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Pharmacology DENTALELLE TUTORING WWW.DENTALELLE.COM CHAPTER TWO A REVIEW OF SOME DEFINITIONS • Pharmacognosy the study of the physical, chemical, biochemical and biological properties of drugs, drug substances or potential drugs or drug substances of natural origin as well as the search for new drugs from natural sources”. It is also defined as the study of crude drugs. • Pharmacology is the study of drugs. • Pharmacokinetics is the study of how a drug enters the body, circulates within the body, is changed by the body, and leaves the body. • Pharmacopoeia or pharmacopoea, in its modern technical sense, is a book containing directions for the identification of samples and the preparation of compound medicines, and published by the authority of a government or a medical or pharmaceutical society. WHAT IS THE BRIEF DEFINITION OF A “DRUG?” •Chemical substances used for the diagnosis, prevention, or treatment of a disease or •Any substance that affects biologic systems CHARACTERIZATION OF DRUG ACTION • Terms used to measure drug response or action: 1. 2. 3. DOSE-RESPONSE CURVE POTENCY EFFICACY 1. Log Dose Effect Curve • The effect a drug exerts on biologic systems can be related quantitatively to the dose of the drug given – A curve will result if the dose of the drug is plotted against the intensity of the effect Dose Effect Curve •dose vs the intensity of response In comparing two drugs, the doseresponse curve for the drug that is more efficacious would have a greater curve height The x-axis (horizontal) is an increasing dose of the drug, and the y-axis (vertical) is an increasing effect of the drug. Log Dose Effect Curve • If this curve is re-plotted using the log of the dose (log dose) versus the response, another curve is produced – The potency and efficacy of the drug’s action may be determined from this curve 2. Potency • the amount of drug required to produce an effect (related to a drugs strength) • Can be expressed in terms of the median effective dose, ED50 • ED50 is the dose of a drug required to produce a specific effect in 50% of the subjects or the dose that produces half the maximum effect Characterization of Drug Action Which curve represents a higher potency? The arrow is shaded proportional to increasing potency. (Dark shading, very potent; light shading, low potency.) Characterization of Drug Action The potency of drug A is greater because the dose required to produce its effect is smaller. The potency of B is less than A because B requires a larger dose to produce its effect Absolute Potency •The absolute potency of a drug is immaterial as long as an appropriate dose is administered Absolute Potency: Example • Meperidine (Eg: Demerol) and morphine are both used to decrease severe pain. HOWEVER, Approx. 100 mg of meperidine is required to produce the same effect as 10 mg of morphine THEREFORE, the absolute potency of oral morphine is 10X that of oral merperidine, OR meperidine is 1/10th as potent as morphine, even though both agents can relieve intense pain. 3. Efficacy • the maximum intensity of effect or response that can be produced by a drug (regardless of dose) • it is the ability of a drug receptor complex to produce an effect. Efficacy of Agent The efficacy of a drug as the height of the curve RECAP POTENCY EFFICACY • relationship between the dose of • the ability of a drug to produce a drug and the therapeutic effect the desired therapeutic effect (the drug’s strength) • the amount of drug needed to produce an effect • Related to the maximal effect of drug, regardless of dose • drug is considered potent when a small amount of the drug achieves the intended effect • means that the drug is effective • A potent drug is not always the most efficacious. (The text only provides examples). • In contrast, many drugs with high efficacy have a low potency (*this differs than the chart provided in the text – see previous slide) Characterization of Drug Action RECAP Potency Vs. Efficacy When comparing two drugs that work equally, the one with the lower dose has a higher potency. They have equal efficacy. Lethal Dose (LD) • Death is the endpoint when measuring LD • LD50 is the median lethal dose when one half of the subjects die – For obvious reasons, “Only” determined in animals. FYI for now – You will see this again in Ch.4 Some Basic Facts: AUTONOMIC NERVOUS SYSTEM (ANS) • Is not under conscious control involuntary • Provides stimulus for internal organs, smooth and cardiac muscle • Is further divided into: 1. Sympathetic Autonomic Nervous System (SANS) 2. Parasympathetic Autonomic Nervous System (PANS) CHEMICAL SIGNALING BETWEEN CELLS • There are different ways our brains transmit messages and commands to body parts for them to “do something” 1. Neurotransmitters 2. Local 3. Hormones Chemical Signaling Between Cells 1. Neurotransmitters • Messengers that move the electrical impulses from a nerve are transmitted across the synapse via neurotransmitters Chemical Signaling Between Cells Neurotransmitters • Responsible for communication between pre & post neurons or between neuron & effector organ (organs that have an effect on other organs) Chemical Signaling Between Cells Neurotransmitters • Are chemical messengers • Take place by the release of chemicals in the synaptic cleft • Neurons will interact with specific receptors • Receptors are usually found on the postsynaptic tissue • At least fifty different agents can transmit messages Chemical Signaling Between Cells Neurotransmitters For the neurotransmitter (or drug acting like a neurotransmitter) to complete the message, it must get inside the cell. After the drug binds with its receptor, the reaction often opens a channel so that the message can get inside the cell. Chemical Signaling Between Cells • 2. Local does not involve systemic circulation • Example: – Histamines can produce a localized allergic reaction – Prostaglandins contract uterine muscles and become important when a baby is born » When released in the stomach, they protect its lining Chemical Signaling Between Cells • 3. Hormones Secreted to produce effects throughout the body; but usually slower than the ones associated with neurotransmitters • E.g: – insulin, – thyroid hormone, – adrenocorticosteroids (naturally occurring compounds that are released by the adrenal gland). MECHANISM OF ACTION OF DRUGS • Drugs elicit a pharmacologic effect at site of action • Drugs do not impart a new function; they only produce either the same action as, or block the action of, an endogenous agent (growing from or inside the body) Mechanism of Action of Drugs Nerve Transmission • Transmission of impulses travels along the nerve producing a nerve action potential – The action potential is triggered by the neurotransmitter released at the previous synapse Mechanism of Action of Drugs Nerve Transmission • When a drug is delivered to the tissue cells, it goes through several steps • The first step in initiating a drug induced effect is the formation of a complex, or bond, between the drug molecule and the cell component called the drug receptor Mechanism of Action of Drugs Nerve Transmission • The receptor site where a drug acts to initiate a series of biochemical and physiologic effects is that drug’s site of action • The molecular event that follows this drug – receptor interaction is called the drug’s MECHANISM OF ACTION Mechanism of Action of Drugs Example: Injection of a Local Drug • Following the injection of a local anesthetic solution (delivery), epinephrine binds to its receptor on vascular smooth muscle (complex formation) and causes the muscle cell to constrict (drug-receptor interaction), resulting in vasoconstriction (mechanism of action) Mechanism of Action of Drugs Receptors • Drug receptors are large, highly specialized molecules that exist either on the cell membrane or within the cell • A single cell may have hundreds of different receptor sites • A drug may interact with a variety of different receptor types producing different pharmacologic effects Mechanism of Action of Drugs Receptors • Once a drug passes through a biologic membrane, it is carried to many different areas of the body, or site of action, to exert its therapeutic effect or adverse effect – To do this, the drug must bind with the receptor site on the cell membrane The neurotransmitter is transmitting the message (like electricity) across the synapse (space where nerve is absent). The neurotransmitter then interacts with the receptor (shaped to fit together), which then may signal an enzyme to be synthesized or activated. Mechanism of Action of Drugs Receptors • Different drugs often compete for the same receptor sites – – The drug with stronger affinity for the receptor will bind to more receptors than the drug with weaker affinity Drugs with stronger affinity for receptor sites are more potent than drugs with weaker affinity for receptor sites Mechanism of Action of Drugs Receptors and Affinity • Drug molecules are binding to receptors and breaking away from receptors • When a drug moves so close to its receptor that the attractive force between them becomes great enough to overcome the random motion of the drug molecule – the drug binds to the receptor • This is called AFFINITY Mechanism of Action of Drugs Receptors and Affinity Greater Affinity = Greater Potency ∴ ,a smaller dose required to cause a specific effect **potency is related to the affinity of a drug** Remember, morphine has a greater potency (smaller dose) than meperidine, thus morphine has a greater affinity than meperidine Mechanism of Action of Drugs Receptors • Drug molecules and their receptors must have similar structures - described as “lock and key” complementary fits – Only 1 drug can bind to a receptor at a time – 2 drugs cannot occupy the same receptor at the same time Mechanism of Action of Drugs Receptor: “Lock & Key” A, Drugs act by forming a chemical bond with specific receptor sites, similar to a lock and key. B, The better the “fit,” the better the response to produce a definable pharmacologic response. Drugs with complete attachment and response are called AGONISTS. C, Drugs that attach but do not elicit a response are called ANTAGONISTS. Mechanism of Action of Drugs AGONIST & ANTAGONIST • When a drug combines with a receptor, it alters the function of the organism: • These drugs are classified as either: 1. AGONIST 2. ANTAGONIST Mechanism of Action of Drugs 1. Agonist Characteristics: Has affinity for a receptor Combines with that receptor Produces an enhancement effect e.g., naturally-occurring neurotransmitters Mechanism of Action of Drugs 2. Antagonist Characteristics: Counteracts the action of the agonist But has no effect in the absence of an agonist It can only decrease the effect of the agonist Mechanism of Action of Drugs • 2. Antagonist 3 different types of antagonists: A. B. C. Competitive antagonist Noncompetitive antagonist Physiologic antagonist Mechanism of Action of Drugs 2A: Competitive Antagonists • A drug that: – – – – has affinity for a receptor combines with the receptor produces no effect competes with the agonist for the receptor Mechanism of Action of Drugs 2A: Competitive Antagonists • The antagonist binds reversibly with the receptor and could be displaced by excessive dose of agonist. • ↓ the potency of the agonist but does not alter its maximal effect. • The dose response curve shows parallel shift to the right. Mechanism of Action of Drugs 2B: Noncompetitive Antagonists • binds to a different receptor site than the agonist; does not displace agonist • ↓ the potency AND the maximal effect of the agonist • the dose response curve shows non-parallel shift to the right. . Mechanism of Action of Drugs 2C: Physiologic Antagonist • Has affinity for a different receptor site than the agonist – ↓ the maximal effect of the agonist by producing an opposite effect via different receptors – e.g. histamine & adrenaline (adrenaline for treatment of anaphylactic shock) Agonists and antagonists and their interactions 50 PHARMACOKINETICS The study of how a drug enters the body, circulates within the body, is changed by the body and leaves the body PHARMACOKINETICS • Factors that influence the movement of a drug are divided into 4 major steps: 1. 2. 3. 4. ABSORPTION DISTRIBUTION METABOLISM EXCRETION Pharmacokinetics Passage of Drugs Through Membranes • The physiochemical properties of drugs that influence the passage of drugs across biological membranes are: 1. lipid solubility 2. degree of ionization 3. molecular size & shape Pharmacokinetics Membranes • Before a drug is absorbed, transported & distributed to the tissues, metabolized, and eliminated from the body, it must pass through various membranes: – cellular – blood capillary These membranes share – intracellular physicochemical characteristics that influence the passage of drugs across their borders Pharmacokinetics Cell Membrane: Composition 1. Lipids (fats) – make membrane relatively impermeable to ions and polar molecules 2. Proteins – structural components as well as act as enzymes during the transportation process 3. Carbohydrates – combined with either proteins or lipids Pharmacokinetics Mechanisms of Drug Transfer Across Membranes 1.Passive Transfer 2.Specialized Transports a. Active b. Facilitated Pharmacokinetics Mechanisms of Drug Transfer Passive Transfer • is simple diffusion Specialized Transfer Facilitated Diffusion where a lipid-soluble • does NOT move substances move across Active Transfer across a the lipoprotein membrane • the substance is concentration • area of ↑ concentration to transported against a gradient area of ↓ concentration concentration gradient •involves transport of • dependent on drugs’ lipid or an electrochemical some macromelocular solubility gradient substances (ex. •Water-soluble molecules • process helped by Glucose) into cell small enough to pass transport carriers – which • blocked by metabolic through membrane pores supply energy to move inhibitors may be carried through drug pores by bulk flow of water • blocked by metabolic inhibitors Pharmacokinetics Passive Transfer Passage of drug and metabolite through membranes. A, Lipid soluble, nonionized: drug easily passes through the cell membrane from area of high to low drug concentration. B, Water soluble, ionized: drug cannot pass through the cell membrane. D, Drug. 58 Pharmacokinetics 1. ABSORPTION • The process by which drug molecules are transferred from the site of administration to the circulating blood – Requires the drug to pass through biologic membranes Pharmacokinetics Factors that influence the rate of absorption of a drug: 1. Physiochemical factors » » » Lipid solubility Degree of ionization Size (molecular weight) & shape of drug molecule 2. Site of absorption » » Determined by the route of administration Blood flow to the area of administration i.e. the more blood flow, the quicker the absorption 3. Drug Solubility » Drugs in solution are more rapidly absorbed than insoluble drugs Pharmacokinetics Rate of Transport Across Membranes • The following factors all aid (speed up) in the rate of transfer across membranes: 1. 2. 3. Non-ionized or uncharged Lipid-soluble pH↑ Pharmacokinetics Oral - Absorption • Unless the drug is administered as a solution, the absorption of the drug in the GI tract involves release from a dose form such as a tablet or capsule Pharmacokinetics Oral - Absorption Release of drug from tablet or capsule involves the following steps: 1. Disruption: initial disruption of coating or shell 2. Disintegration: must break apart 3. Dispersion: drug particles dispersed (must spread) throughout stomach & intestine 4. Dissolution: drug is dissolved in the GI fluids Pharmacokinetics Injection Site - Absorption Absorption of a drug from the site of injection depends on: 1. solubility of drug – ↑water solubility = increased absorption – affected by dose form – drugs in suspension (ex. Insulin) absorbed more slowly than in solution – drugs that are LEAST soluble will have the longest duration of action 2. blood flow at the site Absorption & L.A. When the acidity of the tissue ↑, (as in instances of infection), the effect of a local anesthetic ↓ Therefore, the local anesthetic is a weak bases. RATIONALE: Infections lead to an accumulation of acidic waste products, which lowers the pH of the local area. Local anesthetics must penetrate the nerve cell membrane to cause their action. They become more ionized as the pH drops. This property is a characteristic of weak bases Absorption & L.A. local anaesthetic (L.A.) L.A. tooth • ↓ pH • ↑ ionization • ↑ [H+] infection L.A. EG: Lidocaine’s pKa =7.9(Weak base drug) L.A.*Weak bases are better absorbed when the pH is greater than the pKa In the presence of infection, there may be a reduced clinical effect of L.A. due to the ↓’d pH level. The infection site is more acidic and more ionized and less likely to absorb the L.A drug (weak base). Pharmacokinetics 2. DISTRIBUTION • The passage of drugs into various body fluid compartments such as: intracellular fluids interstitial fluids plasma Pharmacokinetics Distribution • The manner in which drugs are distributed will determine how rapidly it will produce the desired response, duration of response or whether there is any response at all • Distribution is necessary for a drug to be made available at its site of action to exert its activity Pharmacokinetics Distribution All drugs occur in 2 forms in the blood: 1. free drug - the form that exerts the pharmacologic effect 2. bound to plasma proteins - reservoir (storage) for the drug • only the free drug can pass across cell membranes Pharmacokinetics • • • Distribution Drugs are also distributed to areas where no action is desired (nonspecific tissues) Some drugs are poorly distributed to certain regions Some drugs are distributed to their site of action and then redistributed to another tissue site OCCURS... “when a drug moves to various sites in the body, including its site of action in specific tissues” Pharmacokinetics Distribution Drug distribution is determined by: 1. size of the organ 2. blood flow to the organ 3. solubility of the drug 4. plasma protein binding capacity 5. presence of barriers (blood brain barrier, placenta) Drugs can move to various sites of the body, both: site of action & site of no action Pharmacokinetics Distribution & Half-Life Half-life (t1/2) • Amount of time that passes for the concentration of a drug to fall to one half of its blood level • • When the half-life is short, the duration of action is short When the half-life is long, the duration of action is long Pharmacokinetics HALF-LIFE Half-life constant throughout usual doses. Half of the dose of the drug in the body is removed with each half-life. #1, #2 … #5, Number of halflives that have passed. HOW MANY HALF-LIFE’s PASSED AT 1/8TH (12.5%)? Pharmacokinetics Redistribution • Redistribution of a drug is the movement of a drug from the site of action to nonspecific sites of action • a drug’s duration of action can be affected by redistribution of the drug from one organ to another Pharmacokinetics 3. METABOLISM (Biotransformation) • The body’s way of changing a drug so that it can be more easily excreted by the kidneys 3. METABOLISM (Biotransformation) • The liver is the main site for metabolism • Once the drug has gone through biotransformation, it is called a “metabolite” • Drug metabolism produces compounds that are more polar (ionized) and more easily excreted Metabolism 3 Mechanisms: Drugs are Metabolized by: 1. ACTIVE TO INACTIVE (the most common type) – drugs go into body active, are biotransformed in liver and come out inactive 2. INACTIVE TO ACTIVE – go into body inactive (termed prodrug), are biotransformed in liver and come out active (gives delayed response) 3. ACTIVE TO ACTIVE – go into body active, are biotransformed in liver and come out active in another form (gives prolonged effect) Pharmacokinetics 4. EXCRETION • Drugs can be excreted by any of several routes that have direct access to the external environment • Renal (kidney) excretion is the most important Pharmacokinetics Excretion MINOR SITES OF EXCRETION 1. Other: MAJOR SITES OF - Breast milk, sweat EXCRETION 2. Saliva: 1. Kidney – the main excretion route 2. Extrarenal Routes – - Usually swallowed 3. Gingival Crevicular Fluid (GCF): lungs, bile, GI tract, sweat, saliva, and breast milk –When drugs are excreted into GCF, there will be a higher level of drug in the gingival crevices –May ↑ usefulness of drug in the treatment of periodontal disease KNOW ALL ROUTES OF ADMINISTRATION AND EXAMPLES ROUTES OF ADMINISTRATION The routes of administration can be classified as enteral or parenteral • ENTERAL: drugs placed directly into the gastrointestinal tract (GI) by oral or rectal administration • PARENTERAL: drug administration bypasses the GI tract – EG. via injection, infusion, implantation, inhalation and topical administration Routes of Administration Route of administration affects onset and duration of response – ONSET: time taken for drug to begin to have effect – DURATION: the length of a drug’s effect Routes of Administration ADVANTAGES ORAL • simplest way to introduce drug into system • safest • least expensive • most convenient • forms for desired effects • small intestine gives large surface area for absorption • slower onset of action than parenterally administered agents DISADVANTAGES • stomach and intestinal irritation – nausea & vomiting • certain drugs are inactivated by the GI tract’s acidity & enzymes • blood levels of drugs less predictable due to food, pathological condition of GI tract & first-pass effect • drug interaction can occur when 2 drugs combined • requires client cooperation and time for effect Routes of Administration ORAL FIRST-PASS EFFECT: when drugs given orally, they pass through the hepatic (liver) portal circulation which can inactivate some drugs oral dose if first-pass effect THUS, THE LIVER IS INVOLVED IN THE “FIRST PASS” EFFECT AFTER AN ORAL ADMINISTRATION. Routes of Administration ORAL Dental Applications: 1. pain relief 2. prophylactic antibiotics 3. sedation 4. ↓ saliva flow – ex. Valium Routes of Administration RECTAL ADVANTAGES • used if client is vomiting or unconscious • can be used for local (hemorrhoids) or systemic (antiemetic) effect DISADVANTAGES • poor and irregular absorption in the rectum – thus, not used for systemic • client acceptance of this route is poor Routes of Administration INTRAVENOUS (into blood) ADVANTAGES • most rapid drug response – almost immediate onset of action • predictable response • best option for emergency situation • bypasses the liver • bypasses the absorption phase DISADVANTAGES • swelling around injection site • phlebitis (local irritation) • drug irretrievability • allergy • asepsis (to avoid infection) • painful • side effects related to ↑ plasma drug concentrations • expensive Routes of Administration INTRAVENOUS Dental Applications: 1.Emergency 2.General Anesthesia Since the injection is made directly into the blood, the absorption phase is bypassed. Routes of Administration INTRAMUSCULAR (into muscle) ADVANTAGES DISADVANTAGES • irritating drugs may be • not the “ideal” choice for clients tolerated with this route • less control of drug • drug suspensions absorption injected to provide a • long waiting time for onset sustained effect of action • less chance of an allergic response than IV route Routes of Administration INTRAMUSCULAR Dental Applications: 1.emergency – example: Epi-Pen **Intramuscular: absorption of drugs occurs because ↑ blood flow through skeletal muscles Routes of Administration SUBCUTANEOUS ADVANTAGES DISADVANTAGES • injection of solutions or • irritating solutions may suspensions into the cause sterile abscesses subcutaneous tissue to gain access to the systemic circulation • Ex. insulin Routes of Administration INTRADERMAL (into epidermis of the skin) ADVANTAGES DISADVANTAGES • small amounts of drugs • not a good route of administration for most such as local drugs anaesthetics (L.A.) can • drug amounts MUST be be administered small • example: TB skin test • example: allergy test Routes of Administration INTRADERMAL Dental Applications: 1. local anaesthetic (L.A.) 2. test for L.A. allergy Routes of Administration INTRATHECAL •injection into the spinal subarachnoid space – used for spinal anesthesia or treatment of meningitis Routes of Administration INTRAPERITONEAL • placing fluid into the peritoneal cavity where exchange of substances can occur • used for peritoneal dialysis (renal failure); helps to remove waste and excess water from the blood Peritoneum: membrane that lines the abdominal cavity & the abdominal organs Routes of Administration INHALATION (into the lungs) ADVANTAGES • used for local or systemic effect → local: asthma → systemic: general anaesthesia (G.A.) • quick onset • no needles DISADVANTAGES • easily misused: drug abuse (quick onset/ no needles) • absorption time and drug levels may vary Routes of Administration INHALATION Dental Applications: NB: Can also 1. dental nitrous-oxide (laughing be considered gas) Topical 2. emergency oxygen Routes of Administration TOPICAL (to body surfaces) DISADVANTAGES ADVANTAGES • if used on irritated • used for local or systemic effects (since most drugs do not penetrate intact skin) tissues, more chance of side effects • *rarely has systemic side effects (see ‘note’ section) • mucosal inflammation • ease of use increases the likelihood • used on the skin of systemic side effects (corticosteroid creams or • spray-type L.A. could transdermal patch), on the produce same blood oral mucosa (topical level concentration as anaesthetic) and I.V. sublingually (nitroglycerine) Routes of Administration TOPICAL What are Transdermal Patches? Designed to provide continuous controlled release of medication through a semipermeable membrane over a given period after application of drug to the intact skin – eliminates the need for repeated oral dosing. Examples: Routes of Administration TOPICAL Dental Applications: 1. Topical anesthetic – on oral mucosa 2. Sublingual (under tongue) spray/ tablet: no first-pass effect or GI acid degradation; systemic effects – ex. nitroglycerine 3. Emergency – nitroglycerine 4. Subgingival strips & gels: systemic effects are minimized because small doses can be used. ex. Atridox, PerioChip, Oraqix Routes of Administration Repeat slide • 1. 2. 3. 4. 5. 6. 7. Parenteral Routes Routes that usually bypass the GI tract Intravenous (IV) Parenteral describes the Intramuscular introduction of nutrition, a medication, or other substance Subcutaneous into the body via a route other Intradermal than that of ingestion. Intrathecal Inhalation Topical (sublingual & subgingival) Routes of Administration DOSE FORMS • The most commonly used dose forms in dentistry are the tablet and capsule given orally – Liquid solutions or suspensions are often prescribed for children • For injection, the drug may be in solution, such as local anesthetic, or it may be in suspension, such as procaine penicillin G FACTORS THAT MAY ALTER DRUG EFFECTS 1. Patient Compliance – does the patient take the drug? Do they take it correctly? May result from faulty communication, inadequate patient education, or the patient’s health belief system 2. Psychological Factors - The attitude of the prescriber and the dental staff can affect the efficacy of the drug prescribed – A placebo is a dose form that looks similar to the active agent but contains no active ingredients Factors That Alter Drug Effects Tolerance – the need to ↑ dose of drug to obtain the same effect as the original dose (i.e. drug addict) or a ↓ effect after repeated administration of a given dose of a drug 3. Cross-tolerance may occur with related compounds People under stress may need a larger dose for an effect – – *Tachyphylaxis – is an acute form of acquired tolerance (a very rapid tolerance to a drug -within hours) – • an acute (sudden) decrease in the response to a drug after its administration Factors That Alter Drug Effects 4. Pathological State – health of a patient. Patients with: – – hyperthyroidism are extremely sensitive to the toxic effects of epinephrine liver or kidney disease may metabolize or excrete drugs differently, potentially leading to increased duration of drug action 5. Time of Administration – time drug is administered, especially in relation to meals 6. Route of Administration – effect the onset or duration. Enteral routes are slower, less predictable, and safer than parenteral routes 7. Sex – females more sensitive than males (yes, we are ); likely due to smaller size of their hormones Factors That Alter Drug Effects Genetic Variation – variations in ability to metabolize drugs; certain populations have a higher incidence of adverse effects to some drugs—a genetic predisposition 8. Drug Interactions: – A drug’s effect may be modified by previous or concomitant (associated) administration of another drug 9. Age & Weight – due to variations of weight to age 10. Environment – affect action of drugs (i.e. smoking induces enzymes – therefore higher doses of benzodiazepines [eg. Valium] are needed to produce the same effect as compared with nonsmokers 11. Other – patient beliefs; the attitude of both the patient/provider can alter the physiology of the body 8.