazem,

as 15-24 h.Nifedipine, Amlodipin)

v Toxic dose??

v Chronic toxicityCCB are essentially

free of Chronic toxicity.



Clinical Presentationv

Hypotentionv Cardiac dysrhythmics: Bradycardiav Gastroanerities

v Adult Respiratory Distress Syndromev Depressed level

of consciousness,

…

v Hyperglycemia

v Lactic acidosis



The ionic control of

insulin

release

from

humanpancrea

ticcells



Treatmentv Establish ABes

,obtain

intravenous

(IV) access, provide

oxygenation

v Administration of activated charcoal: repeated doses may be

used, especially with ingestions of sustained-released agents.

v Whole bowel irritationwith

polyethylene

glycol

solution

(SR)

v Sodium bicarbonatev Atropin



Treatmentv ea salt: eacl2 10 % (Verapamil and

Diltiazem )v Glucagon (5-10 mg, 2-10 mg/h ): Acts via cAMP to increase

cardiac contractility and also may decrease heart block

v Inamrinone (inhibitor of phosphodiesterase III )v Insulin-Dextrose: 0.1-1 Units/kg/h IV, with mean doses

of

0.5 Units/kg/h

v Hemodialysis and

hemoperfusion are not effective



Hemodialysis and hemoperfusion are not effective

Absorption(%)


Protein Bonding(%)

Terminalhalf-life (h)

Verapamil

>90 4.7 90 3-7

Diltiazem

>90 5.3 80-90 4

Nifedipine >90 0.8-1.4 90 5

Amlodipin

100 21.4 >95 35



Yes No

No Yes


SR PreparationSingle dose activated

charcoal Observe in monitored

setting >12 h ( > 24 h if SR )

elinical evidence of toxicity( hypotension, bradycardia)

Patients presents with eeB overdose


SR Preparation

YesNo

dose activated charcoal


Atropinea salt Glucagon Phosphodiestrase inhibitors Insulin-dextrose…

Whole bowel irritation or multiple

eonsider single dose activated charcoal


Beta-blockersv Beta-adrenergic antagonists

use for nearly 50 years.

(ie, beta-blockers) have been in

v In addition to their traditional role in treating hypertension andother cardiovascular

disorders,beta-blockers are also used foradditiona

lpurposes

such

asanxiety,

migraine

and

headaches,hyperthyroidis

m,disorders.

glaucoma,

various

other



Beta- Receptor

β 1- βv 4

: Eye, Kidney, Heart

β 1

β : Lung, Vascular system,

Metabolic system

2

Nonselective beta-blockers : Propranolol, carvedilol,

timolol, ..Selective beta-blockers: Atenolol, Metoprolol,…

Sotalol,



Pharmacologyv Beta1-blockers reduce heart rate, blood pressure, myocardial

contractility, and myocardial oxygen consumption.

v Beta2-blockers inhibit

relaxation

of smooth

muscle

in bloodvessels, lungs and the gastrointestinal system.

v In addition, beta-adrenergic receptor antagonism inhibits

glycogenolysis and gluconeogenesis, which may result in hypoglycemia.

both



Pharmacology



Pharmacokinetics

OralBioavailibility(%)


ProteinBonding(%)

LipidSolubility

Atenolol

0.750 15 Low

earvedilol 1.625-35 95 High

Metoprolol

5.540-50 12 Moderate- High

Propranolol

3.630 90 High



Toxicityv After acute oral

overdose,signs of

toxicity

usually

beginwithin 30 min and peak by 2 h.

v The lipid solubility of

the degree of clinical

beta blockers can significantly influencetoxicityblood-

observed after overdose owing

to penetration

of brain barrier.

(propranolol,

metoprolol, carvedilol)



Toxicityv The concentration of propranolol in eNS may exceed

that

seenin plasma by as much as

20fold.

v Toxic dose??

v In overdose

of drugs,

a eeB

themay

combination

of a Betablocker

and lead to hypotension,

bradycardia and Death.



elinical

Presentation

v eardiacBradycardiaHypotension eardiac conduction

deffects

v PulmonaryRespiratory depressionBronchospasm



elinical

Presentation

v NeurologicDrowsiness eoma Seizure

v The lipid-soluble

agents (propranolol) haveincreased distribution into the brain, and

theseagents are associated with severe eNS toxicity. Propranolol: ( Direct effect on eNS)



elinical

Presentation

v Other

Beta blockers

may be expected to cause

many

potential effects:Hypoglycemia, Rhabdomyolysis,

Acute

renalrenal

failure on the

basis

of decreased

perfusion, and metabolichypoperfusion

acidosis secondary to



Treatmentv The goal of

to

therapycritical

in beta-blocker

toxicity

is to restoreperfusio

norgan syste

msby increasin

gcardiacoutput

.This may

be accomplished

by improving

myocardialcontractility, increasing heart rate, or

both.

v eardiac monitoring, oxygen

administration,

and reliableintravenous access are essential.

v GI decontaminant: Activated charcoal



Treatmentv Atropin (0.01-0.03 mg/kg IV)

v Glucagon ( 5- 10 mg/ IV bolus, continuous infusion of

1-5 mg/h)Effect: Increase myocardial heart rate and contractilityAdverse effect: Nausea, Vomiting and hyperglycemiav eacl2

v Inamrinone (inhibitor of phosphodiesterase III )



Treatmentv Benzodiazepines are the drugs of choice if seizures occur.

v Bronchospasm: salbutamol, Aminophylin

v Enhanced elimination: Hemodialysis may be useful in

severecase

sof Atenolo

loverdoses

because

of lowby

PB and VDPropranolol

and metoprolol,

are not

removed

hemodialysis.



Digoxinv Digitalis was

introducedinby

to clinical

medicine

William Withering in 1785.He reporte

dtherapeutic

efficacyleaves of

and toxicity

ofDigitalis purpurea.



Digoxinv eongestive heart

failure

v Atrial fibrillation

v Atrial flutter



Pharmacology



Pharmacokinetics

Absorption(%)


ProteinBonding(%)

Half-life

Clearance

55 -7590-100

Digoxin

5.6 25 33-34 h Renal



Toxicityv Drug interactio

nand othe

rfactors,

such

as electrolyteabnormalitie

s,renal or hepati

cfailure,

ischemia,

orinflamation, predispose

to digoxin toxicity.

v Amiodaronedigoxin.

- Reduces

renal and nonrenal

clearance

of

v Beta-blockers (propranolol, metoprolol, atenolol) - May have

additive effects , carvedilol may increase digoxin blood levels in addition to potentiating its effects on the heart rate.



Toxicityv ealcium channel blockers - Diltiazem and verapamil increase

serum digoxin level.

v Potentially toxic interaction may also occure with k-

sparing

diuretics

which

inhibit

tubular

secretion

of digoxin.



Toxicityv Therapeutic range: 0.5-2

ng/ml

v Lethal range: >15 ng/ml

v Toxic dose: >2 - 3 mgv Lethal dose

:>10 mg



elinical Presentation

v

DysrhythmiaHeadacheWeakness Depression eonfusion Disorientation Hallucination

v

(Brady

and Thachyarrhythmia)

v

v

v

v

v


eardiovascular eNS



v Disturbances of

color

vision

v Nausea, vomiting,

and diarrhea

anorexia,

v Blurred vision

v Abdominal pain(uncommon)

v Photophobia


Ocular Gastrointestinal



v Hyperkalemia Hypokalemia

v

v

BradyarrhythmiaTachyarrhythmiaDigoxin toxicity

v

does notbut

v

cause

hypokalemia,hypokalemi

acan

worsendigoxin

toxicity


Acute Toxicity ehronic Toxicity


Treatmentv Initiate supportive

and IV access.

therapy

with

oxygen,

cardiac monitoring,

v Activatedaccidental

charcoal

ingestion.

is indicated

for acute

overdose

or

v Phenytoin and magnesium sulfate

v eorrect electrolyte abnormalities,

hypomagnesemia.

especially hypokalemia and



Treatmentv Treat hyperkalemia

Sodium bicarbonate (1mEq/ml).

v ealciumsetting

is not

recommended

to treat hyperkalemia

in thisbecaus

eventricular

tachycardia

or ventricularfibrillation may be

precipitated.

v Treatment with digoxin-fab fragments



Treatmentv Digoxin fab fragments:1-2-3-

Hyperkalemia > 5.5 meq/mlSerum digoxin level greater than 10 ng/mLIngestion greater than

5 mg in adults, …

Number of vials: 2 ×serum

level

(ng/ml)

×5.6 × Weight(Kg)/ 1000

Acute Toxicity: 10 - 20 vialehronic Toxicity: 3 - 6 vial



Thank

you



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