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  1. Therapeutics Dr Monem Makki Alshok Department of Medicine
  2. References n Davidson’s Principle and Practice of Medicine 3rd edition 2018 n Clinical Pharmacology and Therapeutics Fifth edition edited by Roger Walker and Cate Whittlesea n Cecil’s Essentials Of Medicine . 10th edition 2022 n Current Medical Diagnosis and Treatment 61th edition2022 n Applied Therapeutics the clinical use of drugs 9th ed .
  3. Drug use process (DUP) indicators n Indication for drug therapy n Select drug consider most appropriate drug based on the ability to reach therapeutic goals , consideration of patient variable and cost n Regimen used n Adminstration n Moniter Drug therapy n Evaluate effectiveness
  4. Case presentation n Mr Ahmed, a 67-year-old retired person, has recently moved to your area and has come to the pharmacy to collect his first prescription. He has a PMH of coronary heart disease (CHD) and has recently had a coronary artery stent inserted. He has a long history of asthma which is well controlled with inhaled medicines. Mr Ahmed gives a complete medication history that indicates he takes his medicines as prescribed, he has no medication-related allergies,but does suffer from dyspepsia associated with acute use of NSAIDs . H e has a summary of his stent procedure from the hospital that indicates normal blood chemistry and liver function tests. n Consider drug use process?
  5. What drug–patient, drug–disease and drug– drug interactions can be anticipated ? Drug–drug interactions Drug–Disease interactions Drug–patient interactions Medicines Combination of antiplatelet agents increases risk of bleeding Aspirin should be used with caution in asthma Previous history of dyspepsia Aspirin Previous history of dyspepsia Clopidogrel Possible increased risk of myopathy if simvastatin given with diltiazem Statins Combination of different agents to control angina may lead to hypotension β-Blocker contraindicated in asthma B blockers Steroid inhalers
  6. What drug–patient, drug–disease and drug– drug interactions can be anticipated ? Drug – drug interaction Drugs – Disease interaction Drugs – Patient interaction Medicines Reduces metabolism of simvastatin thereby increasing the risk of side effects Diltiazem Previous history of side effects (e.g.headache, flushing) may result in patient not using spray when required Nitrates (GTN spray) Patient's ability to use inhaler deviceseffectively β2-Agonist inhalers Antimuscarinics may reduce effect of S/L nitrate tablets (failure to dissolve under tongue owing to dry mouth) Antimuscarinic agents can cause tachycardia and atrial fibrillation Antimuscarinic inhalers
  7. The case of Mr Ahmed : monitoring criteria and patient advice Ask patient about any symptoms of dyspepsia or worsening asthma Aspirin Ask patient about any symptoms of dyspepsia Clopidogrel If PPIs don't resolve symptoms, primary care doctor should be consulted Lansoprazole Liver function tests 3 months after any change in dose, or annually Creatine kinase only if presenting with symptoms of unexplained muscle pain Cholesterol levels 3 months after any change in dose, or annually if at target Simvastatin Frequency of use to be noted. I ncreasing frequency that results in a resolution of chest pain should be reported to primary care doctor and anti-anginal therapy may be increased ANY use that does not result in resolution of chest pain requires urgent medical attention Nitrates (GTN spray) Blood pressure and pulse monitored regularly Diltiazem
  8. The case of Mr Ahmed : monitoring criteria and patient advice Contin. Renal function and blood pressure monitored within 2 weeks of any dose change, or annually Ramipril Drugs that may have been prescribed for asthma Salbutamol use should be monitored as any increase in requirements may require increase in steroid dose Salbutamol inhaler Monitor for oral candidiasis Beclometasone inhalers
  9. The case of Mr Ahmed : possible therapeutic regimen Rational Recommendation Medicine Benefit outweighs risk if used with PPI 75 mg daily orally o.d. after food Aspirin Benefit outweighs risk if used with PPI Length of course should be established in relation to previous stent 75 mg daily orally o.d. after food Clopidogrel Decreases risk of GI bleeds with combination antiplatelets Concerns about some PPIs reducing the effectiveness of clopidogrel makes selection of specific PPI important 15 mg daily orally Lansoprazole Low dose selected due to diltiazem reducing the metabolism of simvastatin and increasing the risk of side effect 20 mg daily orally Simvastatin 2 puffs sprayed under the tongue when required for chest pain Nitrates
  10. The case of Mr Ahmed : possible therapeutic regimen—cont'd Rational Recommendation Medicine Used for rate control as β-blockers contraindicated in asthma 90 mg m/r twice a day Diltiazem To reduce the progression of CHD and heart failure 10 mg daily Ramipril Patient should follow asthma treatment plan if peak flow decreases puffs (200 μcg) to be inhaled when required t Salbutamol inhaler Asthma treatment plan which may include increasing the dose of inhaled steroids if peak flow decreases 2 puffs (400 μcg) twice a day Beclometasone inhalers CHD, coronary heart disease; PPI, proton pump inhibitor; GI, gastro-intestinal; m/r, modified release.
  11. Principle of clinical Pharmacy & Therapeutics : n Pharmacodynemic : what the drug does to the body . n Pharmacokinetic : what the body does to the drug .
  12. Pharmacodynamics * Drug targets and mechanisms of action : 1 . Affinity : describes the propensity for a drug to bind to a receptor 2 . Selectivity describes the propensity for a drug to bind to one target rather than another . 3 . Agonists bind to a receptor to produce a conformational change that is coupled to a biological response 4 . Antagonists bind to a receptor but do not produce the conformational change that initiates an intracellular signal.
  13. * The dose–response relationship varies between patients because of variations in the many determinants of pharmacokinetics and pharmacodynamics. n Efficacy describes the extent to which a drug can produce a target-specific response when all available receptors or binding sites are occupied n Potency describes the amount of drug required for a given response. * Therapeutic Index :The ratio of the ED50 for therapeutic efficacy and for a major adverse effect is known as the ‘therapeutic index’.
  14. * Desensitization and withdrawal effects n Desensitisation refers to the common situation in which the biological response to a drug diminishes when it is given continuously or repeatedly. It may be possible to restore the response by increasing the dose of the drug but, in some cases, the tissues may become completely refractory to its effect : examples Tachyphylaxis , Tolerance , Drug resistance n When drugs induce chemical, hormonal and physiological changes that offset their actions, discontinuation may allow these changes to cause ‘rebound’ withdrawal effects ( alcohol, Barbiturates , Glucocorticoids , Opioids , SSRUI )
  15. Pharmacokinetic : what the body does to the drug . n Drug absorption and routes of administration: Enteral { Oral , Buccal , Intranasal , Sublingual (organic Nitrates , Opiates and triptans for migrain ) , Rectal PR .} Parentral ( IV , IM , Subcutaneous SC , Transdermal e .g . Oestrogens , Nitrates , nicotine ) Others ( Topical application: skin , eye , ear . INHALED : airway
  16. Pharmacokinetic : what the body does to the drug . n Drug distribution depends on molecular size , lipid solubility , plasma proteins binding and it’s susceptibility to transporters on cell surface . n VD = The size of the “compartment” into which a drug is distributed following absorption and is determined by the equation: Vd = Dose (mg) drug administered/Initial plasma concentration (mg/L) Vd = D / Co ( Drugs that are highly bound to plasma proteins may have Vd below 10 e.g. Warfarin and aspirin
  17. Drug Elimination via metabolism phase I Oxidation, reduction ,or hydrolysis , Oxidation mainly by hepatic Cytochrome P 450 enzyme . Phase II glucuronidation , sulphonation , Acetylation , Methylation and conjugation with glutathione .) Via Renal or Faecal excretion What is the EHC ? What is t ½ , What is Zero Order kinetics ? .
  18. Zero-order kinetics& TI n ZOK It is less common and means that the rate of elimination is constant and does not depend on the plasma drug concentration. This may be a consequence of a circumstance such as saturation of liver enzymes or saturation of the kidney transport mechanisms. n Therapeutic index (TI): Defined as the TD 50 /ED 50 (the ratio of the dose that produces a toxic effect in half the population to the dose that produces the desired effect in half the population).
  19. Patient- Specific factors that infleunce Pharmacokinetics n Age & sex n Weight n Live function , Renal function , GIT function n Food n Smoking alcohol other drugs
  20. Pharmacogenetic variation that affect drug response n Pharmacokinetic : Aldehyde dehydrogenase 2 deficiency – Alcohol . Slow acetylation in INH therapy . HLA –B 1502 Carbamazepine increased risk of skin reaction SJS . Pseudocholine esterase deficiency ( succinylcholine ) n Pharmacodynemic ( Porphyria , G6PD deficiency )
  21. Questions ( 1 ) A drug M is injected IV into a laboratory subject. It is noted to have high serum protein binding. Which of the following is most likely to be increased as a result? A . Drug interaction B. Distribution of the drug to tissue sites C. Renal excretion D. Liver metabolism ( 2 ) A 25-year-old medical student is given a prescription for asthma, which the physician states has a very high therapeutic index. Which of the statements best characterizes the drug as it relates to the therapeutic index? A. The drug’s serum levels will likely need to be carefully monitored. B. The drug is likely to cross the blood-brain barrier. C. The drug is likely to have extensive drug-drug interactions. D. The drug is unlikely to have any serious adverse effects.
  22. First pass , Vd Which of the following describes the first-pass effect? A. Inactivation of a drug as a result of the gastric acids. B. Absorption of a drug through the duodenum. C. Drug given orally is metabolized by the liver before entering the circulation. D. Drug given IV accumulates quickly in the central nervous system (CNS). An agent is noted to have a very low calculated volume of distribution (V d ) Which of the following is the best explanation? A. The agent is eliminated by the kidneys, and the patient has renal insufficiency. B. The agent is extensively bound to plasma proteins. C. The agent is extensively sequestered in tissue. D. The agent is eliminated by zero-order kinetics.
  23. Rational & Effective Prescribing
  24. The prescriber should have the following 5 aims: n Maximise effectiveness n Minimise risks n Minimise costs n Respect the patient's choices. n Follow the principles of Biomedical Ethics
  25. Another popular framework to support rational prescribing decisions is known as STEPS Steps model includes five criteria to consider when deciding on the choice of treatment: n Safety n Tolerability n Effectiveness n Price n Simplicity.
  26. Principles of Biomedical Ethics n Beneficence, n Non-maleficence, n Justice n Veracity (Veracity or ‘truth telling’ underpins both effective communication and patient consent.)& Fidelity ( Trust ) n respect for Autonomy
  27. Good prescribing is sometimes defined as the lack of irrational prescribing. Prescribing can be described as irrational for many reasons: n Poor choice of a medicine n Polypharmacy or co-prescribing of interacting medicine n Prescribing for a self-limiting condition n Continuing to prescribe for a longer period than necessary n Prescribing too low a dose of a medicine n Prescribing without taking account of the patient's wishes
  28. Prescriptions n In writing prescriptions, use English or the dominant language of the patient. n "Rx" is said to be an abbreviation for the Latin word recipere, meaning "take" or "take thus," as a direction to a pharmacist, preceding the physician's "recipe" for preparing a medication. n The abbreviation "Sig" for the Latin Signatura, is used on the prescription to mark the directions for administration of the medication. n The prescription must be accurately and legibly prepared to identify the patient, the medication to be dispensed, and the mode of drug administration. Avoid abbreviations and Include the therapeutic purpose in the subscription (e.g., "for control of blood pressure") to prevent errors in dispensing.(e.g. Losartan )
  29. Prescription Paper ‫ر‬ ‫ا‬ ‫ﺟ‬ ‫ﯾ‬ ‫ﺗ‬ ‫ﺔ‬ n The superscription includes the date the prescription order is written; the name, address, weight, and age of the patient; and the Rx (Take). n The body of the prescription, or inscription, contains the name and amount or strength of the drug to be dispensed, or the name and strength of each ingredient to be compounded n The subscription is the instruction to the pharmacist, usually consisting of a short sentence such as: "dispense 30 tablets." The signa or "Sig" is the instruction for the patient as to how to take the prescription, interpreted and transposed onto the prescription label by the pharmacist. n Many physicians continue to use Latin abbreviations; e.g., "1 cap tid pc," will be interpreted by the pharmacist as "take one after meal .
  30. ‫ر‬ ‫ﻗ‬ ‫ﻢ‬ ‫ا‬ ‫ﻟ‬ ‫ﺘ‬ ‫ﺴ‬ ‫ﺠ‬ ‫ﯿ‬ ‫ﻞ‬ ‫ﻓ‬ ‫ﻲ‬ ‫أ‬ ‫ﻟ‬ ‫ﻨ‬ ‫ﻘ‬ ‫ﺎ‬ ‫ﺑ‬ ‫ﺔ‬ ‫ﻋ‬ ‫ﻨ‬ ‫ﻮ‬ ‫ا‬ ‫ن‬ ‫ا‬ ‫ﻟ‬ ‫ﻌ‬ ‫ﯿ‬ ‫ﺎ‬ ‫د‬ ‫ة‬ ‫ا‬ ‫ﺳ‬ ‫ﻢ‬ ‫ا‬ ‫ﻟ‬ ‫ﻄ‬ ‫ﺒ‬ ‫ﯿ‬ ‫ﺐ‬ ‫أ‬ ‫ﻟ‬ ‫ﺸ‬ ‫ﮭ‬ ‫ﺎ‬ ‫د‬ ‫ة‬ ‫و‬ ‫ا‬ ‫ﻟ‬ ‫ﺘ‬ ‫ﺨ‬ ‫ﺼ‬ ‫ﺺ‬ Dx: ------------------ -
  31. A 65-year-old man with heart failure is admitted to hospital with a K level of 7.1 mmol/L. Already stabilised on lisinopril 20 mg daily, he had recently been started on spironolactone 25 mg daily. He had a serum creatinine of 160 μmol/L. Questions n 1. What is the mechanism of any possible adverse drug reaction? n 2. How should future episodes of hyperkalaemia be avoided?
  32. Which of the following is the most likely reason for pharmacokinetic tolerance? (A) changes in absorption (B) changes in distribution (C) changes specific to that drug (D) changes in metabolism (E) renal adaptation (D) The most common cause of pharmacokinetic tolerance is an increase in the metabolism of the drug. Since these same enzymes can then metabolize other drugs, this kind of tolerance is not necessarily specific to the drug that induced it)
  33. A72-year-old man is prescribed hydrochlorothiazide for hypertension. Which of the following is the most likely symptomatic side effect? (A) increased serum potassium (B) metabolic acidosis (C) sexual impotence (D) respiratory alkalosis (E) hypernatremia
  34. A 69-year-old man develops renal failure. Which of the following drugs requires a major adjustment in dosage? (A) levofloxacin (B) ceftriaxone (C) amphotericin B (D) clindamycin (E) ampicillin
  35. THE END THANK YOU ‫أ‬ ‫ﻟ‬ ‫ﺴ‬ ‫ﻼ‬ ‫م‬ ‫ﻋ‬ ‫ﻠ‬ ‫ﯿ‬ ‫ﻜ‬ ‫ﻢ‬ ‫و‬ ‫ر‬ ‫ﺣ‬ ‫ﻤ‬ ‫ﺘ‬ ‫ﮫ‬ ‫و‬ ‫ﺑ‬ ‫ﺮ‬ ‫ﻛ‬ ‫ﺎ‬ ‫ﺗ‬ ‫ﮫ‬