PRINCIPLES OF ACUTE POISONINGS’ TREATMENT Lector prof. Posokhova K.A.
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Transcript of PRINCIPLES OF ACUTE POISONINGS’ TREATMENT Lector prof. Posokhova K.A.
PRINCIPLES OF PRINCIPLES OF ACUTE POISONINGSACUTE POISONINGS’’
TREATMENTTREATMENT
PRINCIPLES OF PRINCIPLES OF ACUTE POISONINGSACUTE POISONINGS’’
TREATMENTTREATMENT
Lector prof. Posokhova K.A.Lector prof. Posokhova K.A.
UKRAINEUKRAINE
• In In 43 43 of of 190 190 most controlled large cities of most controlled large cities of our country concentration of substances our country concentration of substances dangerous for health isdangerous for health is overcomes critical overcomes critical allowed concentrations allowed concentrations 520 520 timestimes
• 34 % 34 % of population is under the negative of population is under the negative influence of atmospheric pollution influence of atmospheric pollution
Causes of acute poisoning
community-acquired Causes of acute poisoning
community-acquired
• Drugs• Chemical substances, also of plant origin • Alcohol and it’s surrogates• Pesticides
8 % of all poisonings - children(6 months of age)
Side effects Side effects ((SESE)) of of drugsdrugs
• Takes 5th place among causes of mortality on the Earth after heart-vascular diseases, malignant tumors, lungs diseases, traumas
• Among stationary patients frequency of SE after introduction of drugs makes 2 - 40 %
SE of drugsSE of drugs
• 150 000 – 200 000 people in U.S.A. 150 000 – 200 000 people in U.S.A. die from side effects of drugs die from side effects of drugs annuallyannually
• 76,6 76,6 billion $ are spared in U.S.A. billion $ are spared in U.S.A. annually to treat complications annually to treat complications attached to drugs usageattached to drugs usage
Medical mistakes in clinics
• Doctors: - overdosing - administration of drugs to patients with
allergy - mixing up names of the drugs• Medical nurses: - introduction of other drug by a mistake - violation of drug introduction regime - mistake in medical form - mixing up names of the drugs
Factors that influence on toxicity of the poison
• Physical and chemical properties• Dose• Concentration• Speed of introduction• Way of penetration into organism• Age• Condition of the organism• Accumulation of the poison• Tolerance to the poison
Comparing of dose-effect cures of the drugs with different limits of security
Therapeutic
diapason
Toxic diapason
Drugs А and B
Drug B
Drugs A
0
50
100
0,1 1 10 100 1000
Comparing of dose-effect curves of hypno-sedative drugs A and B
Drug A
Drug B
Breath stop
Narcosis
Sedative effect
0,1 1 10 100 1000
Stages of acute poisoningStages of acute poisoning
• TOXICOGENICTOXICOGENIC – the poison circulates in organism, there are obvious manifestations of its toxic action or its metabolites’ action on corresponding structures (receptors)
• SOMATOGENICSOMATOGENIC – the poison has been excreted from the organism but there are manifestations of damaging of organs and systems (kidney, liver insufficiency, lung edema, etc.)
Toxic damaging of nervous system
• Exotoxic comaExotoxic coma ( (barbituratesbarbiturates), ), complications complications – – toxic brain edema, toxic brain edema, syndrome of lifelong death of brainsyndrome of lifelong death of brain
• Acute intoxicative psychosisAcute intoxicative psychosis ( (atropine) atropine)
• Syndrome of toxic encephalopathySyndrome of toxic encephalopathy ( (salts salts ofof heavy metalsheavy metals, , carbon monoxidecarbon monoxide, , toxicomaniatoxicomania))
Toxic damaging of cardiac-Toxic damaging of cardiac-vascular systemvascular system
• Exotoxic shock• Hypertensive syndrome• Disorders of cardiac rhythm and
conductivity • Cardiac arrest• Acute cardiac-vascular insufficiency
(primary toxicogenic collapse, secondary somatogenic collapse, hematogenic lung edema)
PRINCIPLES OF ACUTE POISONINGSPRINCIPLES OF ACUTE POISONINGS’’ TREATMENTTREATMENT
• Clearing of gastro-intestinal tract, skin, Clearing of gastro-intestinal tract, skin, mucous membranes from the poisonmucous membranes from the poison
• Absorption, destroying or neutralization of Absorption, destroying or neutralization of the poison using specific antagoniststhe poison using specific antagonists
• Elimination of the desorbed poison from the Elimination of the desorbed poison from the blood and tissuesblood and tissues
• Pathogenetic, symptomatic treatment and Pathogenetic, symptomatic treatment and reanimationreanimation
Provoking vomitingProvoking vomiting
• mechanical method• hypertonic solution (10 %) of sodium chloride• Apomorphine hydrochloride (0,2-0,5 ml s.c.)
Contraindications:- coma- elderly patients- lung emphysema- pregnancy- poisoning with cauterizing substances- poisoning with volatile liquids- poisoning with antiemetic drugs- convulsive episode in anamnesis
STOMACH LAVAGESTOMACH LAVAGE
Fabre: stomach lavage performed in time even by an inexperienced person is much more effective than the most modern methods of treatment, if they are used late
- after 4-5 hours – in case of poisoning with spasmolytic drugs, soporific, salicylates
- after 12 hours and more – in case of poisoning with morphine derivates, noxirone
- after 15 min.-1 hour – in case of poisoning with cauterizing substances
- after 1-2 days – in case of poisoning with mushrooms
Gastric lavageGastric lavage
LAXATIVES
If the poison is unknown, only salt laxatives should be used (!!!) -
magnesiummagnesium ( (sodiumsodium) ) sulfatesulfate - 20-3 - 20-30 g0 g
Ricine oilRicine oil is contraindicated in case of is contraindicated in case of poisoning with fat-soluble substancespoisoning with fat-soluble substances
((phosphorusphosphorus, , POSPOS, , oil-productsoil-products, , benzole benzole derivatives etc.derivatives etc.))
Vaseline oilVaseline oil decreases resorbtive ability of decreases resorbtive ability of intestinesintestines
ANTIDOTES
GreekGreek antidoton – anti poisonantidoton – anti poison are used if poison is correctly specifically
identified- physical – absorb the poison (activated
charcoal, other enterosorbents,)- chemical – destroy the poison, transform it into
non toxic substance, form complex substances with it (acids – alkalis, ЕDТА, unithiol, protamine sulfate)
- physiological – act as antagonists relatively to the poison on the level of specific receptors (naloxon, atropine)
Activated charcoalActivated charcoaluniversal antagonist of physical action
1 g adsorbs 1800 mg of mercury dichloride, 950 mg of strychnine, 800 mg of morphine, 700 mg of atropine or nicotine, 550 mg of salicylic acid, it is highly effective in case of poisoning with alkaloidsalkaloids
Single dose - 20-100 g
not effectivenot effective – in case of poisonings with acids, alkalis, phenols, less effective – in case of poisoning with hydrocyanic acid
CHEMICAL ANTIDOTESTannin - 0,5 % solution for poisoning with heavy metals salts
and alkaloids (except morphine, physostygmine, nicotine, atropine and cocaine)
Potassium permanganate - 0,01-0,02 % - food poisonings, alkaloids (morphine, strychnine, nicotine, chinine, physostygmine)
Copper sulfate – poisoning with phosphorus
Sodium chloride – poisoning with silver salts (AgNO3)Iodine (15 drops per 100 ml of water) precipitates silver, lead,
mercury compounds, strychnine, chinineUnithiol (dimercaprol, BAL, i.m.) – poisoning with heavy metals
salts, cardiac glycosidesDeferoxamine – poisoning with iron preparationsEDTA (trilon B) – binding lead, copper, magnesium, radioactive
elements - plutonium, uranium, thorium, yttrium compounds
PHYSIOLOGICAL ANTAGONISTSdo not change physical-chemical condition of the poison
Naloxon – poisoning with opiates
Atropine – poisoning with M-cholinomimetics and POS
Physostygmine – poisoning with atropine, curare-like drugs
Analeptics – poisoning with soporific drugs, narcotics
Flumazenil (anexate) – poisoning with tranquilizers
Potassium chloride – poisoning with cardiac glycosides
Oxygen – poisoning with carbon monoxide
Ethanol – poisoning with methanol, ethylenglycol
MEASURES MEASURES TO ELIMINATE THE POISON TO ELIMINATE THE POISON out of THE ORGANISMout of THE ORGANISM
• substitutive blood infusion substitutive blood infusion (10-15 (10-15 l)l)• hemosorption hemosorption ((plasmaplasma-, -, lymph-sorptionlymph-sorption))• hemodialysishemodialysis ( (artificial kidneyartificial kidney))• peritoneal dialysisperitoneal dialysis• enterosorptionenterosorption• forced diuresisforced diuresis• lung hyperventilationlung hyperventilation• hyperbaric oxygenationhyperbaric oxygenation
Hemodialysis, hemosorption
• Effective, if the substance has a small if the substance has a small volume of distributionvolume of distribution– – theophylline, theophylline, carbamazepin,carbamazepin, lithium carbonate, salicylates, lithium carbonate, salicylates, valproic acid, barbituratesvalproic acid, barbiturates
• Not effective, if the substance has a big if the substance has a big volume of distribution volume of distribution – – rifampicin, lidocainrifampicin, lidocain, , sybazon, anaprilin, dyltiazem, digoxinsybazon, anaprilin, dyltiazem, digoxin
FORCED DIURESIS
In case of poisoning with substancesIn case of poisoning with substances – – weak weak acidsacids ((salicylatessalicylates, , barbiturates, nalidixic barbiturates, nalidixic
acid, antibacterial and antidiabetic acid, antibacterial and antidiabetic sulfonamidessulfonamides, , indometacin, indirect indometacin, indirect
anticoagulants, clofibrateanticoagulants, clofibrate) ) – alkalizing – alkalizing organism liquids withorganism liquids with NaHCONaHCO33
FORCED DIURESISFORCED DIURESIS
• In case of poisoning with substancesIn case of poisoning with substances – – weak alkalisweak alkalis
((chinin, amphetaminechinin, amphetamine, , amitryptilineamitryptiline, , caffeinecaffeine, , theophyllintheophyllin, , novocainnovocain) – ) –
changingchanging pH of mediumpH of medium to acid sideto acid side with with vitaminvitamin С, С, ammonium chlorideammonium chloride
COMMON PHARMACOLOGY COMMON PHARMACOLOGY PHARMACOKINETICSPHARMACOKINETICS
Main principles of drugs penetration through biological membranes
• Barriers: oral administration - barriers of GI mucous membrane cells and endothelial cells of the vessels; intravenous administration – layer of endothelial cells
• epithelium in small intestine is well penetrable – it contains multiple channels (canalicules) through which molecules with relatively low molecular weight (most of drugs) can penetrate; stomach has no canalicules – strong epithelium
• penetration of drugs through cellular membranes - universal mechanisms (role in absorption, distribution, excretion): passive diffusion, facilitated diffusion (with a help of special carriers), filtration, active transport and pinocytosis
• Passive diffusion – along with gradient of concentration (from the zone with higher concentration to the zone with lower concentration ; it doesn’t need any energy and lasts until concentration of the substance from both sides of the membrane becomes equal): acetylsalicylic acid, aminazin, quinine, ether
• Facilitated diffusion – with the help of proteins-transporters: glucose, aminoacids, vitamins (specific gastromucoprotein synthesized in stomach is necessary for absorption of vitamin В12 in small intestine)
• Filtration – through pores in membrane, the size of which is around 0,35-0,8 nm. Substances with low molecular weight (water, urea etc.) penetrate through pores. Ionized particles (cations, anions) practically do not penetrate through pores (the reason is заряд on the cell membrane)
• Active transport – is provided by specific transport systems of the cells and needs energy since happens against gradient of concentration: cardiac glycosides, glucocortecosteroids, input of iodine into thyroid gland
• Pinocytosis – in the place of drug molecule contact cell membrane invagination with formation of a vesicle happens, this vesicle plunges into cell: proteins, nucleonic acids, fat soluble vitamins
Passive diffusionPassive diffusion
Distribution of drugs
size of molecules: high molecular substances (heparin, mannitol) or those closely
connected to plasma proteins do not penetrate through endothelium and stay inside the vessels
low molecular water soluble drugs penetrate through pores of capillaries’ walls and enter intercellular space
level of solubility in lipids: fat soluble drugs go through cell membranes, HEB, placental and
other barriers, enter all organs and tissues- drugs for general anesthesia, psychotropic drugs- levomycitin, metronidazole (for meningitis)- tubocurarin, ditilin, metacin, cephalosporines – do not go into
cerebral tissue creation of depot in fat tissue (ether, other drugs for narcosis –
after-narcosis depression)
Distribution of drugsDistribution of drugs
Intensity of blood circulation in organs and tissues:
Tiopental after intravenous introduction first of all penetrates into muscular tissue which is well blood-supplied (there is necessity in repeated introduction)
Distribution and pharmacological effects of drugs can decrease in case of organic blood supply insufficiency (shock, haemostasis in large blood circulation circle based on heart insufficiency)
CONNECTION OF DRUGS WITH BLOOD CONNECTION OF DRUGS WITH BLOOD PLASMA PROTEINSPLASMA PROTEINS
• Albumin, lipoproteins, 1-acid gycoprotein and globulins
• specific proteins-carriers: glucocorticosteroids – transcortin, vitamin В12 – transcobalamin, iron ions – transferrin, copper ions – ceruloplasmin
free and bound with proteins forms of a drug stay free and bound with proteins forms of a drug stay in condition of dynamic balancein condition of dynamic balance
drug bound with plasma proteins is drug bound with plasma proteins is pharmacologically inactive !!!pharmacologically inactive !!!
• in case of hypoalbuminemiain case of hypoalbuminemia ( (liver diseases, burn liver diseases, burn diseasedisease, , protein starvationprotein starvation, , elderlyelderly): ): increasing of free increasing of free fraction of a drugfraction of a drug, , increasing of pharmacological increasing of pharmacological activity, development of toxic effectsactivity, development of toxic effects
• highhigh level of connection of blood proteinslevel of connection of blood proteins: : diazepam, diazepam, butamid, difenin, indometacin, furosemid, quinidinebutamid, difenin, indometacin, furosemid, quinidine
• competition for binding with plasma proteinscompetition for binding with plasma proteins: : sodium sodium valproate forces out difeninvalproate forces out difenin – – increasing of free increasing of free fraction of the last - toxic effectsfraction of the last - toxic effects
• high level high level of sulfadimetoxin, sulfapirydasin binding of sulfadimetoxin, sulfapirydasin binding with blood proteins causes prolongation of their actionwith blood proteins causes prolongation of their action
Selective distribution of Selective distribution of drugsdrugs
causescauses peculiarities of pharmacodynamicspeculiarities of pharmacodynamics • iodineiodine – – thyroid glandthyroid gland – – synthesis of thyroid synthesis of thyroid
hormoneshormones• grizeofulvingrizeofulvin – – epidermisepidermis, , keratinkeratin – – treatments of treatments of
dermal and onichomicosisdermal and onichomicosis • cyanocobalamin cyanocobalamin – – red bone marrowred bone marrow – – synthesis synthesis
of erythrocytesof erythrocytes• furosemidfurosemid – – endolymph of inner earendolymph of inner ear – – ototoxicityototoxicity• cephalosporinscephalosporins – – cells of epithelium of kidney cells of epithelium of kidney
canaliculescanalicules – – nephrotoxicity nephrotoxicity • 1% 1% of introduced into organism cardiac of introduced into organism cardiac
glycosides distributes into heartglycosides distributes into heart
VOLUME OF DISTRIBUTIONVOLUME OF DISTRIBUTION
volume of distribution – imaginative volume in which the drug is distributed in organism, if to let that organism is a single space (single-camera model), and concentration of the drug in blood plasma equals to concentration in tissues
Distribution volume is calculated according to a formula:
Vd = total quantity of the drug in organism concentration of the drug in blood plasma
Vd of acetylsalycylic acid – 8 litter Vd of rifampicin, lidokain, diazepam, anaprilin, digoxin –
65, 90, 210, 280, 600 litters correspondingly
Depositing of drugsDepositing of drugs
• extra- and intracellular depot of drugs• in blood plasma and on the ways of their excretion
from the organism
• ethambutol – in erythrocytes• tetracyclins – in bone tissue, in teeth• ampicillin, biseptol, nitroxolin, nalidixic
acid – in kidneys• drugs for general anesthesia – in fat tissue
Metabolism of drugs
Metabolism or biotransformation -
complex of processes which provide decreasing of toxicity and accelerate
excreting of the molecule of a drug or other foreign substance after its incoming into the
organism
Reactions of biotransformation• Nonsynthetic - І phase
• Synthetic - ІІ phase
І phase (nonsynthetic reactions):(oxydation, reduction, hydrolysis)
• 1) microsomal reactions• 2) nonmicrosomal reactions
Reactions of І phase - transformation in molecule with formation of functional groups with active hydrogen atom
ORGANS OF DRUGS METABOLISMORGANS OF DRUGS METABOLISM
• liverliver • kidneyskidneys• muscle tissuemuscle tissue• intestinal wallintestinal wall • lungslungs• skinskin• bloodblood
Microsomal enzyme systemMicrosomal enzyme system
Oxydoreductases, esterases, enzymes of proteins, lipids,
glycerophosphatides, lipo- and glycoproteids, bile acids, cholesterol, prostaglandins biosynthesis, enzyme
systems of biosynthesis of couple compounds, ethers of glucuronic
and sulfur acids
Oxydoreductases of microsomes (oxygenases of microsomes, microsomal hydroxydating system, NADPH-
hydroxylase system, monooxygenases of mixed functions)
– these are enzymes which activate molecular oxygen and catalize including of one (monooxygenase) or two (dioxygenases) atoms of oxygen into molecule of substrate (R) Reaction is presented as follows:
R + O2 + DН = ROH + H2O + D
One atom of О2 is included into molecule of the substrate, other is reduced to Н2О, therefore enzyme performs oxygenase and oxydase functions simultaneously. That’s why monooxygenases ate also called oxydases of mixed function. Along with this hydroxyl group (-ОН) forms in molecule of substrate, that’s why monooxygenase is also calles hydroxylating system, and reaction of oxydation – oxydating hydroxylation
CYP CYP 450450
CYPCYP-450 – -450 – hemoproteinhemoprotein, , which is able to interact which is able to interact with substrate of oxydation, to activate oxygen and with substrate of oxydation, to activate oxygen and combine it with substratecombine it with substrate. . Specifically on CYSpecifically on CYР-450 Р-450 reactions of hydroxydation are performedreactions of hydroxydation are performed
large amount of isoforms of this enzymelarge amount of isoforms of this enzyme – – possibility of its binding with different substrates possibility of its binding with different substrates and taking part in their metabolismand taking part in their metabolism There are There are 24 24 isoforms of CYisoforms of CYР-450 Р-450 in microsomes in microsomes of human liverof human liver
Multiplicity of the enzyme has a group characterMultiplicity of the enzyme has a group character: : one isoform of CYone isoform of CYР-450 Р-450 interacts not only with interacts not only with one substrate but with a group of substancesone substrate but with a group of substances
The catalytic cycle of cytochrome P450The catalytic cycle of cytochrome P450
Main ways of biotransformation of drugs
• I phase• Oxydation: diazepam, pentazocin, sydnocarb, phenotiazin,
phenobarbital, aspirin, butadion, lidokain, morphin, codein, ethanol, rifampicin
• Reduction: hestagens, metronidazol, nitrazepam, levomycetin, chlozepid
• Hydrolysis: levomycetin, novocain, cocain, glycosides, ditilin, novocainamid, xycain, fentanyl
• II phase• Conjugation with sulfate: morphin, paracetamol, isadrin• Conjugation with glucuronic acid: teturam, sulfonamides,
levomycetin, morphin• Conjugation with remains of - aminoacids: nicotinic acid,
paracetamol• Acetylation: sulfonamides, isoniasid, novocainamid• Methylation: morphin, unitiol, ethionamid, noradrenalin
Drug-Induced Immune-Mediated Liver InjuryDrug-Induced Immune-Mediated Liver Injury - DILI- DILI
Metabolism in the intestinal wall
Synthetic and nonsynthetic reactions take place
• Isadrin – conjugation with sulfate• Hydrlalasin - acetylation• Penicillin, aminazin – metabolism with
nonspecific enzymes• Methotrexat, levodopa – metabolism with
intestinal bacteria
PRESYSTEMIC ELIMINATIONPRESYSTEMIC ELIMINATION
presystemic elimination – extraction of the drug form blood circulatory system during it’s first going through the liver (first pass metabolism) – it leads to decreasing of bioavailability (and therefore, decreasing of biological activity) of drugs
propranolol (anaprilin), labetolol, aminazin, acetylsalicylic acid, labetolol, hydralasin, isadrin, cortizone, lidokain, morphin, pentasocin, organic nitrates, reserpin
Presystemic eliminationPresystemic elimination
Factors that influence on drug metabolism
Factor Reaction type Age (newborns, children, elderly)
Decreasing of metabolism speed
Pregnancy Increasing of metabolism speed Genetic factor Various reactions Liver pathology Decreasing of excreation speed of drugs, depending on their kinetics, type
and stage of liver disease, increasing of bioavailability and decreasing of excretion speed of orally administered drugs with high hepatic clearence
GI pathology Changes in metabolism in GI epithelium
Nutrition character
Increasing of metabolism speed of certain drugs in case of diet with dominance of proteins and carbohydrates Decreasing of metabolism speed in case of heavy digestive disorders linked with starvation (total or protein)
Environment Increasing of metabolism speed if in contact with chlorine insecticides
Alcohol — one time consumption
Depressing of enzymes that metabolise drugs
— chronic consumption
Induction of enzyme system
Smoking Increasing of metabolism of certain drugs (i.e. theophyllin)
Way of excretion
Metabolism in liver before entering system circulation (first going-through effect) after peroral administration of drugs
Time of introduction of drugs
Circade changes in drugs metabolism
Interaction of drugs
Stimulation and depression of enzyme reaction
INTESTINAL-LIVER RECIRCULATION
Influence of body weight on kinetics of drugs
• In exhausted patients – speeding up of elimination, that’s why it’ s appropriate to introduce the increased dose – 1+1/3
• In patients with overweighting – retention of lipid-soluble drugs in the organism
• For these patients it’s suitable to correct the dose according to “ideal” body weight:
For men ІBW = 50 + [(Н - 150) : 2,5]For women ІBW = 45 + [(Н - 150) : 2,5]
where Н – height in cm• in case of normal body weight the dose is
calculated counting on 1 kg of patient’s body weight
Biotransformation of drugs into active (or more active) metabolites
Initial drug• Allopurinol • Amitriptilin• Acetylsalicylic acid• Butadion • Diazepam• Digitoxin • Codein • Cortizol• Methyldopa • Prednison • Novocainamid • Propranolol
Active metabolite• Aloxantin • Nortriptilin • Salicylic acid• Oxyfenbutazon• Dismethyldiazepam• Digoxin • Morphine • Hydrocortizon• Methylnoradrenalin• Prednisolon • N-acetylnovocainamid• N-oxypropranolol
Elimination of the drugs
drugs can be excreted in forms of metabolites or unchanged forms through different ways: kidneys, liver, lungs, intestines, sweat and mammary glands etc.
Elimination through kidneysfiltration, canalicular secretion and
canalicular reabsorption• filtration (relative molecular weight of drugs is less than 90,
if 90-300 – with urine and bile): ampicillin, gentamicin, urosulfan, novokainamid, digoxin
• Disorders of filtration – shock, collapse (due to decreasing of blood circulation and hydrostatic pressure of blood plasma in glomerular capillaries)
• furosemid (closely connected with plamsa proteins) is not filtrated in glomerular capilaries
• canalicular secretion – active process (with the aid of enzyme system and using energy): penicillins, furosemid, salicilates, chinin
• Disorders of canalicular secretion – in case of disorders of energetic metabolism in kidneys: hypoxia, infections, intoxications
Canalicular reabsorbtion (reversed absorbtion)
lipid-soluble drugs are reabsorbed passively ionized drugs, which are weak acids or alkali are
reabsorbed actively
regulation of level of reabsorbtion - to speed up elimination of drugs – weak alkalis
(antihistamine drugs, chinin, theophyllin) urine is made acidic (with ascorbinic acid, ammonium chloride)
- to speed up elimination of drugs – weak acids (NSAID, including ASA, barbiturates, sulfonamides) urine is made alkaline (introduction of sodium hydrocarbonate)
ELIMINATION OF DRUGS (continuation)
with bile – drugs and their metabolites with relative MM over 3000
enterohepatic (intestinal-liver) recirculation:
cardiac glycosides, morphine, tetracyclines
are excreted with bile in unchanged condition (previously not metabolized): antibiotics of tetracyclines group, macrolides
through lungs – gases and volatile substances: ether for narcosis, ftorotan, N2O, partly – camphor, iodides, ethanol
through intestine: ftalasol, enteroseptol, magnesium sulfate
through sweat glands: iodides, bromides, salicylates
through bronchial, salivary glands: bromides, iodides
with milk: get into organism of the baby – levomycetin, fenilin, reserpin, lithium remedies, meprotan, tetracyclines, sulfonamides etc.
USING DRUGS DURING LACTATION
Absolutely contraindicated• Antibacterial: tetracyclins, levomycetin, fluoroquinolones,
sulfonamides, nalidixic acid, metronidazole
• Antiviral: amantadin, gancyclovir, zidovudin, remantadin
• Cytostatics
• Drugs effecting CNS: difenin, sodium valproate, lithium preparations, barbiturates, reserpin, opioid analgesics (regularly)
• Drugs of other groups: iodides, antithyroid drugs, undirectanticoagulants, radiopharmaceutical drugs (radioactive iodine etc.), Ergot alkaloids, chlorpropramid, cyclosporin
USING DRUGS DURING LACTATION(continuation)
UndesirableBromides, meprobamat, derivatives of benzodiazepine
(diazepam, chlozepid, oxazepam etc.), aminazin, ethosuximid;
M-cholinoblockers, glucocorticosteroids (if dosage is over 100 mg per day), indometacin, salycylates (large doses),
derivatives of sulfonilurea, theophyllin, chloroquin, nitrofuran derivatives (furazolidon etc.), isoniazid,
cymetidin, aluminum containing antacids, estrogens, gold medications, retinoids
GENERAL PHARMACOLOGY GENERAL PHARMACOLOGY PHARMACODYNAMICSPHARMACODYNAMICS
PHARMACODYNAMICSPHARMACODYNAMICS
Pharmacological effect – clinical manifestation of drug influence on the organism
Its basis is primary pharmacological reaction – the result of drug influence on special structures of the organism • Pharmacological effects may be identical but caused by different pharmacological reactions: atropin and adrenalin dilates the pupils, 1st inhibits M-cholinoreceptos, 2nd – activates adrenoreceptors
• In contrary, different pharmacological effects may appear due to the same pharmacological reaction: anaprilinum causes β-adrenoreceptors blockade that resulted in hypotension, antiarrhythmic action and antianginal effect
PHARMACOLOGICAL EFFECTS• Local: astringent, covering, irritating, local anesthesia,
necrotizing, adsorbing• Reflectory: as a result of local irritating (Sol. Ammonii
caustici, Validolum, Charta Sinapis, expectorants of plant origin)
• Resorbtive (systemic – after drug absorption or its introduction to blood): 1) direct (primary) and 2) indirect (secondary): cardiac glycosides: 1 – on heart, 2 – diuretic effect
• Selective action (salbutamol, celecoxyb, doxazosin) • Nonspecific action – on all cells of the organism:
drugs for general anesthesia, salts of heavy metals • Basic (beneficial) action an adverse reaction • Reversible and irreversible
RECEPTOR THEORY OF DRUG ACTION
• Receptors – the places where drugs bind to tissues: macromolecules, enzymes, channels, transport systems, genes
• Agonists: adrenalin, isadrine, morphine etc. • Antagonists: atropin, anaprilin, dimedrol etc.
Конкурентні та неконкурентні антагоністи
• Agonist-antagonist: labetolol (1, 1-adreno-blocker, but activates 2-adrenoreceptors),
pentazocin (agonist delta- and kappa-opiate receptors and mu-receptors antagonist)
RECEPTOR THEORY OF DRUG ACTION
TYPES OF RECEPTORSTYPES OF RECEPTORS
Specific structures of cells:Specific structures of cells:
N- and M-cholinoreceptors, - і -
adrenoreceptors, dophamine-, opiate-,
histamine-, serotonin-, receptors to
angiotensin II, leucotryenic-, prostaglandine-,
polypeptic and steroid hormones etc.
Receptors – specific cell sites
Opiate receptorsGABAc receptors
steroid-receptor Serotonine receptor
TYPES OF RECEPTORSTYPES OF RECEPTORS
Receptors-enzymes: acethylcholinestherase (Proserine), monoaminoxydase in neurons of CNS (Nialamid), angiotensin converting enzyme (ACE-blockers – Captopril, Enalapril), K-,Na- ATPase (cardiac glycosides - Digoxin), H-,K-ATPase (proton pump) (Omeprasol), COG-1, COG-2 (nonsteroidal antiinflammatory agents – Diclofenac, Indometacin, Piroxycam, Meloxicam etc.)
Receptors - enzymesReceptors - enzymes
cholinesteraseMAO
Cox - Cyclooxygenase ACEangiotensin converting enzyme
RECEPTOR THEORY OF DRUG ACTION
• Receptors – ionic channels• Na+ - channels – local anesthetics, antiepileptic,
antiarrhythmic drugs • Са2+ - channels – Nifedipin, Amlodipin,
Verapamil, Dilthiazem• Voltage-dependent К+- channels – Amiodaron,
Ornid (Brethylium tozylat), d-Sotalol• АТP-dependent К+- channels: - blockers - Butamid, Maninil (stimulate secretion
of insulin by -cells of pancreas) - activators – Minoxidil, Diazoxid (decrease AP)
• Receptors - Genes • Thyroid gland hormonal preparations
Receptors – ionic channelsReceptors – ionic channels
sodium (Na+) channels
calcium channelsVoltage-dependent potassium channels
thyroid hormone receptor thyroid hormone receptor - genes- genes
NONSPECIFIC ACTION OF DRUGSDue to their physical and chemical properties
• Mannit increases osmotic pressure in kidneys canalicules
• Direct chemical interaction: Antacides (MgO, NaHCO3) neutralize HCl, Trilon B (EDTA) binds salts of heavy metals, Na citrate binds Ca-ions
• Physical-chemical interaction: Protamine sulfate binds Heparin
• Due to the same structure with metabolites of the organism drugs interferences with corresponding metabolic processes : Sulfonamides (have the same structure to PABA), Mercaptopurin (to folic acid and purin)
Factors effecting the properties of drugsFactors effecting the properties of drugs
Exogenous Exogenous • chemical structure and physical-chemical
properties • pharmaceutical form and the ways of its
introduction • doses • regime of feeding • environment factors (meteorological, circadian
rhythm) EndogenousEndogenous
• age • sex • pregnancy • diseases
Chemical structure and physical-chemical properties
• Degree of ionization: methyl, ethylic group – weak ionization, high lipidotropic activity; hydroxyl, amino-group – high ionization, high hydrophilic properties, weak penetration through the membranes
• Fluoric atom in molecules of GCS, neuroleptics increases their
activity
• Space structure: distance between nitrogen-atoms 0,6-0,8 nm – ganglionblockers, 1,4-1,5 nm – myorelaxants
• weak solubility in lipids – bad penetration through the membranes (tubocurarini chloridum), high solubility in lipids – penetration through the HEB (mellictin )
• Large active surface – enterosgel, activated charcoal
• Effecting of cell membranes with detergents
Pharmaceutical form and the routs of its administration
these factors effecting the bioavailability
Bioavailability of drugs complex of pharmacokinetic processes that
maintenance active concentration of drug in the area of specific receptors (part of administered drug that reaches the systemic circulation and effects specific receptors)
FOOD - DRUGSFOOD - DRUGS
Tea, coffee Fructs’ and vegetables’ sour juices Milk Thyramine-containing products (aged cheese, smoked meat and fish, beans, bananas, red vine) Cauli-flower, dogrose Beans, tomatoes, liver, kidneys
Barbiturates Haloperidolum, theophylline Calcium chloride, tetracyclines, isoniazidum Tetracyclines, ampicilline, griseofulvin, calciferol MAO-inhibitors Indirect anticoagulants Hormonal contraceptives
↑ absorption ↓ absorption ↓ absorption ↓ absorption ↑ toxicity ↓ of action (antagonism) ↓ of action (antagonism)
Food and bioavalabilityFood and bioavalability
Drugs absorbtion
bioavalability
Spironolactone, hydralazine
Anapriline, hydantoine, griseofulvini
Furosemid, isoniaside, cefalexine
Drugs and milk
• Glucocorticosteroids: prednisolone, dexamethasone
• NSAID: voltaren, butadion, indometacine
• Antibiotics: tetracyclines, fluoroquinolones
• Increase of absorption
• Decrease of absorption
• Decrease of absorption
Antibiotics and tonic drinksAntibiotics and tonic drinks
• Macrolides (erythromycine, spiromycine, klaritromycine)
• Linkosamides (linkomycine, clindamycine)
• Tetracyclines
• Decreas of absorption
• Decreas of activity
Tannin-containing productsTannin-containing products
• Alkaloids (papaverine, platyphylline, codeine, reserpine)
• Neuroleptics of phenothiazine and buthyrophenone groups (aminazine, haloperidole etc.)
• Decreas of absorption
• Decreas of therapeutic activity
tea
Green tea Green tea • Xanthines
(Theophyllinum) –Increase of absorption,
Increase of adverse reactions (insomnia, nervousness)
• Indirect anticoagulants – decrease of effectivenes
Drugs and caffeine-containing productsDrugs and caffeine-containing products
Morphine, papaverine, codeine, atropine, aminazine, haloperidol, hormonal contraceptives, ergotamine
Decreas of absorption
Decreas of therapeutic activity
Paracetamol, aspirine
increase of analgesic effect
Grapefruit juiceGrapefruit juice
• Calcium antagonist, Calcium antagonist, terfenadine, terfenadine, ciclosporineciclosporine
• Decrease of
biotransformation in liver, increase of their blood concentration, increase of toxicity
Diet in case of administration of IMAODiet in case of administration of IMAOIt is necessary to exclude such products which contain
DOPA and thiramine (which is formed from casein during the process of transforming under the influence of bacteria)
Aged cheese, kefirMarinated herringSmoked meat and
fishRed vine, beer, yeast
Beans, oranges, tangerines,
lemons, grape, chocolate,
bananas, caviar (red and black)…
INFLUENCE OF BIOLOGICAL RHYTHMSINFLUENCE OF BIOLOGICAL RHYTHMS
• Glucocorticoids are administered between 6 Glucocorticoids are administered between 6 and 8 in the morningand 8 in the morning
• Theotard (long-acting form of theophylline) is Theotard (long-acting form of theophylline) is used in the evening (exacerbation of BA at used in the evening (exacerbation of BA at night)night)
• Maximum effect occurs if use diuretics till 10 Maximum effect occurs if use diuretics till 10 a.m.a.m.
• Toxicity of Haloperidolum changes during the Toxicity of Haloperidolum changes during the day in 5 timesday in 5 times
• Angina attacks more frequently appears from Angina attacks more frequently appears from 2 to 6 p.m.2 to 6 p.m.
Influence of sex of the patient on Influence of sex of the patient on drug actiondrug action
• Morphin, nicotine, coffeine – women are more sensitive
• Changes of theophyllin, paracetamol, prednisolon metabolism accordingly different phases of menstrual circle
• Pregnancy – worse absorption and slow biotransformation of drugs
• During menstruation anticoagulants can course severe uterus bleeding
Influence of pathological processes Influence of pathological processes on drug actionon drug action
• Myocarditis increases the toxicity of cardiac glycosides
• Cardiac glycosides act only when cardiac insufficiency
• Paracetamolum and other antipyretics act when hyperpyrexia
• Pathology of liver leads to inhibition of drugs metabolism and increases their toxicity
• Inhibition of drugs elimination is observed in kidney pathology
• Smoking provokes risk of thrombosis during administration of hormonal contraceptives
PATHOLOGY OF ENZYMES (enzymopathya)PATHOLOGY OF ENZYMES (enzymopathya)
• Decreased activity of glucoso-6-phosphatdehydrogenase: sulfonamides, levomycetinum, drugs for malaria, salicylates, vit C, nitrates lead to hemolysis
• Insufficiency of catalase: H2O2 is not metabolized with appearance a foam and can course severe burn of wound
• Insufficiency of butyrilcholinesterase: duration of dithylinum action changes to several hours instead of 2-5 minutes
• Insufficiency of acethyltransferase in liver leads to violation of isoniazid, sulfonamides, novocainamid biotransformation