General Principles Of Pharmacology PDF

# General Principles of Pharmacology Dr/ Eman Abdel Wahed Mohamed ## Pharmacology - It _is_ the science of drugs (Greek _pharmakos_, medicine or drug, and _logos_, study). - It can be defined as the study of substances that interact with living systems through chemical processes, especially by bin...

# General Principles of Pharmacology Dr/ Eman Abdel Wahed Mohamed ## Pharmacology - It _is_ the science of drugs (Greek _pharmakos_, medicine or drug, and _logos_, study). - It can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. - These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. ## Divisions of Pharmacology - **Pharmacokinetic:** what the body does to the drug (ADME). - **Pharmacodynamic:** what the drug does to the body. - **Pharmacotheraputic:** deals with the use of the drug. - **Toxicology:** branch of pharmacology, deals with the undesirable effects of chemicals and drugs on living systems. ## Drug - May be defined as any substance that brings about a change in biologic function through its chemical actions. - In the great majority of cases, the drug molecule interacts with a specific molecule in the biologic system that plays a regulatory role. This molecule is called a **receptor**. ## Source of Drugs ### Natural: - **Plant source:** Digoxin, morphine, atropine, pilocarpine - **Animal source:** insulin and heparine - **Minerals:** magnesium sulphate, ferrous sulphate and iodine. - **Microorganisms:** fungi and bacteria.....antibiotics as penicillin. ### Synthetic: - **Chemically:** barbiturate, sulpha, aspirin - **Genetic engineering:** (rDNA technology) e.g. Human insulin ## Drug-Body Interactions - The interactions between a drug and the body can be conveniently divided into two classes: - **Pharmacodynamic processes:** It deals with the biochemical and physiological effects of drugs and their mechanisms of action. - **Pharmacokinetic processes:** This includes absorption, distribution, metabolism and excretion of drug. ## Pharmacokinetics - It is the branch of pharmacology that is concerned with both the rates with which drug uptake and elimination proceed and with those processes that influence the time course of drug movement between one biological compartment and another. - The rates of absorption and distribution govern the time of **onset** of the drug's action; the rates of metabolism and excretion govern its **duration**; while the size of the dose, in combination with these effects, governs the **intensity**. ## Routes of drug administration - There are two major routes of drug administration, **Enteral** and **Parenteral**. ### Enteral 1. **Oral**: the commonest route, convenience, safe and economic. - **Not suitable for:** emergency (delayed onset), irritant drugs, comatosed and unconscious pt., GIT disturbance as in diarrhea or constipation. - **Drugs destroyed by:** gastric acidity (benzyle penicillin), or by digestive enzymes (e.g. Insulin). - **First-pass metabolism:** (Metabolism of the drug that occurs during transport from the gut lumen to systemic circulation) by the intestine or liver limits the efficacy of many drugs when taken orally. For example more than 90% of nitroglycerin is cleared during a single passage through the liver. 2. **Sublingual** - Placement under the tongue allows the drug to diffuse into the capillary network (superior vena cava) and therefore to enter the systemic circulation directly (rapid absorption). Administration of an agent by this route have the advantages, that the drug avoid the destruction by gastric enzymes, bypasses the intestine and liver and is not inactivated by metabolism (avoid 1st pass), and the excess drug can be easily removed from the mouth. - **Disadvantage of this route:** that is not suitable for drugs that cause V.C. of sublingual mucosa, or irritant. 3. **Rectal** - Useful when the oral route is unavailable due to vomiting or loss of consciousness. Suitable for children. The rectal absorption is irregular, incomplete and may cause irritation. ### Parenteral - Injections are employed if the drug is ineffective by other routes (e.g. adrenaline is destructive when given orally, streptomycin is not absorbed from the gut), when the drug has a local irritant action, or in emergency. 1. **Intravenous:** Most rapid and potent mode of administration, because 100% of drug enters the circulation, no first metabolism by the liver. Suitable for emergency, very irritant and large volume drugs. The drug must be aqueous only, sterile and pyrogen free. The effect of the drug is immediate. 2. **Intramuscular:** More rapid and complete absorption than with oral route. The drug is slightly irritant. Aqueous suspension, suspension or oily solution can be used. 3. **Subcutaneous:** this route of administration, like that of IM injection, requires absorption and is somewhat slower than the IV route. Used for non irritant drugs. Aqueous suspension, suspension or oily solution can be used. 4. **Intra-arterial:** diagnostic (e.g. arteriography) or therapeutic (thrombus dissolution). 5. **Intra dermal:** sensitivity test (e.g. penicillin). 6. **Intra peritoneal:** in peritoneal dialysis. 7. **Intra cardiac:** in cardiac arrest (e.g. adrenaline) 8. **Intra articular:** e.g cortisone in chronic arthritis. 9. **Intra bone marrow:** for blood transfusion in children. 10. **Intra thecal:** in case of acute CNS infections or spinal anthesia, drugs directly introduce into the cerebrospinal fluid (CSF). - **NB:** Subcutaneous implantation e.g. levonorgestrel (Norplant) provides effective contraception for 5 years. ## Other: 1. **Inhalation:** Inhalation provides the rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium, producing an effect almost as rapidly as by intravenous injection. Absorption from the alveolar membrane is extremely rapid because of its thinness, extensive surface area and also of its rich blood supply. - Used for administration of drugs in the form of gases, vapour, volatile liquids (as in anaesthesia), aerosols (isoprenaline aerosols) or powders. Some drugs may irritate the pulmonary epithelium. 2. **Topical:** applied locally to the skin e.g. corticosteroids. 3. **Transdermal:** a drug applied to the skin for **systemic effect** e.g.nitroglycerine. ## Absorption of Drugs - Absorption is defined as the ***passage of a drug from its site of administration into the plasma.*** It is therefore ***important for all routes of administration, except intravenous injection.*** - ***Drug passage across cell membrane*** - The body is basically a series of polar, aqueous media chambers separated by phospholipid barriers containing polar groups. ## Transport Mechanisms - The cell membrane basically consists of a phospholipid bilayers in which are embedded proteins (integral membrane proteins, such as receptors and transport molecules). - In terms of solubility, phospholipids are **amphiphilic:** the tail region containing the apolar fatty acid chains is **lipophilic**, the remainder - the polar head - is **hydrophilic**. - Phospholipids aggregate spontaneously into a bilayer in an aqueous medium, their polar heads directed outwards into the aqueous medium, the fatty acid chains facing each other and projecting into the inside of the membrane. - The hydrophobic interior of the phospholipid membrane constitutes a diffusion barrier virtually impermeable for charged particles. Apolar particles, however, penetrates the membrane easily. This is of major importance with respect to the absorption, distribution, and elimination of drugs. - Molecules that do not contain electrical charges (uncharged) or whose electron distribution is not distorted (nonpolar) are compatible with the nonpolar region of cell membranes (lipophilic part). i.e. dissolve freely in membrane lipids, and consequently diffuse readily across cell membranes. - For charged or polar molecules, the aqueous pores that exist within the protein channels can provide an alternate route. These pores allow the passage of some poorly lipid-soluble nonelectrolytes, as well as some charged molecules. However, they must be low in molecular weight. ### 1. Passive transfer - **Simple diffusion** - It takes place when a drug molecule moves from a region of relatively high concentration to low concentration without requiring energy (rate of passage is directly proportional to the concentration gradient and the surface area of the membrane, and inversely proportional to membrane thickness). - The xenobiotic must be lipid soluble and nonionized. The diffusion and movement of drugs continue until equilibrium has been achieved on both sides of the membrane. This equilibrium is achieved faster with highly permeable and hence lipid-soluble drugs, and when the membrane has a large surface area. The vast majority of drugs gain access to the body by this mechanism. - Simple diffusion depends on: - Lipid solubility and lipid water partition coefficient (↑↑↑P.O →↑↑↑ absorption). - Ionization which depend on: pH of the medium and pKa of the drug. - **Filtration:** - It occurs along hydrostatic or osmotic pressure gradient through large pores in endothelium and glomeruli. The drug is water soluble, MW is small, and free. - This type of transport not requires energy or carrier. ### 2. Specialized transfer. - **Active transport:** - It requires a specific membrane carrier and the expenditure of metabolic energy. Because of these requirements, the process can be inhibited by metabolic poisons, is saturable, and the carrier sites are subject to competition from other chemicals. However, active transport can occur against a concentration gradient. - Special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose. - A substance to be carried forms a complex with a component of the membrane (transmembrane protein) on one side; the complex is then carried through the membrane, the drug or substance is released, and the carrier returns to the original surface and state to repeat the process. - The carrier shows **specificity**; for instance, L-dopa but not D-dopa is transported. - **Facilitated diffusion:** - The transfer of drugs by facilitated diffusion has many of the characteristics associated with active transport, including being a protein carrier-mediated transport system that shows saturability and selectivity. - It differs from active transport, however, in that no energy input is required. In facilitated transport the movement of the transported molecule is from regions of higher to regions of lower concentrations, so the driving force for facilitated transport is the **concentration gradient**. - **Pinocytosis:** - In pinocytosis, the transport of water-insoluble substances such as vitamins A, D, E, and K is accomplished in the following manner. First, they are engulfed by the membranes; they are then dissolved in the membranes and released unchanged in the inside compartment. - Pinocytosis is **energy dependant**. | Mechanism | Direction | Energy Required | Carrier | Saturable | |:-------------------|:--------------------|-------------------|:-------|:----------| | Passive diffusion | Down gradient | No | No | No | | Facilitated diffusion | Down gradient | No | Yes | Yes | | Active transport | Against gradient | Yes | Yes | Yes | ## Factors Affecting Absorption 1. **Effect of pH on drug absorption:** - Hydrogen ion concentration (pH) has particular relevance to drug absorption since approximately 75% of all clinically utilized drugs can behave as either weak acids or weak bases (i.e., they can take up or release a hydrogen ion and become charged, polar entities). - **Generally, a drug will pass through cell membrane more easily if it is uncharged**. - Therefore, the amount of drug absorbed depends upon its ratio of charged to uncharged species, which is determined by the pH at the site of administration and the pKa of the drug (it is the pH at which 50% of the drug is ionized and 50% is unionized e.g. aspirin pKa is 3.5) - **For weak acid** - A neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion). - Acidic drugs are uncharged when protonated, the dissociation equilibrium can be expressed as follows: AHA¯+H+ - If the hydrogen ion concentration ↑↑ (pH becomes lower)→ ↑↑The drug in the nonionized form →↑ number of lipid-soluble molecules. - **For weak base** - A neutral molecule that can form a cation (a positively charged molecule) by combining with a proton. - Basic drugs are charged when protonated the equilibrium dissociation constant can be expressed as follows: BH+ B + H+ - If the hydrogen ion concentration ↑↑↑↑the drug in the ionized form. - Obviously, gastric absorption will be significantly curtailed. - The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule's pKa and the pH of the medium as follows: log (Protonated/Unprotonated) = pK−PH - The lower the pH relative to the pKa, the greater will be the fraction of drug in the protonated form. - Because the uncharged form is the more lipid-soluble, more of a weak acid will be in the lipid-soluble form at acid pH, while more of a basic drug will be in the lipid-soluble form at alkaline pH. 2. **Solubility of the drug:** - The ratio of hydrophilic to lipophilic properties (partition coefficient) that a drug has will determine whether the drug can permit cell membrane. - After oral administration, a drug may be incompletely absorbed, e.g, only 70% of a dose of digoxin reaches the systemic circulation. If a drug is too hydrophilic, the drug cannot cross the lipid cell membrane; if too lipophilic, the drug is not soluble enough to cross the water layer adjacent to the cell. 3. **Nature of the drug formulation:** - Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. 4. **Route of administration:** - Absorption from mucous membrane: alveoli > sublingual > S. intestine, rectum > stomach. - Absorption from parentral site: I.V. > I.M. > S.C. 5. **Total surface area available for absorption:** - The total absorptive area of the small intestine and its microvilli has been estimated to exceed 200 m² for the intestine versus 1 m² for the stomach. In fact, most drugs, whether nonionized or ionized, and whether acidic, basic, or neutral, are absorbed mostly from the small intestine. 6. **Blood flow to the absorption site:** - Blood flow to the intestine is much greater than the flow to the stomach; thus absorption from the intestine is favored over that from the stomach. Increasing the blood flow enhances the absorption of drugs, whereas decreasing the blood flow reduces absorption. 7. **Gastric Emptying Time:** - Because drugs are mostly absorbed from the upper part of the small intestine, the rate of gastric emptying plays a crucial role in drug absorption. If rapid absorption is desired, drugs should be taken on an empty stomach. - -Metoclopramide →↑ motility →↑ emptying→↑ absorption of rapidly disintegrated drugs such as propranolol and paracetamol and↓ absorption of slowly disintegrated drugs such as Digoxin. - -Atropine→→↓ motility→↓ emptying→↓ absorption of propranolol and paracetamol and ↑ absorption of Digoxin. 8. **Presence of food and other drugs (gut content):** - Meals, especially those with a high fat content, retard absorption - Some drugs also affects absorption of other drugs - e.g. Milk &antacid→↓ absorption of tetracycline. - Cholestyramine & Charcoal →↓ absorption of most drugs. - Tea & Tetracycline →→ Iron abs. 9. **Contact time at absorption surface:** - If a drug moves through the Gl tract very quickly, as in severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. 10. **Chemical instability:** - Some drugs, such as penicillin G are unstable in the pH of the gastric contents. Others, such as insulin may be destroyed in the Gl tract by degradative enzymes. ## In conclusion: - **Acidic drugs** - non-ionized in acidic medium (in stomach) → can absorbed in stomach. - In alkaline medium (intestine)→ more ionized & less lipid soluble - Acidic drugs can be reabsorbed again from renal tubules if urine is acidic, while alkaline urine enhances their excretion. - On the contrary; weak base drugs will be better absorbed from intestine & acidic urine enhance their excretion. - **Things to consider:** - If PH<pKa →↑ protonated form i.e. AH,BH+ - If PH > pKa →↑ unprotonated form i.e. A, B - The drug to be absorbed - unionized, uncharged, unpolar - The drug to be excreted - ionized, polar - **Weak Acid** in acidic media, pH < pKa - R.COOH (crosses membranes) - **Weak Acid** in basic media, pH > pKa - R.COO- + H+ (better cleared) - **Weak Base** - R.NH (better cleared) - **Weak Base** - R.NH, +H+ (crosses membranes) ## Other considerations: - The ratio of hydrophilic to lipophilic properties (partition coefficient) that a drug has will determine whether the drug can permit cell membrane. - Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption. - Absorption from mucous membrane: alveoli > sublingual > S. intestine, rectum > stomach. - Absorption from parentral site: I.V. > I.M. > S.C. - The total absorptive area of the small intestine and its microvilli has been estimated to exceed 200 m² for the intestine versus 1 m² for the stomach. In fact, most drugs, whether nonionized or ionized, and whether acidic, basic, or neutral, are absorbed mostly from the small intestine.