PHARMACODYNAMICS-PHARMACOTHERAPEUTICS

Drug evaluation: a. Animal evaluation: through experiments conducted in animals b. Clinical evaluation: through clinical trials Pharmacodynamics includes: 1. Mechanism of drug action a. Receptor-mediated actions: the drug acts through interactions with particular receptors within the body. The action occurs in 2 steps: i. Binding: it is the interaction between the drug & the receptors ii. Signaling: it is the post-binding changes that mediate the drug action b. Non receptor-mediated actions: i. Actions on non receptor targets: the drug acts by interaction with cellular molecules that serve other cellular functions than being receptors ii. Chemical actions: the drug acts by its chemical properties e.g. electric charge or basic group iii. Physical actions: the drug acts by its physical properties e.g. osmosis or adsorption 2. Dose-response relationship a. Dose-response curves b. Factors modifying drug action Pharmacotherapeutics includes: 1. Prescription writing: which deals with a. Types of prescriptions b. Patient non-compliance 2. Therapeutic effects 3. Adverse drug reactions 4. Drug interactions

A drug is any substance used in treatment, prophylaxis or diagnosis of a disease and is recognized in a pharmacopoeia. During its life period it is given many types of names; first a chemical name that describes its formula, then it is given a code name during screening & initial evaluation. The promising drug is given a unique generic name. After delivering it for use, the company that sells it may give it another trade name e.g. Acetylsalicylic acid (chemical)= Aspirin (generic) = Rivo or Aspeol (trade). Animal evaluation: Pharmacological profile tests: to define the effects on various body organs and systems in more than one experimental animal species e.g. the effects on the heart, the effects on the CNS etc. Two types of experiments are used: In vitro experiments: conducted on isolated organs In vivo experiments: conducted on the whole animal Safety tests: to detect possible toxic effect for the drug Acute toxicity studies (< 24 hours experiments) e.g. to determine LD50 of the drug Subacute toxicity studies (days to weeks) Chronic toxicity studies: since the seventies, special types of chronic toxicities were required to test for mutagenicity, carcinogenicity, teratogenicity & addiction liability

Drug evaluation

Clinical Evaluation After researchers test new therapies in the laboratory and in animal studies, the experimental treatments with the most promising laboratory results are moved into clinical trials. A clinical trial is a research study in human volunteers to answer specific health questions. Clinical trials are sponsored or funded by a variety of organizations or individuals such as physicians, medical institutions, foundations, voluntary groups, and pharmaceutical companies, in addition to federal agencies such as the National Institutes of Health. Clinical trials help to address health issues in large groups of populations in natural settings. During a trial, more and more information is gained about an experimental treatment, its risks and how well it may or may not work. Clinical trials are conducted in phases. The trials at each phase have a different purpose and help scientists answer different questions: In phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. In phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. In phase IV trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use. To avoid biasing during trials, blind technique may be used. In single blind trials, the patient does not know if he is receiving the new drug or something else e.g. an old drug or a placebo. In double blind trials both the patient and the investigator do not know what is the treatment used. Number Small Number (20-80) Small Number (100-300) Large Number (1000-3000) Very large number Type of participant Healthy volunteers Patients Patients Patients Method of administration Non Blind Single Blind Double Blind Bind or non-blind

Phase Phase Phase Phase

I II III IV

Mechanism of drug action

Receptor-mediated mechanisms . Receptors are specific cellular macromolecules (usually proteins) that interact with a ligand (binding) to stimulate or block a response (signaling). The pharmacological actions mediated by the receptors are characterized by sensitivity (i.e. very small concentration of the ligand is enough to elicit the action), selectivity (i.e. each receptor has the type of ligand that can interact with it) & specificity (i.e. they elicit the same response each time they interact with the ligand). LIGAND BINDING Binding forces between the ligand & the receptor: 1. Covalent bonds: They are very strong bonds irreversible interaction with the receptors e.g. phenoxybenzamine & -receptors. This leads to long duration of action of the drug since recovery occurs only by synthesis of a new receptor. They may be also seen in non receptor mediated actions e.g. organo-phosphorous compounds & choline esterase enzyme, alkylating agents and DNA, omeprazole & gastric proton pumpsetc. 2. Electrostatic bonds: They are less strong bonds reversible interaction with the receptors. They are responsible for most drug receptor interactions. This leads to variable duration of action of the drug depending on how rapid the body gets rid of the drug since recovery occurs when the drug leaves the receptors. 3. Other types of bonds: a. Hydrogen bonds: They are similar to ionic bonds but occur between a hydrogen atom (which carries + charge due to its attachment to an electronegative atom e.g. O, N, S) and an electronegative atom. They are important in interaction between protein molecules or inside the double helical structure of the DNA. b. Van der Waals bonds: They are weak bonds between induced dipoles that arise from distortion of orbits of outer electrons when atoms are in close proximity. They are present between molecules of very large sizes. c. Hydrophobic bonds: They are characteristic type of bonds formed when a thin film of water encloses the 2 molecules e.g. between general anaesthetics & neuronal membranes. Types of ligands: 1. Agonist: the drug is called complete agonist if it has affinity (i.e. interacts with the receptor) and efficacy (i.e. the interaction pharmacologic effect). e.g. acetyl choline, norepinephrine, epinephrine, morphine 2. Partial agonist: the drug is called partial agonist if it has affinity but incomplete efficacy (i.e. the interaction with the receptor weak response e.g. succinyl choline, nalorphine, levallorphan 3. Antagonist: the drug is called antagonist if it has affinity but no efficacy (i.e. the interaction no pharmacologic effect) e.g. curare, naloxone. However; if the receptor is pre-occupied with an agonist; the displacement of the agonist will terminate its action.

There are 2 types of pharmacological antagonists: competitive antagonists where the antagonist competes with the agonist for the receptors & non-competitive antagonists where the antagonist can not compete with the agonist for the receptors. Types of pharmacological antagonists: Competitive antagonists Bind to the active site The duration concentration of antagonist Cause shift to the right in the dose-response curve i.e. Emax & the slope are not affected EC50 is increased Examples: atropine, curare, naloxone Theories of ligand-receptor Interaction: 1. Receptor occupation theory: The drug effect is proportional to the fraction of receptors occupied The maximum effect occurs when all receptors are occupied 2. Paton's rate theory: The drug effect is proportional to the rate of association/dissociation between the receptors & the drug. The maximum effect occurs with the highest association/dissociation rate. Non-competitive antagonists Bind to the allosteric site or irreversibly to the active site The duration rate of receptors turnover Cause downward shift in the dose-response curve i.e. Emax & the slope are decreased EC50 is not affected Example: Phenoxybenzamine

CELLULAR SIGNALING Cellular signaling involves 2 processes: 1. Transduction: it is the conformation change in receptors that makes the receptor interacts with other intracellular molecules multiple changes in other cellular proteins. Thus the most important function of transduction is amplification e.g. binding of epinephrine to 2-adrenergic activates 100 G-proteins activates 10000 adenyl cyclase enzyme activates receptors stimulate glycogenolysis leading to release of 1000000 glycogen phosphorylase enzyme 100000000 molecules of glucose 2. Response: it is the cellular activity, as enzyme catalysis, rearrangement of cytoskeleton (movement), or specific gene activity that follows transduction.

The most important signal transduction systems are: 1. G-Protein Receptors 2. Tyrosine Kinase Receptors 3. Ion channel Receptors 4. Non-membrane bound Receptors 5. Nitric Oxide Receptors

1. G-Protein Receptors The G-protein receptor is a peptide made of 7 transmembrane domains; with 6 loops connecting the transmembrane segments (3 extracellular & 3 intracellular). The G-protein binds to the 3rd cytoplasmic loop while the ligand binds to a site surrounded by 7 transmembrane domains. Nterminal end of the peptide is the extracellular tail and the C-terminal end of the peptide is the cytoplasmic tail. The G protein can bind with GTP (active form) or GDP (inactive form). Conversion from one inactive active form is triggered by ligand binding.

The G proteins are heterotrimers (i.e., made of 3 different subunits: G, G & G). There are at least 20 different kinds of G molecules; the most famous of these are: 1. Gs : It is linked to activation of adenylyl cyclase enzyme c-AMP. It is associated with the receptors for many hormones e.g. -adrenergic receptors for adrenaline, V2 receptors for vasopressin, glucagon, parathyroid hormone, ACTH & LH receptors. 2. Gi: It is linked to inhibition of adenylyl cyclase enzyme c-AMP. It is associated with the receptors for 2 adrenergic receptors for adrenaline, M2,4 receptors for acetylcholine and somatostatin receptors. 3. Gq (Gp): It is linked to activation of phospholipase C enzyme IP3 & DAG (IP3 Ca++ release & DAG PKC activation). It is associated with the receptors for 1 adrenergic receptors for adrenaline and M1,3,5 receptors for acetylcholine, V1 receptors for vasopressin, and AT1 angiotensin receptors.

2. Receptors linked to Tyrosine Kinase (RTKs) These are receptor proteins that have tyrosine kinase activity i.e., they can add a -PO4 group to tyrosine residues of inactive proteins making them active. Binding signal ligand e.g. insulin or growth factor causes 2 single tyrosine-kinases receptors to aggregate into a dimmer. Each unit of the dimmer first phosphorylates the others tyrosine residues. Then, the activated) phosphorylated dimer binds relay proteins, activating them which in turn (by cascade effect can activate up to 10 others etc. These relay proteins trigger the cellular response through either production of a second messenger or turning on gene expression.

Turning RTKs Off occurs by quickly engulfing and destroying the ligand-receptor complex by receptor-mediated endocytosis. Failure to stop responding to a signal e.g. for growth factor ). receptors could lead to uncontrolled mitosis ( cancer The insulin is the classic example of these receptors. It leads to phosphorylation of relay proteins called insulin receptors substrates (IRS) e.g. IRS-1 & IRS-2. These IRSs mediate the actions of insulin through phosphorylation of other cellular components e.g. glycogen synthase ( activates glycogen deposition in the liver) or hormone sensitive lipase ( inhibits fat cell lipolysis) etc. JAK-STAT receptors (for interferon, most interleukins, growth hormone, prolactin, and erythropoietin) are similar to RTKs but the pathway is much shorter so the response tends to be much more rapid. The dimer receptor activates a Janus kinase "JAK" which phosphorylates tyrosine residues of several Signal Transducer and Activator of Transcription "STAT proteins.

3. Ion channel Receptors The ion channel receptor is a protein pore in the cell membrane. It opens in response to binding a signal molecule e.g. a neurotransmitter as acetylcholine (Ach) or GABA. The opened channel lets extracellular ions flood into cell, changing its membrane potential & triggering very rapid response in the cell.

The nicotinic Ach receptor is the classic example. It is a pentamer made of 5 homologous polypeptide subunits: 1 2 . Each subunit is made of 4 membrane spanning regions (M1M4). Ach binds to the subunit and the adjacent subunit while the pore is formed by the 5 M2 subunits. Opening of this mixed Na+-K+ channel leads to entry of Na+ into and escape of K+ from the cell. This leads to induction of end plate potential (in skeletal muscles) or fast excitatory postsynaptic potential in the autonomic ganglia.

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4. Non-membrane bound Steroid Receptors These receptors are located intracellularly (cytoplasmic or nuclear). The action mediated by these receptors is very slow and occurs in 6 steps: 1. Ligand penetration through the cell membrane (the drugs which act by this mechanism should be lipophilic in nature). 2. Ligand binding to the ligand binding domain of the receptor ligand-receptor complex. However, this complex is inactive since heat shock proteins (e.g. hsp90) are bound to the DNA binding site. Dissociation of hsp followed by dimerization active homodimer 3. Nuclear translocation through the nucleopore. 4. DNA binding to glucocorticoid responsive elements (GRE) on the nuclear DNA 5. DNA activation initiates gene transcription mRNA synthesis 6. New protein synthesis mRNA passes to the ribosomes to initiate new protein synthesis which mediate the actions of the steroid ligand. (In case or cortisol; it is called lipomodulin or lipocortin since it activates phospholipase A2 enzyme to release arachidonic acid)

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5. Nitric Oxide (NO) Receptors NO receptors are protein receptors inside the cell. NO binds either to a metal ion or one of the S atoms (e.g. on cysteine) of the receptor. Binding triggers an allosteric change in the protein which, in turn, triggers the formation of a "second messenger" within the cell. The most common protein receptor for NO seems to be guanylyl cyclase enzyme that generates the second messenger cyclic GMP (cGMP). NO is synthesized within cells from arginine by the enzyme NO Synthase (NOS): 1. nNOS (or NOS-1): found in neurons 2. iNOS (or NOS-2): inducible NOS found in macrophages 3. eNOS (or NOS-3): found in the endothelial cells

It diffuses freely across cell membranes to interact with its receptors before being destroyed by phosphodiesterase enzyme. NO receptors are activated by many drugs that increase NO level e.g. nitrovasodilators (nitrites, nitrates as nitroglycerine & sodium nitroprusside) and phosphodiesterase inhibitors (e.g. sildenafil).

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Non receptor-mediated mechanisms . 1. NON RECEPTOR PROTEINS: Examples of drugs acting through enzymes: Aspirin inhibits cyclooxygenase enzyme (COX) Physostigmine inhibits ACh esterase enzyme Examples of drugs acting through cell wall or cell membrane: Penicillin antibiotic binds to penicillin binding protein of the cell wall Polyene antifungal drugs bind to ergosterol of the cell membrane Examples of drugs acting through ion pumps: Digitalis inhibits Na+/K+ ATPase (Na/K pump) Omeprazole inhibits H+/K+ ATPase (proton pump) Examples of drugs acting through microtubules: Colchicine (anti-inflammatory drug used in gout) binds to tubulin protein to inhibit neutrophil migration Vincristine (cancer chemotherapeutic agent) binds to tubulin protein to inhibit cell division Examples of drugs acting through ribosomes: Tetracycline & aminoglycosides (antibiotics) bind to 30s r-RNA Chloramphenicol & macrolides (antibiotics) bind to 50s r-RNA Examples of drugs acting through mitochondria: Niclosamide (antihelminthic drug) uncouples oxidation & phosphorylation

DRUGS CAN ACT BY CHEMICAL ACTION: 1. Antacids neutralize HCL in peptic ulcer 2. Citrates interact with calcium to inhibits blood coagulation 3. Protamine neutralizes heparin by its positive charge in treatment of heparin overdose 4. Chelation: This means the capacity of organic compounds to form complexes with metals chelates which are more water soluble easily excreted. This is useful in treatment of heavy metal poisoning. Examples: EDTA (calcium), BAL (mercury, arsenic, gold and antimony), Penicillamine (copper) Antithyroid drugs (copper), Disulfiram (copper) & Desferrioxamine (ferrous).

DRUGS CAN ACT BY PHYSICAL MEANS 1. Demulcents & emollients (e.g. olive oil) are used for dry skin 2. Adsorbent (e.g. kaolin & pectin) are used in diarrhea 3. Lubricants (e.g. liquid paraffin) are used in constipations 4. Osmosis e.g. Lactulose as osmotic purgative Mannitol as osmotic diuretics.

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Dose-response relationship Dose-response curves

The dose-response relationship can be represented graphically by 2 types of curves: the qualitative (All/None) dose-response curve and the quantitative (graded) dose-response curve 1. All/None dose-response curve is obtained if the percentage of patients who respond to the drug is depicted against log the dose e.g. the % of patients in whom the arrhythmia is terminated by different doses of an antiarrhythmic drug

Parameters that can be obtained from the All/None curve: 1) ED50: It the dose that cures 50% of cases. It is used for comparison between drugs e.g. the drug with lower ED50 is more potent than that with higher ED50. 2) LD50: If we are concerned about the toxicity of the drug we may draw the relation between the % mortality in animals treated by the drug (rather than the % responders) and the log of the dose. In such case the dose that kills 50% of animals is called LD50. LD50 gives an idea about the absolute toxicity of the drug i.e. the drug with lower LD50 is considered more toxic than the drug with higher LD50. Comparison between LD50 obtained by oral and IV administration can gives a rough idea about drug absorption (e.g. if LD50 oral is equal to LD50 IV; this means that bioavailability of the oral route is 100%). It can also give an idea about formation of toxic metabolites for the drug (e.g. if LD50 estimated after 72 hours is lower than LD50 estimated after 24 hours; formation of toxic metabolite is suspected. The site of action of the drug can be anticipated from observing the cause of death of the animals during conducting the experiments e.g. if the animals suffer from convulsions before death; the drug is expected to act on the CNS. The dose used should not exceed 10% of the estimated LD50. . It 3) Therapeutic index (TI): it is the ratio between ED50 & LD50 (i.e. TI = LD50/ED50) gives an idea about the safety of the drug (i.e. if the TI is large (i.e. the LD50 is much the drug is safer. Examples of drugs with narrow therapeutic higher than the ED50) index are aminoglycosides, anticoagulants, antiepileptics, hypoglycemic agents, lithium, quinidine, theophylline and tricyclic antidepressants 2. Graded dose-response curve is obtained if the degree of response is depicted against log the dose e.g. decreases of blood glucose against the dose.

Parameters that can be obtained from the graded dose-response curve: 1) Efficacy (Emax): is the maximal effect produced by the drug (= the maximum value of the dose-response curve) 2) Potency of the drug is assessed from 2 parameters: a. ED50: it is dose that produces 50% of the maximal response and is estimated similar to the All or none curve. The lower the ED50 the more potent the drug is. b. Slope of the middle portion of the curve (it reflects the effect of the drug produced by one unit of the dose. The steeper the curve (i.e. the higher the slope) the more potent the drug is.

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Factors modifying drug action

[1] Age: Younger patients can not tolerate the adult dose; accordingly the dose of the drug for the children should be reduced. Various methods & formulas are used for calculating the child dose: a. Surface area method: The child dose= Adult dose X Surface area (m2)/ 1.73 b. Age method: The child dose= Adult dose X Age (years) / age + 12 c. Weight method: The child dose= Adult dose X Weight (Kgs) / 70 d. Percentage method: The dose is calculated as a percent of adult dose: 1 month (12.5%) 2 month (15%) 1 year (25%) 2 years (33%) 7 years (50%) 12 years (75%) [2] Sex: Young females: certain drugs act specifically in the female organs e.g. sex hormone (estrogen & progesterone), ergot alkaloids & oxytocin Pregnant female: some drugs can cause teratogenicity e.g. thalidomide & antithyroid drugs. Lactating female: some drugs can pass to the fetus in milk e.g. ephedrine & phenobarbitone. [3] Pathological States: The presence of certain disease may make the patient more sensitive to certain drugs e.g. In bronchial asthma: -blockers asthmatic attack. In myasthenia gravis: competitive skeletal muscle relaxants and quinine myasthenic attack [4] TOLERANCE: Definition: It is reduced responsiveness to the drug on repeated administration so that higher doses are needed to produce the same effect. Mechanisms: Pharmacokinetic tolerance: it is tolerance due to decrease drug level e.g. Diminished intestinal absorption e.g. furosemide tolerance due to gut edema in Heart failure Diminished delivery of the drug to the site of action e.g. furosemide tolerance due to hypoalbuminemia in nephrotic syndrome or ascites Increased elimination of the drug e.g. increased metabolism due to enzyme induction with phenobarbitone Pharmacodynamic tolerance: it is tolerance without decrease of drug level e.g. Decreased sensitivity of the receptors e.g. opiates Decreased number of receptors [down regulation] e.g. 2-agonists as salbutamol Increased number of receptors [up regulation] e.g. H2-recptor antagonists as ranitidine Depletion of neurotransmitters e.g. depletion of dopamine with amantadine Increased release of the neurotransmitter e.g. increase Ach release with ipratropium Activation of counter regulatory mechanism e.g. salt and water retention with some antihypertensive drugs

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Special types of tolerance: a. Tachyphylaxis: It is acute tolerance but you can not get the same effect by increasing the dose e.g. tolerance due to depletion of norepinephrine from few doses of ephedrine b. Cross tolerance: It is tolerance to related drugs e.g. cross tolerance between different members of opioids or xanthine bases. [5] Psychological factors: Some patients may respond to a PLACEBO (an inert substance that closely resembles the active drug) the same way they respond to the active drug. The placebo may be used for psychological therapy and in control studies to differentiate the true effect of the drug from that 2ry to psychological factors [6] Drug interactions: The response to the drug may be affected by administration of another drug: Antagonism: decreased response by a second drug Synergism and potentiation: increased response by a second drug

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Prescription writing Types of prescribed medications: 1) Self-medication (OTC agents):

OTC (Over-the-counter) drugs are drugs dispensed without a prescription. They include drugs with high safety margin e.g. simple analgesics, antacids, laxatives, antitussives and expectorants nasal and oral decongestants and antihistaminics. Importance of OCT drugs: 1. OTC drugs may aggravate preexisting disease e.g. nasal decongestant in hypertensive patients 2. OTC drugs may cause drug interaction e.g. aspirin leads to bleeding in patients receiving warfarin 3. OTC drugs may lead to complications e.g. peptic ulcer with NSAIDs 4. The doctor can help the patient to choose the appropriate OTC drug in certain situations

2) Prescribed-only medication:
These are the drugs that can not be dispensed without a prescription. In Egypt, there are 3 types of prescriptions: 1. Ordinary prescription: used for drugs that needs specialist for prescribing e.g. digoxin 2. Special prescription: used for some drugs with low addiction liability e.g. sedative hypnotics. These drugs are called table II drugs 3. Narcotic prescription: used for drugs with high addiction liability e.g. morphine. The prescription forms are supplied by the local health authorities. The doctor writes 2 forms of the prescription (one to be kept by the dispensing pharmacist). This prescription can be dispensed only once within 5 days from its date. The drug dose is written both numerically & alphabetically. The patients and doctors identity are included clearly in the prescription.

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Patient Non-Compliance
Definition: Causes: Patients do not obey physician's instructions

1. Drug causes: e.g. Painful drugs Addicting drugs Complexity of the regimen 2. Doctor causes: e.g. Inefficient doctor Insufficient instructions Explanations with difficult medical terms 3. Disease causes: e.g. Disease associated with amnesia Asymptomatic disease (e.g. hypertension)

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Therapeutic effects of drugs

The prescribed drug may be 1. Curative i.e. get rids of the disease process e.g. Chloramphenicol 2. Symptomatic i.e. improve the symptoms while the disease process is not affected e.g. morphine 3. Prophylactic i.e. used in case of anticipation of a disease to prevent its occurrence e.g. chloroquin in malarial prophylaxis 4. Replacement i.e. replace a deficient element in the body e.g. vitamins & hormones.

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Adverse drug reactions

These are the harmful effects of the drugs. They are complicating 5 to 15 % of therapeutic drug courses. They are classified into: A) Type A or Augmented action: i. Intolerance (may occur at doses less than therapeutic dose): e.g. tinnitus after a single, small dose of aspirin due to a lower threshold to a normal pharmacologic action of the drug ii. Side effect (occurs at therapeutic dose) e.g. 5. Primary pharmacological action e.g. dry mouth from antihistamines 6. Secondary pharmacological action e.g. thrush while taking antibiotics iii. Overdose (occurs at doses slightly higher than therapeutic dose) e.g. seizure from excessive lidocaine iv. Toxic effect (occurs at very high doses) e.g. hepatotoxicity from acetaminophen B) Type B or Bizarre action: i. Allergic reactions: immune-mediated adverse effects ii. Idiosyncratic reactions: genetically-mediated adverse effects C) Type C or Continuous type: This adverse effect occurs only with prolonged use of the drug e.g. interstitial nephritis occurs with acetaminophen-aspirin combination for several years D) Type D or Delayed type: This adverse effect may occur even after cessation of drug use. There are 3 types i. Teratogenicity: It is drug-induced fetal malformations (Teratos = monster; genesis = production). It is caused by some drugs when given early in pregnancy when the organs are being formed (organogenesis). The most vulnerable period lies between the 3rd and the 10th week of intrauterine life. Major teratogens in humans: Thalidomide (phocomelia), cytotoxic drugs (abortion or fetal anomalies), I131 (fetal goiter), tetracyclines (dental enamel hypoplasia). ii. Mutagenicity: It is drug-induced gene abnormalities e.g. with metronidazole iii. Carcinogenicity: It is drug-induced neoplasm e.g. with IM iron or radioactive drugs E) Type E or End of dose adverse effects: These are adverse effects that occur after cessation of therapy e.g.: Withdrawal syndrome with morphine Acute Addisonian crisis with chronic corticosteroid therapy Ischemic Heart Disease after abrupt cessation of -blockers Hypertension after clonidine withdrawal Thromboembolism after withdrawal of oral anticoagulants Tardive dyskinesia after cessation of phenothiazines

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ALLERGIC REACTIONS Allergic reactions are adverse effects mediated by immunologic mechanisms. They are classified into: 1. Type I (immediate) hypersensitivity 2. Type II (cytotoxic) hypersensitivity 3. Type III (immune complex) hypersensitivity 4. Type IV (delayed, cell-mediated) hypersensitivity) 5. Non classified hypersensitivity 6. Pseudo-allergic reaction

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IDIOSYNCRATIC DRUG REACTIONS Idiosyncratic drug reactions are genetically-determined adverse reactions that are unmasked only by drug administration. Pharmacogenetics is the field of pharmacology concerned with the genetic defects that underlie the idiosyncratic drug responses. 1. Acetylation Polymorphism 2. Atypical pseudocholine esterase enzyme 3. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency 4. Cytochrome P450 system 5. Porphyrias 6. Malignant hyperthermia 7. Steroid Induced Glaucoma

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Drug interactions
Definition: It is the modulation of the pharmacologic activity of one drug (the object drug) by the prior or concomitant administration of another drug (the precipitant drug). Types: In these reactions, the pharmacologic properties of the object drug and/or the precipitant drug can be either enhanced or diminished: Potentiation: the combined effect drug A and Drug B = the effect of drug A + the effect of drug B (when used separately) Synergism: the combined effect drug A and Drug B > the effect of drug A + the effect of drug B (when used separately) Antagonizism: the combined effect drug A and Drug B < the effect of drug A + the effect of drug B (when used separately) Mechanisms of drug interactions: Pharmaceutical interaction: interactions that occur outside the body e.g. adding penicillin to streptomycin in the same syringe Pharmacokinetic interactions: interactions that affect the action of the drug 2ry to changing its blood level: 1. Absorption interactions 2. Distribution interactions 3. Metabolism interactions 4. Excretion interactions Pharmacodynamic interactions: interactions that affect the action of the drug without changing its blood level: 1. Synergism: e.g. antihistaminic drugs enhances sedatives action 2. Antagonism: e.g. aspirin reduces the diuretic action of loop agents Drug-nutrient interactions: Food decreases absorption of penicillin, tetracycline, erythromycin, levodopa, phenytoin, and digoxin. Food increases absorption of spironolactone, griseofulvin, and itraconazole. Vitamin K found in green leafy vegetables, tomatoes, coffee, beef liver, green tea and some nonprescription vitamin-mineral products can antagonize the anticoagulant effect of warfarin Vitamin B6 found in avocados, beans, peas, sweet potatoes, bacon, beef liver, pork, tuna, and some nonprescription vitamin-mineral products increases the metabolism of levodopa producing decreased antiparkinsonism effects Tyramine-rich food e.g. bananas, broad beans, cheese (especially aged), chocolate, coffee, figs, fish (smoked or pickled herring), processed meat (bologna, fermented meat, salami, pepperoni, summer sausage), liver (beef or chicken), raspberries, wines (especially red), yeast preparations, yogurt can lead to hypertensive crisis with monamine oxidase inhibitors.

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Sometimes, we can terminate the action of the agonists by drugs that do not interact with the receptors e.g. drugs which interacts with the agonist (chemical antagonism e.g. protamine sulfate and heparin) or interact with the other cellular components to produce an action opposite to that produced by the agonist (physiological antagonism e.g. epinephrine and histamine).

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The partial agonist is also called agonist-antagonist because if it is given when the receptors are empty (i.e. in absence of another agonist) it will stimulate the receptors (i.e. acts as a weak agonist) while if it is given when the receptors are occupied with another agonist it will displace it and produces a weaker action (i.e. it acts as a weak antagonist).

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Both the agonist and antagonist bind to the same site on the receptor. This type is usually reversible since the agonist can displace the antagonist from the receptors to terminate its action.

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The agonist and antagonist bind to different sites on the receptor. This type is usually irreversible since the agonist can not displace the antagonist from the receptors to terminate its action.

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Response Emax 1 2 3 Right shift

EC50

EC50

EC50

Dose (log)

1:Agonist alone 2 :Agonist + small dose Antagonist 3 :Agonist + high dose Antagonist

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Response Emax 1 Emax 2 Emax

3

EC50

Dose (log)

1:Agonist alone 2 :Agonist + small dose Antagonist 3 :Agonist + high dose Antagonist

Down shift

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The number of the receptors is not constant but the receptors are cycling (old receptors are internalized inside the cell and the new ones are externalized to the outside) and their number is continuously changing depending on the rate of recycling. Binding of the agonist increases receptor internalization the number of recruited receptors [down regulation] while binding of the antagonist the number of recruited receptors [up regulation]. It is to be noticed that only a small number of the cell receptors are recruited while the remaining is spare.

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Gs protein is also the target of the cholera toxin; binding of the toxin to Gs keeps it turned "on". The resulting continuous high levels of cAMP cause a massive loss of salts from the cells of the intestinal epithelium.

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The relay protein are first order protein kinases, thus initiating a cascade of activation of second order tyrosine kinases. The human genome encodes 90 different tyrosine kinases and in this way a cascade of expanding phosphorylations occurs within the cytosol.

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Targeting the pathway linked to tyrosine kinase receptors is now utilized in cancer treatment: 1) Monoclonal antibodies for EGF receptors are now applied in breast cancer treatment e.g. trastuzumab inactivates HER-2: Human Epidermal growth factor Receptor 2 & cetuximab inactivates HER-1: Human Epidermal growth factor Receptor 1. 2) Tyrosine kinase inhibitors e.g. gefitinib & erlotinib are used to block the action of the EGF receptors on the cells of certain lung cancers. 3) Second order tyrosine kinase inactivators e.g. imatinib mesylate inactivates the cytosolic tyrosine kinase ABL which is activated by platelet derived growth factor (PDGF) in chronic myelogenous leukemia.

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Sometimes we use the LD1 (the dose that kills 1% of animals) and ED99 (the dose which cures 99% of patients) instead of LD50 and ED50.

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It should be noted that low ED50 means a more potent drug but it does not essentially mean a more effective drug; efficacy of the drug is assessed by the Emax and not the ED50.

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If the adverse drug reaction takes the form of well known disease, it is called iatrogenic disease (drug-induced diseases) e.g. drug-induced bronchial asthma, peptic ulcer or Parkinsonism.

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Step-1: The allergen enters the body & is recognized by sIg on a B-lymphocyte. The B-lymphocyte then proliferates and differentiates into plasma cells.

Step-2: The plasma cells produce & secrete IgE. The Fc portion of IgE binds to the surface of mast cells and basophils.

Step-3: The next time the allergen enters the body, it cross-links the Fab portions of the mast cell-bound IgE

Step-4: This cross-linking triggers mast cell degranulation releases histamine & other inflammatory mediators early phase of allergic reactions that appears within minutes after exposure to the allergen.

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Possibly this is due to a higher number of Th2 cells which produce IL-4, a cytokine that can increase production of IgE, and a lower number of Th1 cells that produce gamma-interferon, a cytokine that decreases IgE production.

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Late phase allergic reactions may begin several hours after exposure to antigen. It is thought that basophils play a major role here. Cell-bound IgE on the surface of basophils of sensitive individuals binds a substance called histamine releasing factor (possibly produced by macrophages and Blymphocytes) causing further histamine release.

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Step-1: The Fab of IgG reacts with epitopes of host cell while phagocytes bind to its Fc portion.

Step-2: Phagocytes discharge their lysosomes causing cell lysis

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Step-1: IgG or IgM reacts with epitopes of host cell to activate the complement pathway.

Step-2: Membrane attack complex (MAC) then causing lysis of the cell.

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NK cells attach to the Fc portion of the antibodies & release perforins (pore-forming proteins) & granzymes (proteolytic enzymes) that pass through the pores to activate intracellular enzymes host cell apoptosis (destruction of the structural cytoskeleton proteins & degradation of the chromosomes). The cell breaks into fragments that are removed by phagocytes without releasing its contents.

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Step-1: Large quantities of soluble antigen-antibody complexes form in the blood & are not completely removed by macrophages.

Step-2: These antigen-antibody complexes lodge in the capillaries between the endothelial cells and the basement membrane.

Step-3: These antigen-antibody complexes activate the classical complement pathway vasodilation

Step-4: The complement proteins and antigen-antibody complexes attract leukocytes to the area

Step-5: Lysosomal discharge

massive inflammation & microthrombi formation.

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Step-1: Binding of CTL to a crossreacting normal cell triggers perforins, enzymes & chemokines.

Step-2: This leads to apoptosis followed by phagocytes

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Type I (immediate) hypersensitivity This is the most common type of hypersensitivity, seen in about 20% of the population. Mechanism: IgE is made in response to an allergen e.g. penicillin. In allergic individuals, the levels of IgE may be thousands of times higher than in those without allergies. Manifestation: 1) Localized anaphylaxis (the allergen is usually found localized in the mucous membranes or the skin) urticaria, angioedema, inflammatory pruritus, vomiting, diarrhea, bronchospasm 2) Systemic anaphylaxis (the allergen is usually picked up by the blood and the reactions occur throughout the body) anaphylaxis. Management: 1. Symptomatic treatment: Epinephrine (life saving in severe cases) vasoconstriction & bronchodilatation Corticosteroids: local (mild) or systemic (severe) Antihistamines Bronchodilators. 2. Preventive treatment: Cromolyn: inhibits histamine release Desensitization shots: are very dilute allergen given by injection stimulate the production of blocking antibodies (IgG & IgA) neutralize much of the allergen in secretions before binding to mast cells IgE. They also suppress IgE production by inducing tolerance &/or activating T8-suppressor cells. 3. Recent treatment: Injections of monoclonal antibodies against the Fc portion of human IgE can block its attachment to the Fc receptors on mast cells.

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Type II (cytotoxic) hypersensitivity Mechanism: specific IgG or IgM antibodies directed at drug-hapten coated cells. This leads to host cell lysis by either: a) Opsonization: b) Complement activation: c) Natural killer (NK) cells: Manifestation: Hemolytic anemia (e.g. alpha methyl dopa) Neutropenia (e.g. carbamazepine) Thrombocytopenia (e.g. quinidine) Management: Systemic corticosteroids Transfusion in severe cases

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Type III (immune complex) hypersensitivity Mechanism: This is caused when soluble antigen-antibody (IgG or IgM) complexes, which are normally removed by macrophages in the spleen and liver, form in large amounts and overwhelm the body. Manifestation: One or more of the following occur 1 to 3 weeks after drug exposure (e.g. methimazole): Serum sickness: fever, rash, arthralgia, lymphadenopathy, urticaria (a combination of type I & type III hypersensitivity) Vasculitis in various organs; it may also take the form of acute glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus etc Management: Consider: NSAIDs, Antihistamines & Systemic corticosteroids Plasmapheresis if severe

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Type IV (delayed, cell-mediated) hypersensitivity) T8-lymphocytes become sensitized and differentiate into cytotoxic T-lymphocytes (CTL) Manifestation: Presentation of drug molecules (e.g. topical neomycin) to T cells allergic contact dermatitis, maculopapular drug rash etc. It occurs 2 to 7 days after cutaneous drug exposure. Management: Consider topical corticosteroids & Antihistamines Systemic corticosteroids if severe

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Non classified hypersensitivity They are difficult to classify because of a lack of evidence supporting a predominant immunologic mechanism 1. Cutaneous drug reactions (i.e. maculopapular rashes, erythroderma, exfoliative dermatitis, and fixed drug reactions) 2. Specific Drug Hypersensitivity Syndromes e.g. Lupus-like syndrome with hydralazine & procainamide; anticonvulsant hypersensitivity syndrome with carbamazepine & phenytoin; Stevens-Johnson syndrome, toxic epidermal necrolysis with sulfonamides & anticonvulsants

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Pseudo-allergic reaction It is not true allergic reactions e.g. anaphylactoid reaction after radiocontrast media. It is similar to type I hypersensitivity but histamine release is not mediated by IgE.

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1. Acetylation Polymorphism Acetylation is a conjugation reaction catalyzed by N-acetyltransferase (NAT) that transfer acetyl group from acetyl Coenzyme A to the acceptor amine resulting in formation an amide. It determines the fate of aromatic amines (e.g. procainamide, sulfonamides), hydrazines (e.g. isoniazid INH, hydralazine) or some drugs without free amino groups but have an amino group introduced via metabolism (e.g. sulfasalazine, caffeine, nitrazepam, clonazepam). Acetylator polymorphism arises due to the existence of two NAT isoforms which are products of different genes: NAT1 is expressed in virtually all individuals NAT2 is expressed only in rapid acetylators. Approximately 90% in Middle Eastern people &, 50% of African-Americans are "slow" acetylators, a phenotype that is rare among Asians (10% in Japanese populations). Clinical significance: 1. INH-induced neurotoxicity: is the first recognized drug toxicity associated with slow acetylator status. It can be corrected with administration of vitamin B6 (pyridoxine). 2. INH-induced hepatitis: slow acetylators older than 35 years have a high risk for elevated hepatic transaminases (37%) compared with a moderate risk (13%) for rapid acetylators. However, the progress of the clinical picture to the jaundiced state did not differ between the 2 groups. In the young patients, the risk is much less but still higher in the slow acetylator group (13% vs 4%). 3. Phenytoin-INH interaction: INH non-competitively inhibits phenytoin hydroxylation causing reduced renal excretion and enhanced accumulation toxic reactions 4. Drug-induced systemic lupus erythematosus SLE: is similar to idiopathic SLE except there is no renal or CNS involvement. It occurs with smaller dose & shorter onset in slow acetylator receiving more than 35 different drugs many of which contain primary amino group; the most common are hydralazine & procainamide. 5. Sulfasalazine-induced hemolytic anemia: is more common in slow acetylators since it is hydrolyzed into sulfapyridine & 5-aminosalicylate; both are metabolized by Nacetylation.

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2. Atypical pseudocholine esterase enzyme Pseudocholine esterase is an enzyme synthesized by the liver and released to the plasma. It can hydrolyze ester bonds especially those of choline esters e.g. succinylcholine. Multiple allelic variants with lower affinity for succinylcholine have been identified at the cholinesterase gene locus: The W genotype is the normal genotype The K variant has about 30% lower activity (homozygotes: 1 in 3500) The S variant has no cholinesterase activity (homozygotes:1 in 100,000) Clinical significance: 1. Succinylcholine apnoea: Succinylcholine is a depolarizing type neuromuscular blocking agent of short duration of action because of rapid degradation by plasma pseudocholinesterase. Atypical plasma pseudocholinesterase causes prolonged muscular relaxation and apnoea lasting several hours after succinylcholine. 2. Cocaine toxicity: Cocaine and procaine are also hydrolyzed by cholinesterase. Forty percent of the fatalities associated with cocaine use in the clinical setting occur after an apparently safe dose due to atypical plasma pseudocholinesterase enzyme. A 50% decrease in cholinesterase may not be clinically significant for succinylcholine metabolism but is significant for cocaine toxicity. Procaine may induce much less common complications than cocaine since amides complex to procaine to slow its absorption from the site of injection. 3. Dibucaine Number (DN) Dibucaine is a local anesthetic that inhibits the pseudocholinesterase enzyme but the effect on normal cholinesterase is 20 times that of the atypical variant. The DN (the % inhibition under standardized conditions) is used as marker for patients with low pseudocholine esterase activity e.g. DN 78, normal (homozygous) DN of 40 - 70, intermediate group (heterozygous) DN 20, affected group (homozygous recessive)

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3. Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency Inheritance of G-6-PD deficiency is sex-linked: i.e. the defect is fully expressed in affected males and is never transmitted from father to son, but only from mother to son. In females, only one of the two X chromosomes in each cell is active. Consequently, female heterozygotes for G-6-PD deficiency have two populations of red cells; deficient cells and normal cells. The 2 common types identified are The American Blacks type: affects older red cells and is associated with mild hemolytic anemia. The Mediterranean type: affects younger red cells and leads to more severe hemolytic anemia. Clinical significance: 1. Drug-induced hemolytic anemia: is haemolysis on exposure to oxidant drugs (e.g. antimalarials, sulphonamides, aspirin etc.) due to decreased glutathione synthesis. 2. Some clinical diseases are associated with G-6-PD deficiency e.g. favism, hemolytic anemia occurring during infection, neonatal icterus, hereditary nonspherocytic hemolytic anemia

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4. Cytochrome P450 system Cytochrome p450 superfamily involves many isoforms. CYP2D6 is one isoform involved in the metabolism of many drugs; the first of them was the obsolete antihypertensive agent debrisoquine. Approximately 5-10% of the Caucasians are poor metabolizers (PM) of debrisoquine. This disorder is inherited as an autosomal recessive trait. On the other hand, some individuals have two or more copies of the CYP2D6 gene in which case CYP2D6 activity may be exaggerated. These are called hyperextensive metabolizers (HM). Biotransformation of at least 30 therapeutic agents has been shown to be impaired in individuals with the PM phenotype of CYP2D6. Clinical significance: 1. Debrisoquine-induced postural hypotension: PM phenotype may exhibit plasma debrisoquine concentration about 4 fold greater than normal individuals marked postural hypotension. Hypotension is also reported with many -blockers e.g. propranolol and with propafenone (an antiarrhythmic drug with -blocking activity). 2. Simvastatin myopathy: In PM; myopathy occurs more frequently & the patients can not tolerate therapy: homozygous for the wild-type allele 17 % did not tolerate therapy one mutated CYP2D6 gene 46% did not tolerate therapy two mutated CYP2D6 genes 80% did not tolerate therapy at a very low dose In HM due to multiplication of the CYP2D6 gene simvastatin fails to lower serum cholesterol 3. "Phenocopying phenomenon: Extensive metabolizers receiving inhibitors of CYP2D6 behave as if CYP2D6 activity were absent e.g. Uultra low dose quinidine increase the degree of -blockade in those receiving timolol eye drops SSRIs increase the incidence of side effects associated with tricyclic antidepressants

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5. Porphyrias The porphyrias are genetic or acquired deficiencies in the activity of enzymes in the heme biosynthetic pathway. Delta-aminolevulinate synthase (ALA synthase), is the rate-limiting & the first of the eight enzymes in the heme pathway. Deficiencies of one of the other seven enzymes reduced production of heme overproduction of heme precursors (in an effort to overcome the metabolic block) accumulation of intermediates prior to the deficient enzymatic step. All of the heme intermediates are potentially toxic & their overproduction causes the characteristic neurovisceral and/or photosensitizing symptoms of porphyrias. There are two tissue-specific isoforms of ALAS: 1. ALAS-N (the nonspecific; encoded by a gene localized on chromosome 3p21): its level in the liver is under positive feedback control (by porphyrogenic chemicals) and negative feedback control (by heme) i.e. the level of ALA-N increases when the liver needs to make more heme e.g. following induction of hepatic cytochrome P450 (since its prosthetic group contains heme), or hepatic heme oxygenase (since it enzymatically degrades heme). 2. ALAS-E (the erythroid encoded by a gene localized at Xp11.21): contains a functional iron responsive element (not present in ALAS-N); so it is upregulated by increased heme concentrations. Accordingly, there are 2 types of porphyries: those in which the genetic defect is limited to the liver (the acute hepatic porphyrias) and those in which the defect resides only in erythropoietic tissues (the erythropoietic porphyrias). In the hepatic porphyries -but not in erythropoietic porphyries- stimulation of hepatic ALAS activity (e.g. by induction of cytochrome P450 or heme oxygenase) exacerbates or initiates acute attacks, while increasing hepatic heme concentration (e.g. by infusion of heme or inhibition of heme oxygenase) induces clinical remission. Clinical significance: Most agents that exacerbate acute porphyria have the capacity to induce ALAS activity in the liver: drugs (e.g. barbiturates, sulfonanides) chemicals (ethyl alcohol), and hormones (e.g. estrogen)

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6. Malignant hyperthermia Malignant hyperthermia (MH) is an inherited myopathy characterized by a hypermetabolic state which is triggered when the patient is exposed to some anesthetic agents. A mutation in the ryanodine receptor (a calcium release channel) has been shown to cause MH in about 20% of affected human families. Other two mutations not involving the ryanodine receptor fc20 and fc34 - have been isolated and mapped and seem to cause MH-like responses. Inheritance of MH is autosomal dominant (i.e. 50% of children of MH susceptible parents are potentially at risk.

Clinical significance: Typically MH is triggered by succinylcholine or potent inhalational agents (halothane, isoflurane, enflurane, desflurane, sevoflurane) volatile anesthetics. Classic MH most often manifests in the operating room, but it can also occur within the first few hours of recovery from anesthesia. The syndrome is though to be due to a reduction in the reuptake of calcium by the sarcoplasmic reticulum necessary for termination of muscle contraction. Consequently, muscle contraction is sustained, resulting in signs of hypermetabolism, including acidosis, tachycardia, hypercarbia, glycolysis, hypoxemia, and heat production (hyperthermia). Management: When MH is diagnosed early and treated promptly, the mortality rate should be near zero. Whenever anesthesia is administrated, dantrolene should be readily available. It is the only known drug that treats MH. It impairs calcium-dependent muscle contraction and controls hypermetabolism manifestations.

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7. Steroid Induced Glaucoma Steroid-induced glaucoma is secondary open angle glaucoma due to topical or systemic glucocorticoid use. 25% of the general population will develop steroid-induced increases in IOP after 4 weeks of qid topical steroids. 5% of the population is "super-responders" - these patients develop pressure elevations greater than 10 to 15 mm Hg with topical steroid use and may develop a pressure rise within 2 weeks. Steroid induced glaucoma also occurs with oral steroids but the exact incidence is not well defined. Topical steroids should not ophthalmologist for IOP changes. be prescribed unless patient can be monitored by an

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Absorption interactions a. Due to altered GI pH-values e.g. antacids decreases the absorption of iron and opens the enteric coated preparations e.g. proton pump inhibitors b. Due to formation of insoluble complexes or chelated compounds e.g. antacids containing divalent & trivalent anions bind antibiotics (tetracyclines & fluoroquinolones) c. Due to binding to bile acid sequestrant drugs e.g. cholestyramine decreases absorption of digoxin/digitoxin, statins, loop diuretics, warfarin d. Due to altered GI function i. acceleration of gastric emptying e.g. metoclopramide enhances absorption of simple analgesics ii. slowing of gastric emptying e.g. atropine delays absorption of L-DOPA

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Distribution interactions a. Due to displacement from albumin binding e.g. NSAIDs displace warfarin and some members of the old generations oral hypoglycemic drugs b. Due to displacement from tissue binding e.g. quinidine displaces digoxin from the muscles

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Metabolism interactions a. Due to changes in hepatic blood flow e.g. propranolol (which decreases portal blood flow) will affect the metabolism of flow-dependent drugs (high extraction ratio drugs) e.g. lignocaine b. Due to changes in hepatic microsomal enzyme activity; the most famous examples are shown in this table Inducers Phenobarbital, phenytoin, rifampicin, dexamethazone Phenobarbital, phenytoin, rifampicin Phenobarbital, ethanol, rifampicin, dexamethazone Not identified Phenobarbital, phenytoin, rifampicin, nicotine Inhibitors Cimetidine, erythromycin, ketoconazole Cimetidine, SSRIs, mibefradil Cimetidine Ketoconazole, SSRIs, PPIs Cimetidine, SSRIs Cimetidine, erythromycin, ketoconazole, quinolones Substrates Astemizole, estrogen, -blockers, opioids Phenytoin, S-Warfarin, Valproic acid, Tolbutamide Diazepam, Rwarfarin, Theophylline

P450 3A4 P450 2D6 P450 2C9 P450 2C19 P450 1A2

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Excretion interactions a. Due to changes in glomerular filtration (by altering the renal blood) e.g. diuretics may alter the elimination of drugs eliminated by filtration e.g. aminoglycosides b. Due to changes in urinary pH (by altering passive reabsorption) e.g. acidifying urine with ascorbic acid increase serum phenobarbital levels, and alkalizing urine with antacids can decrease serum salicylate c. Due to competition with active transport in the renal tubules e.g. probenecid inhibits the excretion of penicillin d. Others e.g. diuretics leads to lithium retention because they decrease the level of sodium which competes for excretion with lithium and quinidine which is excreted by the kidney in preference to digoxin digoxin toxicity

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Drug interactions between bile acid sequestrant (i.e., cholestyramine and colestipol) and oral warfarin is due to 1) binding warfarin in the GI tract as well as 2) interfering with the enterohepatic circulation of oral anticoagulants. The first binding interaction can be greatly reduced by separating the doses and giving the oral anticoagulant product at least two hours before or six hours after giving cholestyramine. However, the effects on enterohepatic circulation cannot be avoided by separating the doses, and replacement therapies for cholestryramine should be considered. However, these therapies can be used concomitantly if the anticoagulant effect is closely monitored, and the binding resin and oral anticoagulant are consistently taken the same number of hours apart every day so that any interaction that may occur will be consistent and can be compensated for by titrating the dosage of warfarin.

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In some instances, predictable drug-drug interactions in patients are beneficial, and clinicians allow them to occur because they result in lower doses of the drug(s) being administered while still achieving therapeutic serum drug levels. For example, administering penicillins (renally-excreted) with the drug probenecid significantly elevates serum levels of penicillin and prolongs its half-life.

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