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87 Cards in this Set
- Front
- Back
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Factors affecting drug absorption (related to the drug): |
1- Water and lipid solubility 2- Ionization 3- Valency 4- Nature (organic / inorganic) 5- Pharmaceutical preparation: - Dosage form - shape & size (rate of dissolution & desentigration) - Exepient (filler)
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Factors affecting drug absorption (related to the patient): |
1- Route of administration IV> inhalation>IM >SC > oral> skin. 2- Absorbing surface : surface area, vascularity & state of health. 3- Systemic Circulation 4- Specific factors: intrinsic factor 5- Presence of other drugs: Adrenaline & local anasthesia, Milk & Tetracycline
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Tertiary amines |
Non-ionized thus better absorption |
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Quaternary ammonium compounds |
ionized thus poor absorption |
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Streptomycin |
high pKa (highly alkaline) thus always ionized thus NOT absorbed (used for treating infection in the GIT= locally) |
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Rapid rate of disintegration & dissolution |
Paracetamol & Propranolol |
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Slow rate of disintegration & dissolution |
Digoxin |
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Factors affecting oral absorption (related to the patient): |
1- Surface area & vascularity 2- State of absorbing surface 3- Motility of the gut and rate of dissolution 4- pH 5- Specific factors 6- Gut contents: presence of food & other drugs 7- First pass effect
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Effect of presence of food (Good / Bad) |
(Bad) bec food dilutes the drug & it may compete with them for absorption (e.g. aminoacids compete for the same carrier for L-DOPA) (Good) with IRRITANT drugs e.g. aspirin& iron
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Tetracycline can't be taken with |
MILK bec it decrease the absorption of Ca & Fe by chelation |
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Cholestyramine & Charcol |
decrease the absorption of many drugs by adsorption |
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Grape Fruit Juice |
increase absorption by inhibiting "p. glycoprotein" (which cause reversed transport of drug from gut wall to the lumen) |
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Tea |
decrease iron reabsorption by its content of tannic acid. |
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First Pass Effect |
metabolism of the drug in the gut wall or liver before reaching the systemic circulation. |
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Gut First Pass Effect |
1- Gastric acidity: destroys benzyl penicillin 2- Digestive enzymes: destroy insulin & pituitary hormones 3- Mucosal enzymes: destroys chlorpromazine (treats psychosis) |
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Hepatic First Pass Effect |
1- Drugs extensively metabolized: Lidocaine: given as IV instead Nitroglycerine: given sublingual 2- Drugs metabolized to a large extent: Propranolol: to avoid increase the dose. |
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Bioavailability |
the fraction of unchanged drugs reaching systemic circulation after any route of administration. |
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Bioavailability Curve |
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One compartment (Intravascular) model |
Drugs: -too large MW -distributed in a volume of plasma of 4 L (6%) - e.g. HMW Heparin & highly bound to plasma ptn such as Warfarin
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Two compartment (Extracellular) model |
intravascular & interstitial Drugs: -low MW - hydrophilic (water soluble) - distributed to a volume of 14L (20%) - e.g. quaternary ammonium compounds |
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Multicompartment (Extra & Inra) model |
-distributed to total body fluids 42L (60%) -low MW -Lipid soluble |
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Factors affecting distribution of drugs: |
1- Physiochemical properties of the drug: -MW -degree of ionization -lipid solubility 2- Binding to Plasma proteins 3- Passage across barriers |
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Drugs that bind strongly to plasma proteins |
Salicylates (NSAID) & Sulfonamides |
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Drugs carried in the blood in 2 forms: |
Free: - pharmacologically active - diffusible - metabolized - excreted Bound: -inactive - non-diffusible -not metabolized -not excreted |
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The amount of drug bound to plasma protein will change according to: |
1- Affinity to binding sites: competition between drugs as a drug may displace another one from its binding site e.g. Salicylates (NSAID)| Warfarin= Hemorrhage Sulfonamides | Bilirubin = Kernicterus 2- Hypoalbumenemia e.g. starvation, malnutrition, therapeutic dose becomes toxic e.g. Phenytoin (anti-epileptic) 3- the more the binding the more the duration.
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Passage to CNS across BBB: |
-non-ionized, lipid soluble e.g. Physostigmine but Neostigmine can't - inflammation (Meningitis) increase its permeability so Penicillin can pass |
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Passage to fetus across placental barrier: |
-acts like cell membrane so, non-ionizable, lipid soluble pass more easily -Drugs that pass may cause: during pregnancy: Teratogenicity e.g. Thalidomide & Tetracycline during labour: neonatal asphyxia e.g. Morphine & Barbiturate. |
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Passage through breast milk: |
-most drugs are predictable in milk -pH is more acidic (7) than plasma, so basic drugs ionize and accumulate in milk (ion trapping) -more fat than plasma which favours retention of lipid soluble drugs. |
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Redistribution |
-highly lipid soluble drugs as Thiopentone -then redistributes to less perfused tissue; skeletal muscle - lastly fatty tissue - the durationdepends on the rate of redistribution not the excretion |
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Apparent volume of distribution |
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High Vd means |
occupy multicompartment (alcohol all over the body ex. 40L) or concentrated in tissues(e.g. digoxin in heart ex. 500L) |
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Low Vd means |
retained in vascular compartment due to high molecular weight or high binding to plasma ptns. |
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In cases of drug toxicity |
dialysis can be done only with small Vd which means most of the drug is present in the circulation e.g. aspirin (high affinity to plasma pths) |
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Phase I |
(Non-synthetic) = oxidation, reduction & hydrolysis |
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Results of Phase I Metabolism |
1- Inactivation (the commonest fate) 2- Activation 3- Maintain Activation 4- Toxification |
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Examples on Metabolism leading to Inactivation: |
1- Adrenaline & Noreadrenaline -> Vanil Mandilic Acid (VMA) 2- Seretonin -> 5-Hydroxy-Indol-Acetic-Acid (HIAA) |
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Examples on Metabolism leading to Activation: |
Inactive drug (prodrug) -> Active metabolite Phenoxybenzamine (inactive) -> Ethylenimonium (Active) |
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Examples on Metabolism leading to Maintain Activation: |
Phenacitin (active) -> Paracetamol (active) Diazepam (active) -> Nor-diazepam (active) |
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Examples on Metabolism leading to Toxification: |
1- Methyl alcohol (cheap beer) -> Formaldehyde -> Blindness 2- Parathion & Malathion(insecticide) -> Para-oxone & Mala-oxone -> Toxic to insect & man |
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Phase II |
(Synthetic, Conjugation) usually leads to inactivation may lead to activation e.g. Morphine -> Morphine-6-glucuronoid |
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Phase II Examples: |
1- Glucuronic acid: aspirin, paracetamol, morphine, chloramphenicol 2- Acetic acid (acetylation): isoniazide, sulfonamides, hydralazine 3- Methylation: Noreadrenaline -> active adrenaline, histamine 4- Glycine: aspirin 5- Sulfation |
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Enzymes responsible for drug metabolism |
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Factors affecting hepatic microsomal enzyme activity: |
1- Drugs 2- Age 3- Sex 4- Pathological conditions 5- Starvation 6- Genetic factors |
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Drugs which stimulate the activity of hepatic microsomal enzymes: |
- Phenobarbital, Phenytoin, Carbamazepine (anti epileptic) - Rifampicin , Griseofulvin (AB,AF) - Cortisol, Testosterone - Coffee, Tea, Tobacco smoking |
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Effect of drugs which stimulate the activity of hepatic microsomal enzymes: |
- they increase the metabolism of other drugs thus decreasing their duration of action (other drugs: oral anti-coagulant, oral hypoglycemia & oral contraceptives.) - they also increase their own metabolism (auto-induction) -> tolerance |
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Drugs which stimulate the activity of hepatic microsomal enzymes:
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- Sodium valporate (anti epileptic)
- Chloramphenicol, Erythromycin, Ciprofloxacin (AB) - Ketoconazole (AF) - Grape Fruit - Cimitidine, Omeprazole (proton pump inhibitors) - Estrogen GECKOES 3C |
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Effect of drugs which inhibit the activity of hepatic microsomal enzymes:
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- they decrease the metabolism of other drugs
- they also decrease their own metabolism e.g. Theophylline (in bronchial asthma) -> Increase its plasma -> Toxicity |
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Hepato-toxic drugs: |
carbon dioxide carbonterachloride ozone |
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Drugs decreasing hepatic blood flow: |
beta-blockers (propranolol) H2-blocker (Cimitidine) treats peptic ulcer |
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Effect of AGE on the activity of hepatic microsomal enzymes: |
in the extremities of age, drug metabolism is loweres so drug dose should be reduced
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Grey Baby Syndrome |
Premature neonates can NOT conjugate chloramphenicol Grey Baby Syndrome. |
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Effect of sex on the activity of hepatic microsomal enzymes: |
Androgens stimulate while oestrogen and progesterone inhibit the metabolism. |
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Effect of pathological conditions on the activity of hepatic microsomal enzymes: |
in liver disease, drug metabolism is reduced leasing to increased susciptibility to drug toxicity e.g. effect of diazepam is prolonged and it may cause coma when given in the therapeutic dose |
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Effect of starvation on the activity of hepatic microsomal enzymes: |
enzyme activity is decreased with inhibition of conjugation process e.g. depletion of glycine with inhibition of glycine conjugation. |
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Effect of genetic factors on the activity of hepatic microsomal enzymes: |
genetic determined polymorphism is responsible for variation in drug toxicities. e.g. Succinylcholine is metabolized by pseudocholinestrase, deficiency of this enzyme -> Succinylcholine apnea |
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Passive Renal excretion for |
- water soluble - non-bound - M.W. < 500 |
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Excretion of weak acid drugs |
- Penicillin, Frusemide, Uric acid & Probenicid - Probenicid decreases excretion of Penicillin & Frusemide (diuretic) N.B. beneficial for penicillin but NOT for Frusemide bec. site of its action is the lumen. |
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Excretion of weak basic drugs |
Digoxin, Quinidine (antiarrythmic) Quinidine decreases clearance of Digoxin
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Alkalinization of urine |
- by Na or K Acetate, Bicarbonate or Citrate - increase renal excresion of acidic drugs = Ion trapping - Aspirin & Phenobarbitone |
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Acidification of urine |
- by Ascorbic acid or ammonium chloride - increase renal excresion of basic drugs = Ion trapping - Amphetamine & Ephedrine |
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Clearance of some drugs depends mainly on renal excretion: |
- water soluble - little or NO metabolism (exc in active form) - Caution in renal ptn - Atenolol, Nadolol, Barbitone, Gallamine |
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Drugs excreted in Saliva |
Morphine, Aspirin, Iodine & Mercury
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Drugs excreted in Stomach |
Morphine |
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Drugs excreted in Bile |
- excreted in large intestine - reabsorbed through enterohepatic circulation e.g. Morphine, Rifampicin & Phenolphthalin (long duration of action) - Some antimicrobials excreted in active form e.g. Ampicillin, Rifampicin (treat cholycystitis & Typhoid carrier) |
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Advantages of excretion of drugs in Bile |
-longer duration of action - Some antimicrobials excreted in active form can treat local disease e.g. cholycystitis & Typhoid carrier - Not contraindicated in renal patients |
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Give reason: gastric wash is done in cases of Morphine overdose. |
Bec Morphine is excreted through the stomach. |
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Drugs excreted in sweat |
Vit B1, Mercury (Hg), As & Rifampicin |
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Mechanism of action of drugs: Physical: - Adsorption |
- Kaolin in diarrhea (adsorption of toxins which affect mucosal water reabsorption)
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Mechanism of action of drugs: Physical: - Osmotic |
- Magnesium sulfate (MgSO4) as saline purgative (increase bulk of food so reflex contraction) - Mannitol as osmotic diuretic |
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Mechanism of action of drugs: Chemical: - Neutralization |
- sodium bicarbonate (antacid) + HCL treat hyperacidity - Protamine sulfate (Basic) + Heparin (Acid) Chemical antagonism (used as Heparin antidote) |
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Mechanism of action of drugs: Chemical: - Chelation |
Organic compound + Heavy metal = Non toxic easily excreted compound: - Dimercaprol (BAL) for Mercury & Arsenic - Sodium Edetate for Calcium - d.Penicillamine for Copper - Desferrioxamine for Ferric Iron |
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Mechanism of action of drugs: Interfere with cell division |
Anti-cancer |
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Mechanism of action of drugs: interfere with metabolic pathway |
Sulfonamide compete with PABA in bacteria leading to inhibition of folic acid synthesis |
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Mechanism of action of drugs: Inhibition of enzymes |
Physostigmine ( Cholinestrase ) Aminophylline ( Phosphodiestrase ) Aspirin ( Cyclooxygenase ) |
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Mechanism of action of drugs: action on ionic channel |
Procaine (local anesthetic) = Na channel blocker = membrane stabilization Verapamil = Ca channel blocker |
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Affinity |
ability of the drug to bond to a receptor to form a drug-receptor complex |
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Efficacy (Intrinsic Activity) |
ability to evoke a response = Emax |
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Potency |
refers to the doses of drug required to produce a certain effect. ED50 |
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Occupation theory |
the action of the drug is "directly proportional" to the number of receptors occupied |
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Spare receptors |
receptors that remain free even after the drug produces its maximal response |
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Rate theory of Paton |
the action of the drug is "directly proportional" to the rates of association & dissociation |
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Competitive Antagonist |
- bind REVERSIBLY - can be displaced -> Surmountable - PARALLEL shift to the right -> decrease Potency - NO effect on the maximum response= same efficacy - example: Propanolol, Atropine, Naloxone |
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Non-competitive Antagonist:
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- Non-Parallel shift of the curve to the right= decrease in Potency - Decrease the maximum response (Emax)= decrease the efficacy
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Non-competitive Antagonist: Reversible |
- the block ends by the metabolism of the blocker - of short duration - e.g.: Nicotine LD, Succinylcholine
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Non-competitive Antagonist: IRReversible |
- the block ends by the synthesis of new receptor - of long duration - e.g.: Phenoxybenzamine, organophosphrus compounds |
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Ligand gated ionic channel receptors: |
- change the membrane permeability - milliseconds bt binding & cellular response - e.g. Acetylcholine + Nicotinic - Na influx - dep Acetylcholine + M2 -K efflux - hyperpolarization GABA + GABA(a) - Cl influx - hyperpolarization (NN- MK (2Mac))
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G protein- coupled receptor & second messenger |
- regulate intracellular 2nd messanger (a-sub) or - opening of ion channel (b & gamma sub) - few seconds- minutes -e.g. Adrenaline+b -> Gs -> inc. cAMP Adrenaline+a -> Gi -> dec. cAMP Acetylcholine+M1&3 -> Gq-> Phospholipase C -> IP3 & DAG -> Ca+Calmodulin (Bs & Ai) |
