General pharmacology 4th lecture

Done by: Ammar Aldawoodyeh

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Note: in the next 2 paragraphs when the Dr says concentration of drug it means its concentration in the plasma. Last lecture we talked about first order kinetics and second order kinetics, and we said that the half life of drugs which are subjected to first order kinetics is stable, because the definition of first order kinetics is fixed fraction of the drug is eliminated by unit of time, so at high concentration the half life is the same as the half life in low concentration, this is in first order kinetics. In zero order kinetics the half life is prolonged at high concentration (is longer than the half life in low concentration), and this is due to saturation of the enzymes which are responsible of the elimination of the drug or of drug metabolism. The relation of first and zero order kinetics to the clearance is the opposite; the clearance in first order kinetics is different in high concentration from the clearance at low concentration, while in zero order kinetics the clearance is stable at high concentration and at low concentration, so the clearance is not proportional to the concentration of the drug, and again it's because of the saturation of the enzymes so their activity cannot be expanded, while in first order kinetics the enzymes are not saturated and their activity can be expanded according to the concentration of the drug. Mathematically the clearance could be expressed by the equation: Cl = Vd x Kel Cl: the clearance, Vd: the volume of distribution, Kel: the constant of elimination. So clearance is the volume of drug that could by cleared by unit of time, and from the previous lecture: Kel= 0.693/t , t: half life. So we can write the first equation as: Cl = Vd x 0.693/t . And this means that the clearance is dependent on volume of distribution and the half life, directly proportional to the volume of distribution and indirectly proportional to the half life.

The Loading Dose

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Now we have loading dose, what do we mean by loading dose? We said that in most drugs we need 4-5 half lifes to reach steady state serum drug concentration, but in some diseases, for example acute heart diseases like acute congestive heart failure we need fast treatment and rapid relief of the patient from that acute condition, so it's impossible to wait from 4-5 half lifes to reach steady state serum drug concentration, and I said in last lecture that steady state serum drug concentration is the best concentration that give the therapeutic effect, but in this case (acute congestive heart failure) the drug we use is digoxin which has half life of 35 hours, and we cannot wait for about a week (5*35 "35 is the half life"), therefore in this condition (acute condition which is treated by a drug which have fairly long half life) we should not wait the frequent doses to reach a steady state serum drug steady state serum drug concentration, so we have to give a loading dose, we have to give a high dose, so suddenly the steady state serum drug concentration will reach steady state serum drug concentration. So when we need to reach steady state serum drug concentration in shorter period of time we should give loading dose (acute condition which is treated by a drug which have fairly long half life). We can calculate the loading dose from this equation: LD = Vd x Css LD: loading dose, Css: steady state serum drug concentration Actually Css is the expected steady state serum drug concentration. Homework :P Q: if we want to reach Css of 0.1 mg/ml and the Vd is 10 liter what is the loading dose? A: 10 liter = 10000 ml LD = 10000 ml * 0.1 mg/ml = 1000 mg = 1 g So you have to pay attention and convert the units.

The Maintenance Dose

The Maintenance Dose: is the frequently administered dose, Not the initial single dose, the initial single dose is could loading dose, the maintenance dose is obtained from this equation: MD = Cl x Css , Cl: clearance Remember that the loading dose equation was LD = Vd x Css Now steady state serum drug concentration is given by this equation:

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Css = F.D/ Vd.Kel. F: bioavailability, = the doses interval (for example if the drug is given 3 times daily the doses interval is 24/3= 8 hour). Because Cl= Vd.Kel so we can write the equation of Css as: Css = F.D/ Cl. Remember that if the drug is administered intravenously (F) is deleted, because the drug is completely inside the drug circulation. Now we have finished the pharmacokinetics, let's talk about another branch of the pharmacology which is Pharmacodynamics

Pharmacodynamics
Pharmacodynamics: is the effect of the drug on the body, while the effect of the body on the drug is pharmacokinetics, so Pharmacodynamics includes mainly mechanisms of the action of the drug and how drugs can produce there effect.

Mechanisms of drug actions

There are mainly 10 different mechanisms of drug action, and the main and the most common one is could transmembrane signaling mechanisms, or drug receptor interaction. Note: the Dr here repeated the examples many times, so I think we should memorize them. So the 10 mechanisms are: 1- Transmembrane signaling mechanisms: we'll talk about it later. 2- Physical or physicochemical properties: for example MgSO4 act as purgative ( )because of its physical effect, it absorbs the water from the GIT, making the stool more liquid, Manitol on the other hand will retain the fluid in the renal tubules and can act as a diuretic, so this is due to physical characteristics by absorbing water.

3- Chemical interactions: the simplest example on the Chemical interactions is the interaction between the acids and antacids (or the alkaline preparation), the equation says acid + base salt + water , that the acid and alkaline neutralize each other, so the mechanism of the action of the alkaline drugs is chemical interaction, like antacids for patient with peptic ulcers, another example is the
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protamine SO4 (+) it can antagonize the effect of heparin (-), heparin is anticoagulant, when there is toxicity with heparin, the antidote which is used to antagonize it is protamine SO4 , so these drugs are chemically based, one will neutralize the charge of the other. 4- Chelation: is interaction between substance A and substance B, which make substance B less toxic , less absorbable form GIT and easily excretable from the urinary tract, so substance A is could the chelator substance and B is the toxic one, so A combines with B and make a substance which cannot be easily absorbed by GIT and if it's absorbed it'll be easily eliminated from the urinary tract, so it will be retained both in the GIT and in the urinary tubule, example BAL which is abbreviation of (I can't understand what he said) which can be used as a Pb (lead) and AS (arsenic) poisoning.

5- Blockade of active transport system: such as blockage of Na pump by Digoxin, when we discuss the cardiac glycoside of drug acting on the cardiovascular system, digoxin is important one and its mechanism is through blockage of active ion transport system, mainly Na pump, Na pump is an enzyme called Na-K ATPase, and it can be blocked by digoxin. Other example is blockage of H+ pump though a drug could Omeprazole or proton (hydrogen) pump inhibitor, this pump is H-K ATPase, and this drug is used in treatment of peptic ulcer, it inhibits H+ secretion that's the acid HCl secretion in the stomach. 6- Enzyme inhibition: and the best example that you can understand at this time is inhibition of acetylcholinesterase by a drug called Neostigmine, it's classified as anticholinesterase, acetylcholine is a neurotransmitter and its effect is terminated by enzyme could acetylcholinesterase which can be inhibited by anticholinesterase, and the end result is the accumulation of acetylcholine in the body which means augmentation of acetylcholine effect. 7- Blockade of ion channels: and the best example of blocking Na channels is the use of local anesthetics, and you as a future dentist should be highly interested in this group of drugs because no dental procedure could be done without the use of local anesthetics, so blocking of Na channels leads to blockage of nerve Impulse initiation and transmission.

Ca+2 channels also could be blocked by drugs called Ca+2 channel blockers, which are mainly used in treatment of hypertension. 8- Inhibition of cell wall and protein synthesis: and of course this won't be directed toward humans, but toward the foreign microorganisms which cause infection, this mechanism of action explains the effect of anti-microbes or antibiotics on the bacteria.

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9- Effects on nucleic acid synthesis and functions: anticancer drugs mainly producing their effect by attacking the nucleic acid synthesis or functions, and subsequently these cells which are tumor and malignant cells are killed. 10- Replacement therapy: treatment with hormones and vitamins, when there is vitamins deficiency the mechanism of the exogens vitamins supplementation is replacement therapy, and the same for hormones deficiency like hypothyroidism which is treated with replace of thyroid hormone, and hypo-function of the suprarenal gland, which leads to a addison disease that is treated with supplementation with corticosteroids, and the treatment type 1 diabetes mellitus, which is treated with exogens supplementation with insulin.

Drug-Receptor Interaction
Let's now go back to transmembrane signaling mechanisms, or drug-receptor interaction: It has been stated that drug-receptor interaction is one of the commonest mechanisms of drug action, for many drugs each one has a specific receptor, and these drugs specifically interact with their specific receptor, it's like interaction between the key and the lock, there is only one key to open one lock, occupation of the drug of its specific receptor is called the affinity of this drug to its specific receptor (Affinity: the ability of the drug to combine to its receptor). When the drug occupy this receptor there will be initiation of certain chemical reaction which will end into pharmacological effect, and the ability to produce an effect is called intrinsic activity, so drugs according to affinity and Intrinsic activity could be classified into: 1- Agonist: has high affinity and high intrinsic activity: like acetylcholine and norepinephrine to their cholinergic receptor and adrenergic receptor respectively producing their effect and binding many receptors. 2- Partial agonist: high affinity as the Figure (1) agonist but with less intrinsic activity, as Nalorphine which is a partial agonist to opioid receptor (we'll talk about it in systemic pharmacology) and Pindolol partial agonist to receptors in the sympathetic nervous system. 3- Antagonist: has high affinity but with low intrinsic activity, so it occupy the same receptor as the agonist preventing it from producing it's normal activity, like blockers with epinephrine and atropine with acetylcholine.

Drug response

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This is called drug response curve (Fig 2) it's a representation of the relationship between the effect With the dose, and usually this curve is sigmoid And this means that at smaller doses the effect is small And it gradually increase until we reach the Maximum Effect above which higher doses will not increase the effect anymore. The horizontal line (P) represents the Potency Of the drug, we'll take about it later, but it means The effect of the drug per unit of weight. The perpendicular line (E) represent the efficacy of the Drug, as the effect increase the efficacy of the drug is increased.
(2)

Figure

The cross in the middle represents the variability in drug action, the perpendicular line of this cross state that different effects could be produced by the same dose, so the same dose could cause 20, 50 or 70% of the maximum effect, while the horizontal line (in the cross) represents the variability of the drug that's different doses can produce the same effect. The slope of the line represents the safety of the drug (we'll discuss it in few minutes), the steeper the line the more harmful or toxic is the drug, the flatter the line the more safe is the drug, why? When the line is steep that means that the difference between the dose that causes minimum effect and the dose that causes maximum effect is small, but if the curve become flattened the difference between the doses that cause the maximum and minimum effect is large and expanded.

Effective, Toxic and Lethal Doses

To understand figure (3) let's assume that we have 100 rat, we gave them X drug started with the lowest drug dose, as we increase this dose certain percentage of the rats will be responding to the drug, and as we increase the dose more percent of them will be responding to the drug, until we reach the dose with which all the rats response, from this graph we can calculate the dose which give us an effect in 50% of the tested animals, this dose is called ED50 (effective dose 50).

Figure (3)

Effective dose 50 is the dose which give us an effect in 50% of tested animals, when we continue rising the dose some of the animals start to have toxic effect of the drug, and as we increase the dose all the tested animals will have the toxic effect,
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again we can calculate TD50 (Toxic dose 50): which is the dose that shows toxic effect in 50% of the animals, and still we can increase the dose so some of the animals will die, and on certain dose all of them will die, similarly the dose which can kill 50% of the tested animals is called Lethal dose 50 (LD 50). Now the ratio between TD50 and ED50 is called therapeutic index or ratio which is the measure of the safety of the drug, so the equation will be: Therapeutic index or ratio = TD50/ED50 The higher the therapeutic index the more safe the drug is, and vice versa, for example Digoxin is drug with low therapeutic index, that means the difference between toxic dose and effective dose is small, while Paracetamol is regarded as very safe drug because the toxic dose is about 20 time the effective dose. I want you to understand the difference between therapeutic index and therapeutic range.

The Therapeutic Range

Therapeutic range is defined as the range between two serum drug concentrations one is high and the other one is low, the high one above which toxicity is more common and the low one below which therapeutic failure or the ineffectiveness of the drug is more common.
Figur(4)

So therapeutic range is range of serum drug concentration, while therapeutic index is a ratio between two doses.

Potency and Efficacy

Potency: It is the effect of the drug per unit of weight. Efficacy: It is the maximal Ceiling effect of the drug after which there is no increase in response even when the dose is increased. Figure (5) explains the meaning of potency, there is two drugs, codien and aspirin, which one is more potent? Codien, because it can produce the same effect in lower dose. Figure (6) represents the meaning of efficacy, which mean The maximum effect of the drug, we cannot increase the
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Figure (5)

effect of thiazide by increasing the dose after we reached The maximum effect, so fusimide here have more efficacy Than thiazide, why? Because frusimide can reach higher Figure (6) maximum Effect than thiazide.

Factors Modifying Drug Response

1. Size of the patient: In term of body weight, if we give the same dose to different patients who have different weights, those who have lower weight will respond better than those who have higher body weight, and that's why in some drug specially drugs with low therapeutic index we give them on body weight bases, mg per kg. Some times when we want to be more accurate we give the drugs on the bases of surface area of the body, because the surface area is more proportional with effect of the drug than the weight of the body, it's more proportional to basal metabolic rate of the body, and it's given as mg per m2. 2. Age of the patient: we have already explained this previously, and of course the two extremities of age should be given lower doses of the drug, because in infancy or the early childhood the enzyme system is immature, and in geriatric group the enzymes are aged. 3. Genetic factors (Polymorphism): also we have already explained it; we have given you these examples of isoniazid in the Eskimo and in the Egyptians. 4. Nutritional factors: malnutrition leads to low body weight and decreased enzymatic activity therefore increased drug effect, so in people who suffer from malnutrition should receive less dose than normal ones. 5. Race: it has been shown that Propranolol is less effective in lowering blood pressure in black patients. 6. Intercurrent diseases: as we have already discussed in metabolism of the drugs, advanced Kidney and liver diseases should receive less doses because the elimination of these drugs is reduced in these diseases, like gentamicin is impaired in case of renal diseases, morphine is impaired in case of liver diseases, and patient with respiratory diseases are highly affected by normal doses of morphine. 7. Sex: usually female respond more effectively than males for doses of the drug, and it's usually because of the body weight, because usually females have lower body weight than males of their same age, and the other factor is probably the hormonal factor. 8. Drug interactions: can play a role in determining the drug response

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9. Psychological factors: also can play a role, and it's sometimes called Placebo effect; we have two types of medication, active medication and placebo medication, for example a tablet of aspirin, not the whole tablet is aspirin, there is aspirin plus some additives called inert expanders, binding material and the aspirin, the placebo tablet of the aspirin is the same in color, in shape, in size, but it doesn't contain aspirin, this is called placebo preparation, and placebo preparation is regarded as a method for treatment or cure of patient by suggestion ) , (not by the actual effect of the drug, it depends on the psychological effect on the patient, and this is what is called placebo effect.
Let's talk now about the 8th one which is drug interactions:

drug interactions
when we administer two drugs, like drug A and drug B, the interaction between them could be: 1- Increased effect of each other which could be: a. Potentiation: for example Aspirin + codien will potentiate the effect of each other, so if we have 300 mg of aspirin + 10 mg of codien will have more effect than 600 mg of aspirin or 20 mg of codien, it's like 1+1>2. b. Addition: Aspirin + paracetamol, so 300 mg of aspirin + 500 mg of paracetamol we'll have an effect similar to 600 mg of aspirin or 1g of paraceramol.
2-Decreased effect: also called Antagonism, which have many types:

a. Competitive antagonism: 2 drugs have the same receptor as atropine + acetylcholine; atropine will displace acetylcholine from its receptor preventing it from producing its effect (one chair and 2 students competing on who sets on it, the stronger one will set, so the drug with higher concentration will displace the other). b. Physiological: 2 drugs acting on 2 different receptors, like epinephrine + acetylcholine, and one have the opposite effect of the other, for example let's take the effect of acetylcholine on the bronchi, it binds to cholinerenergic receptor on it causing the it to constrict, while epinephrine binds to adrenergic receptor on the bronchi causing bronchial dilatation, this is called physiological antagonist (two students pulling a rope, the net effect is on the stronger side).

c. Chemical: like we have already explained Heparine + protamine sulphate. d. Physical: charchoal + toxins, charcoal physically absorb toxins.

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Adverse Drug Reactions (ADRs)

Is defined as undesirable effects produced by therapeutic doses of the drug, they can be harmful which mean that we need dose reduction or even withdrawal of the drug, They may resemble a disease called Iatrogenic disease, so any disease which is caused by drug treatment is called iatrogenic disease. For example Cushing syndrome called be produced by chronic use of high dose of corticosteroids, this is called iatrogenic disease by corticosteroid therapy.

Types of ADRs
ADRs could be easily classified according to these letters: A- Augmented : ADRs result from exaggerated pharmacological response. For example: sever bradycardia can be caused by propranolol, Propranolol can lower the heart rate, but not so sever to induce bradycardia, but sometimes the patient receiving propranolol might have augmented effect of propranolol which is bradycardia, in which the pulse rate will be below 40 or 50. Another example is the hypoglycemia induced by insulin, the aim of insulin therapy is to normalize bold sugar level, but the most common side effect of insulin is hypoglycemia. B- Bizarre (strange): for example allergy or hypersensitivity which is caused by the use of penicillin, so it's cannot be explained on the pharmacological bases of the drug, or cannot be expected or predicted in any case. C. Continuous use of drugs: nephropathy which is produced by prolonged use of non-steroidal anti-inflammation drugs (NSAIDs). D. Delayed effect: some of the ADRs could be produced years after the intake of the drug, not only on the patient himself, but it has been found that Diethylstilbestrol, an estrogen product, can produce Vaginal carcinoma in daughters of the women who were taking this drug 30 or 40 years ago, so not only the women who have been taking the drug is affected. E. End of treatment.: also can produce AEDs, and the best example is sudden withdrawal of the beta blockers, anti-therapeutic drugs and corticosteroids, so not

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only the intake of the drug can produce ADRs, sudden withdrawal, or sudden stoppage of the drug can cause harmful effect.

Drug Tolerance
Is defined as Decrease in intensity of response after repeated use of the drug, the most famous example is tolerance to smoking, when the smokers start they start with one cigarette, and they end up with 2 or 3 packet, and this is due to the decrease in response to the drug or chemical after chronic use of it, this repeated using will lead to increasing the dose to have the same previous effect. Causes of the tolerance could be: 1- Kinetic: such as Barbiturates which can induce the microsomal enzyme system and subsequently increasing the dose to have the previous effect. 2- Dynamic: like most CNS drugs, which can cause habituation or adaptation of the CNS to these drugs.

3- Cross tolerance: like morphine and heroine, patient who is tolerant to morphine might be tolerant to a drug of the same group called heroine, and patient who are tolerant to alcohol might be tolerant to barbiturates.
Note: Tachyphylaxis: Rapid development of tolerance, for example Ephdrin, tolerance usually takes long take to develop, while tolerance to Ephdrin might be after few minutes or few hours, "tachy" means acceleration, like tachycardia.

Receptor Regulation
Upregulation: Increase in number or sensitivity of the receptors after prolonged treatment with an antagonist, let us chose Propranolol as an antagonist, patient who are receiving it for a long period of time, should be advised not to stop it suddenly, because after long period of treatment with it these receptors increase in both number and sensitivity, so the endogenous epinephrine will combine with these receptors and producing nearly fetal effect like sever hypotension and tachycardia. Downregulation: Decrease in number or sensitivity of the receptors after prolonged treatment with an agonist, prolonged treatment with sympathin (I'm not sure about the name) subsequently the receptor will be decreased in both the number and activity.

sry for not including any pic in the script but the it's the nature of this lecture. What a great loss for the class to lose some special students

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wish you the best of luck

^_^
Ammar Aldawoodyeh

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