General Pharmacology

The Second Lecture Discussing some routes of administration of drugs and pharmacokinetics

Done By : Mu'ad Al-Zou'bi

Injections: 1- Intravenous (IV): - Bolous: the whole amount of the drug is given at once by using a syringe. - Infusion: the drug is given by an administration set, drop by drop. The advantages of intravenous injection: - It's a rapid route of administration. - We are going to be sure that the total dose, very large dose is administered to the patient. - It's suitable for irritant drugs because the drug is diluted by the infusion solution. The disadvantages of intravenous injection: - Sometimes it's difficult to find the suitable vein as in young children, or infants. - Any injection needs an expert unlike the oral administration. - The risk of toxicity is more common after intravenous injection because the effect is very rapid and the is a property called non-recall, after for example oral administration, a patient took a tablet and this patient had side effects of toxicity we can get rid of this tablet by inducing vomiting (this is recall) but after any injection there is a non-recall phenomenon, we cannot recall the injected. - They are more expensive because they need sterilization, a syringe & an expert. 2- Subcutaneous (SC): The advantages of subcutaneous injection: Classifying the drugs on the basis of - Self administration like the administration of insulin, the speed of absorption: diabetic patients will be trained to inject themselves 1- IV injection (the fastest) subcutaneously. 2- SC & IM injection (in between) 3- The oral method (the slowest) - Complete but slow absorption, slower than intravenous because in IV injection the drug will be directly put in the blood stream but in SC,IM and any other route of administration, the drug will transfer through various cell membranes and the number of these membranes will determine the speed of absorption. - Absorption of subcutaneously administered drugs could be delayed and duration of action of the drug could be prolonged by adding a vasoconstrictor, this is important for us as dentists, no dental procedure could be performed without the administration of local anaesthesia, and there are usually two types of local anaesthetics,pain and mixed types, pain local anaesthetics may have short duration (half an hour to one hour), if we want to prolong the duration of this local anaesthetic, we can either give higher doses of the drug or we mix the drug with a vasoconstrictor (such as adrenaline or noradrenaline), these vasoconstrictors will delay the onset of action and prolong the duration of action of the local anaesthetic because vasoconstrictors will delay the rate of absorption of the drug from the injected site. The disadvantages of subcutaneous injection: - Painful, any injection is a painful procedure. - Pain might be increased if the injected drug is irritant, this produces local irritation and local pain. - Unlike the IV injection where we can give a very large dose, in SC injection w can only give a limited, small dose.
Adrenaline = Epinephrine Noradrenaline = Norepinephrine

3- Intramuscular (IM): The advantages of intramuscular injection: - Larger volume than SC injection. - Depot or sustained release preparation are possible, the drug is released from the injected solution in the muscle very slowly, which is called extended release or slow release which can give us a long duration but unfortunately a slow onset of action The disadvantages of intramuscular injection: - Painful, any injection is a painful procedure. - Needs an expert. - Sometimes there might be erratic absorption (or unpredictable, the amount that will be absorbed cannot be accurately predicted) as phenytoin an diazepam. 4- Intrathecal injection: Giving the drug in the solution form into the cerebrospinal fluid (CSF), into the intrathecal space (the space between the arachnoid and pia mater). Itrathecal drug is usually given for the production of spinal anaesthesia, if we give a local anaesthesia, all the nereves below the site of injection will be anaesthetized, some patients cannot tolerate general anaethesia, and they need to perform an opereation in the leg, the hip, the bladder, or the appendix, for people who cannot tolerate general anaesthesia these operation could be performed by spinal anaesthsia or local anaesthesia inrathecally.

- Phenytoin is an antiepileptic or anticonvulsant. -Diazepam is a hypnotic and sedative (the trade name is Valium)

Inhalation : - Local effect - Bronchodilator - This inhaler that you see in the neighboring is used usually used for the treatment of bronchial asthma. - The canister contains the drug suspended in an inert gas under pressure, the drug might be in the form of solution or powder particles suspended in an inert gas, and pressing the valve against the canister, each time a constant amount of the drug will be released and the patient is asked to take deep breath (deep inspiration), so that the released drug will be directed into the lungs or alveolar spaces producing its effect by dilating the brochi which are already constricted in bronchial asthma. - Systemic effect General anaesthesia General anaesthesia is administered through an endotracheal tube which usually passes the larynx to the trachea, and here the anaesthetist (the person who is responsible for anaesthesia administration) will administer the endotracheal tube by means of the laryngoscope, and then the general anaethetic is administered through this tube as volatile liquid mixed with a carrier gas usually air or in oxygen.

The advantages of the inhalation method: - Rapid effect - No first pass effect The disadvantages of the inhalation method: - Some of the drugs might be irritant and in case of inhalation for the local effect by an inhaler might produce irritant cough. - Some particles may be precipitated in mouth or throat and might produce irritant cough. Topical : Local effect, such as eye drops applied on the eye, antiseptic solution applied on the skin, ointment, cream, lotion, gargle (patients with gingival or buccal region or throat region are asked to have gargle and usually antiseptic gargle to be used frequently for treatment of these sorts of disease) Systemic effect, for example, nitroglycerin ointment or skin patches, nitroglycerin will be absorbed directly to the blood producing its effect (it's used for the treatment of angina pectoris), in skin patches the drug is impregnated in an adhesive plaster and the adhesive plaster is stuck on certain area of the skin and the drug will be slowly absorbed from the site of administration (application). The topical method usually give high local concentration and effect with limited systemic and side effects especially if the topical formulation is intended to produce local effect such as the eye drops, ointment, cream, lotion and gargle. Absorption from the topical formulation could be increased when there are cuts or abrasions or the intact skin of the young children or infants (very thin skin).

Pharmacokinetics & Pharmacodynamics: Pharmacokinetics: it's what the body does to the drug. It deals with: absorption,distribution,metabolism and excretion (ADME) of the drug and the mathematical relationships of these parameters. So the drug to be useful it has to be absorbed into a fluid for dissolution then it has to be distributed from the site of absorption to the site of effect (the target site) and then the drug to be useful and safe it has to be removed after the production of its intended effect. Pharmacodynamics: it's what the drug does to the body. In another way it means how the drug produces its effect or by what mechanism of action the drug produces its effect. It deals with the pharmacological actions and the mechanisms by which these actions are performed. The pharmacokinetic processes: 1- Absorption: The passage of drug from site of administration (from out-side), after administering it through a suitable route of administration to the blood stream. To do so the drug has to pass through some cell membranes, but in case of IV administration, there is no process of absorption because the drug directly, immediately enters the blood, it does not pass through cell membranes to reach the blood, it will directly pass from the syringe or the infusion set to the blood.

The other routes of administration (than IV injection), some cell membranes (one or more) should be passed through by the drug to reach the blood stream. Cell membranes are composed of phospholipid bilayer and there are many pores inside this bilayer. The most important method of drug absorption is called passive diffusion or simple diffusion. Most effective drugs nowadays are electrolytes (either weak acids or weak bases), they are usually ionized, and the ionization usually is a reversible reaction, always there is a molecular fraction (M) and an ionized fraction (I). The molecular fraction is usually lipid soluble and less water soluble, while the ionized fraction is highly water soluble and less lipid soluble, this means that the highly lipid soluble fraction can easily move through the lipid bilayer of the cell membrane, while the highly water soluble fraction cannot move this lipid bilayer but only can move through the pores or channels through this bilayer, so for the drug to pass easily through the cell membrane, it has to be mainly in molecular fraction because it's highly lipid soluble. The movement of the drug through the cell membrane passively is dependent on these factors: - Concentration gradient direct proportion, the higher the concentration of the drug, the higher the rate and extent of absorption (the faster the movement of the drug through the cell membrane). - Lipid solubility direct proportion, the greater the lipid solubility (in other words, the greater the molecular fraction), the greater the rate and extent of absorption (the faster the movement of the drug through the cell membrane). - Degree of ionization indirect proportion or inverse proportion, the higher the degree of ionization (in other words, the higher the ionized fraction, the higher the ionization), the slower is the rate and the less is the extent of passing the drug through the cell membrane.

Hasselbalch Henderson Equation For acids pKa = pH + log M/I For bases pKb = pH + log I/M

Hasselbalch Henderson Equation M: the concentration of the molecular fraction I: the concentration of the ionized fraction. pH: of the solution in which the drug is dissolved.

Now, let's assume that a drug in a slolution is 50% ionized, this means that M/I equals one, log1=zero, so pKa=pH, how can we define pKa or pKb now ? Example 1: Aspirin is an acidic drug pKa = 3.4, - In the stomach pH = 1.4, 2 so 3.4=1.4+log M/I, log M/I=2, M/I=10 , M/I=100, M=100 I (molecular fraction is a hundred times the ionized fraction), that means that aspirin will be mainly in the molecular fraction in the stomach so, it can be easily absorbed from the stomach - In the duodenum pH 7.4, -4 so, 3.4=7.4+log M/I, log M/I= - 4, M/I=10 , M/I=1/10000, I=10000 M (aspirin is mainly in the ionized fraction in the duodenum, which is less absorbable) While it has been said that other factors can play a role in the absorption of aspirin, not only the pKa & the pH, aspirin has been said to be mainly absorbed in the intestines although the ionized fraction is greater, this is due to the very large surface area of the small intestines (it's been said that if we spread the inside surface of the intestines the

mucousa of the small intestines with its villi- , it will have the same surface area as a football yard), thats why the rate of absorption is fast, rapid from the small intestines. How does aspirin behave in urine pH = 6.4? pH=6.4, pKa=3.4 3.4=6.4+log(M/I), log(M/I)=-3, M/I=1/1000, I=1000M The ionized fraction of aspirine in the urine is a thousand times the molecular fraction. It will be easily excreted in the urine. Example 2: Ephedrine is a basic drug pKa =9.4 - In the stomach pH = 1.4, 8 8 so, 9.4 = 1.4 + log I/M , log I/M = 8 , I/M = 10 , I = 10 M - In the duodenum pH 7.4, so, 9.4 = 7.4 + log I/M , log I/M = 2, I/M = 1/100, I= 100 M How does Ephedrine behave in urine pH = 6.4? pH=6.4, pKb=9.4 9.4=6.4+log(I/M), log(I/M)=3, I/M=1000, I=1000M The ionized fraction of Ephedrine in the urine is a thousand times the molecular fraction. It will be easily excreted in the urine. Question What is the effect of acidification or alkalinization of urine on excretion of aspirin and ephedrine? 1- Aspirine (acidic drug): -Acidification, lowering the pH of the urine (pKa=pH+logM/I) pKa-pH pKa-pH pKa-pH) - log(M/I) = pKa-pH, M/I=10 , M=I x 10 , I= M/(10 - lowering the pH will increase the value of (pKa-pH), and increase the value of pKa-pH (10 ), and this means that the I value will decrese (dividing M on a greater number) - This means that the acidification of the urine will affect the excretion of an acidic drug by lowering the ratio of the ionic fraction which adversely affect excretion. - You can work it out the same way to complete the question !

We can make use of acceleration of elimination of acidic drugs by alkilinization in case of toxicity with acid, we need to enhance the elimination of the acid, this can be done by alkalinizing the urine simply by giving the patient sodium bicarbonate (NaHCO3) intravenously. In patients who are intoxicated with a basic drug for example Ephedrine, Clonidine, amphetamine, we can increase the urinary elimination rate of the drug acidification of the urine by the administration of ammonium chloride (NH4Cl) intravenously.

In general: - Alkilinization of the urine can enhance the urinary excretion of acidic drugs - Acidification of the urine can enhance the excretion of basic drugs - Alkalinization of the urine can take place by the administration of alkaline solution (sodium bicarbonate) intravenously. - Acidification of the urine can take place by the administration of acidic solution (ammonium chloride) intravenously.

This is the cell membrane which is composed of the lipid bilayer which allows the lipid soluble fraction to pass through and the protein channels (the pores) which only allows the water soluble ions to pass through. There's another method of absorption which is important for the minority of the drugs, the facilitated diffusion, this process requires a carries (carrier-mediated transport), for example, levodopa and iron are absorbed by this process. The other process, which is the active transport - Facilitated diffusion and active transport can pass against the concentration gradient (from the low concentration side to the high concentration side), that's why it either needs a carrier to take the drug from the low concentration side to the high concentration side against the concentration gradient or energy is spended to carry the drug from the low concentration side to the high concentration side, this energy is derived from the hydrolysis of ATP to ADP releasing one unit of energy which is used for the transfer of the drug against the concentration gradient

- In the passive, simple diffusion the drug passes with the concentration gradient (from the higher concentration side to the lower concentration side) through the cell membrane

The factors affecting the rate and degree of absorption: 1- The lipid solubility, the degree of ionization and the concentration gradient (discussed above) 2- The surface area (discussed above) 3- Transit time or gastric emptying time (the rate of passing of the drug from the stomach to the intestines), for a drug that's mainly absorbed from the intestines, the faster the transit time, the faster is the rate of absorption while for a drug that's mainly absorbed in the stomach the slower the rate of gastric emptying, the greater the rate and extent of absorption because will be retained in the stomach for a longer period of time. 4- Blood flow, the greater the blood flow to an organ or to a site of absorption, the faster are the rate and extent of absorption, and the less the flow to the administered site the slower is the rate of absorption and the longer is the duration of action of the drug (already mentioned in the example of mixing the local anaesthetic with a vasoconstrictor, the vasoconstrictor will delay the rate of absorption because it will decrease the blood flow to that area).

The terms which are related to the absorption of the drug: Bioavailability (F): The fraction of the unchanged unmetabolized drug, which reaches the systemic circulation following drug administration. Of course intravenous bioavailability is 100% (IV,F=100%), because the drug in an unchanged or unmetabolized form will be inside the blood, and as a definition of bioavailability.

The measurement of the bioavailability: These are two curves, the Y-axis represents the concentration of the drug in the blood, the X-axis represents the time following administration (the concentration-time curve). The area below the curve is called area under curve (AUC). For IV administered drugs: first (at t=0) the highest concentration because the whole amount will be inside the blood stream then the concentration starts to decline as the time passes (due to the process of metabolism and/or excretion). For another route of administration (in this example orally IV = Intravenous administered drug) we cannot see the highest concentration at zero time because the concentration of the drug in other routes of administration than IV is continuously increasing (unlike the IV administration which starts at the maximum concentration and then continuously and slowly decreasing),here there's an absorption process in which the drug is constantly and continuously increasing in concentration until it will reach the peak (the highest point or concentration) then the processes of metabolism and elimination will exceed the process of absorption so that the concentration of the drug will be constantly declined. The bioavailability of the drug can be measured by giving it in two different routes (but one of them should be intravenous route because it will give the bioavailability of 100%), then the bioavailability could be measured by this equation: F = AUC oral/ AUC IV (it's not limited to the oral rout just as an example) An important note: different routes and different brands give different bioavailabilities . Different routes: enteral, parenteral, topical etc., each route of administration even when we take the same dose of the same drug by different routes can give us different bioavailabilities. Different brands: the trade names, even for a drug which is synthesized or produced by these different companies even it has the same constituents it might give us different bioavailabilities due to differences in manufacturing processes of these drugs and usually depends on the particle size of the drug, the finer the particles of the drug, the larger the total surface area of the drug and the faster is the rate of absorption. For drugs with a very low therapeutic index (a very low margin for safety) it should be advised that brands and routs of administration shouldn't be exchanged, a patient who is treated on certain route of administration shouldn't be shifted to another route because other routes can give different bioavailabilities, either more or less, if it's more, it might give us high incidence of toxicity, if it's less, it might give us high incidence of therapeutic failure, and the same is true for changing the brand or the trademark.

PO = Per Oris

The factors of incomplete bioavailability (why bioavailabilities are variable): Usually intravenous route gives us F=100% but other routes usually give less than 100% this deficit in bioavailabilities is due to some factors: 1- Acid liability: for some drugs the bioavailability is reduced because they are acid labile for example benzyle penicillin, it cannot be taken orally because it could be easily destructed by gastric acids, that's why it's given by injection, acid liability is a factor which can lower the bioavailability of some drugs. 2- The incomplete absorption: a drug might not be completely absorbed, for example some drugs taken after a heavy meal, they are not completely or totally absorbed so their bioavailabilities will be limited. 3- Metabolism by enzymes in the gut wall or the liver with the process called (first pass effect or first pass metabolism), for example glyceryl trinitrate (nitroglycerin).
First Pass Effect: the metabolism of orally administered drugs by gastrointestinal and hepatic enzymes, resulting in a significant reduction of the amount of unmetabolized drug reaching the systemic circulation.

For orally administered drugs mainly, the drug will pass through cell membranes of the GI tract and the to the portal circulation and the to the liver and then to the systemic circulation, during the passage of the drug through the GI tract, the portal circulation and through the liver, some of it might be changed or metabolized, so the amount of unmetabolized or unchanged drug will be decreasing as the drug is reaching the systemic circulation, this process is called first pass effect, that's why for example nitroglycerin is not effective when it's taken orally because more than 95% of nitroglycerin will be metabolized or destructed the first pass effect, this oral route can be bypassed either by giving the drug by injection or sublingually (as in case of nitroglycerin). First pass metabolism is not limited to the oral route (certainly all the drugs which are given orally can pass through the portal circulation and might be exposed to the first pass effect), any route which might pass through the portal circulation to the liver might be exposed to first pass effect (in some patients even the rectal administration although the majority of the venous drainage of the rectum is through the systemic circulation but some of it might be through the portal circulation).
- Orally administered drug is highly exposed to the first pass effect because it has to pass through the portal circulation. -Rectally administered drug is partially exposed to metabolic first pass effect. - The other routes of administration cannot be exposed to the9 first pass effect simply because they don't pass through the portal circulation.

The process of first pass effect can be bypassed or circumvented by giving the drug in other route of administration than the oral one.

2- Distribution: the movement or carriage of the drug from the site of absorption to the site of effect (target organ). It is the process by which a drug reversibly leaves the blood stream and enters the extracellular fluid and then the cells of the tissues (the target cell or the effector cell). Factors affecting distribution: 1- Blood flow 2- Capillary permeability - The higher the blood flow and the greater the capillary permeability, the faster is the rate of distribution and vice versa. 3-Binding of drug to plasma proteins and tissues, binding of drug to plasma proteins means limiting the drug to the intravascular space and only small portion of the drug will move to the tissue and the opposite is true, drugs with low protein binding they move through the cell membranes to the extracellular fluid and to the cellular spaces so that their concentrations are very low in the blood. 4- Hydrophobicity or lipophilicity : the greater the hydrophobicity (lipophilicity), the faster is the rate of distribution. Plasma protein binding: P+D PD

P=Plasma protein D=Free unbound drug PD=Bound drug to protein (plasma protein-drug complex) It's a reversible reaction, at any moment, there's a free protein molecule, a free drug molecule and plasma protein-drug complex.

Only the free unbound drug fraction can pass membranes and producing effect, metabolized and excreted (passes the membrane, combine a receptor producing an effect, passing membrane to the liver for example will be accessible for metabolism, passing membrane in the kidney will be accessible for renal excretion). The bound fraction cannot pass cell membranes, so the bound fraction is not effective, could not be metabolized, and could not be excreted. Acid drugs usually bound to albumin which is a major plasma protein, while basic drugs usually bound to 1 acid glycoprotein.

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Note:
- The passive diffusion includes (the simple diffusion and the facilitated diffusion), both of them follow the concentration gradient but they differ in the need for a carrier or channel protein. - The active transport is the process which can transport materials against the concentration gradient. I mentioned this note because I think the doctor mentioned something different as you'll find in this lecture, so I preferred to mention this and leave the mission of making sure of this information to you, you can ask the doctor (I think it's just a kind of forgetting or a mistake).

! ) ( ""

- I tried my best, please forgive me for any mistake or shortage in information (if present) ! " Mu'ad Al-Zou'bi"

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