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Michael Soriano Clinical Pharmacist

• PHARMACOLOGY • Pharmacokinetics • Pharmacodynamics • Quality Use of Medicines • Acute Pain Management • Anticoagulants • GI Drugs

• The science which concerns the effect of the drugs on the body (pharmacodynamics), and the effect of the body on the drugs: absorption, metabolism, distribution, and excretion (pharmacokinetics). • Pharmacology is the study of how drugs work.

Anticholinergics) . • The intended effect is usually predictable depending on the pharmacological profile of the drug (ex. dispense or administer to a patient would do to the patient.Pharmacology • We as health professionals should always be aware of what a drug that we prescribe.

but would have varying effects between a 30-year-old patient and a 75-year-old patient. • Example: Two different brands of perindopril erbumine 4mg would have the same intended effect.Pharmacology • Pharmacodynamics is more of an exact science than pharmacokinetics because it is only dependent on the drug and its characteristics. .

Pharmacokinetics • The science which concerns the effect of the body on the drugs: absorption. • Bioavailability: The fraction of an administered drug that reaches the systemic circulation. metabolism. and excretion (pharmacokinetics). distribution. .

Pharmacokinetics PHARMACOKINETIC PROFILES The ―LADMER‖ system • (LIBERATION) –more dependent on drug • ABSORPTION • DISTRIBUTION • METABOLISM • EXCRETION • (REABSORPTION) –more dependent on drug .

Pharmacokinetics Side effects Drug is effective Drug not effective 0800 1200 1800 .

Ex. • • • • • • Decline in lean body mass Increase in body fat stores Decline in total body water Decline in renal mass Decline in hepatic blood flow Decline in glomerular filtration .Pharmacokinetics -in the elderly There are important age-related changes in body composition and functioning which are relevant to the pharmacokinetics of drugs.

Most drugs are absorbed from the gastrointestinal tract by simple diffusion and there are no age-related changes in the absorption of these drugs. . Drugs absorbed into the blood stream via active transport mechanisms (iron. *the bioavailability of some drugs may also be increased by reduced first pass liver metabolism in older people. calcium. Factors affecting drug absorption include patients‘ comorbid illnesses. but these changes do not lead to clinically significant changes in drug absorption. magnesium and vitamin B12) are poorly absorbed in the elderly. timing of drug administration and other accompanying products.Pharmacokinetics ABSORPTION Age-related changes lead to a decrease in small-bowel surface area and an increase in gastric pH.

Fat soluble drugs such as diazepam. chlormethiazole. average lean body mass falls and adipose tissue increases (from 18 per cent to 36 per cent in men and from 33 per cent to 48 per cent in women between the second and eighth decades). Water soluble drugs such as paracetamol. Total body water falls both in absolute terms and as a percentage of body weight5 These changes markedly affect the volume of distribution of highly fat or water soluble drugs.Pharmacokinetics DISTRIBUTION With ageing. chlordiazepoxide. digoxin. cimetidine and ethanol have decreased distribution to tissues resulting in higher serum concentrations. . lignocaine and thiopentone are distributed more extensively in older people resulting in prolonged plasma half-life and action since plasma half-life is directly proportional to volume of distribution.

A decrease in hepatic blood flow prolongs the duration of effect in drugs that undergo extensive first pass metabolism.Pharmacokinetics METABOLISM Age-related changes lead to decreased liver size. hepatic blood flow and enzyme activity. .

Glomerular filtration declines as a consequence of a decrease in renal blood flow and kidney size and a decrease in functioning nephrons Elimination of a drug is affected by reduction in renal function if 60% of the drug is renally excreted. .Pharmacokinetics ELIMINATION Most drugs are eliminated by the kidney as either the parent compound or as a metabolite or metabolites.

Pharmacokinetics in practice The Effect of Food on Medications Dosage Form Modification Compliance issues .

FOOD-DRUG INTERACTIONS Poor acid stability Chelation Acid Dependency Bile acid or fat enhanced drug dissolution Avoiding hypoglycaemia Gastrointestinal side effects Therapeutic relevance *Levodopa .

DOSAGE FORM MANIPULATION Altered medication absorption Medication stability Occupational health and safety Local irritant effects Failure to reach site of action Unacceptable/undisguisable taste *Nifedipine OROS .

COMPLIANCE ISSUES <100% Compliance=<100% drug effect .

Poor Compliance
Side effects
Drug is effective

Drug not effective




The effects of ageing on pharmacodynamics may be due to alterations in receptor and/or target organ responses or, perhaps more importantly, changes in homeostatic responses.

The concurrent use of multiple medications, usually as a result of co-morbidities and the prescribing cascade.
Under-prescribing of beneficial medications to older adults is equally prevalent. Under- prescribing may result from avoidance of over-prescribing, adverse effects or complex medication regimens, as well as from a belief that older adults will not benefit from medications intended as primary or secondary prevention or from aggressive management of chronic conditions such as hypertension or diabetes mellitus.

How many drugs would usually be prescribed in practice? How many drugs should be in the patient‘s regimen? . incontinence. glaucoma and insomnia.Polypharmacy THE PRESCRIBING CASCADE A new resident comes in with dementia.

Polypharmacy Could be avoided by: Quality Use of Medicines • Regular review of medications • Benefit • Side effect • Regular review of medical condition • Regular review of goals/patient needs .

digoxin.Polypharmacy Various studies found that 2. respectively. warfarin and theophylline. cardiac disease. cardiac arrhythmias. prevention of thromboembolism and respiratory disease. prescribed mainly for joint pain. blood dyscrasias and postural hypotension. The most frequent drug-related causes of hospitalisations in a Melbourne study were gastrointestinal bleeding. The most commonly implicated drugs were NSAlDs.9% to 31% of all hospitalisations of older people are attributable to medication-induced illnesses. .

#NOF 5 years ago. incontinence. osteoporosis. dry eye syndrome. eczema. # wrist last year. Medical History: Alzheimer’s disease. . COPD. He complains of constantly losing his belongings and thinks the woman next door (Miss G.) has stolen them. An MMSE was done 6 months ago (16/30). shingles. is a 68-year-old male who is a new resident in your nursing home (4 weeks ago).Sample case study 1 Mr T.

Medications Medication Dose (according to drug chart) Purpose/comments Osteoporosis Shingles Anti-platelet Osteoporosis Alzheimer’s dementia provided by family provided by family Eczema Dry eyes Alzheimer’s disease Incontinence COPD COPD provided by family Alendronate 70mg1 tablet weekly Amitriptyline 25mg1 tablet nocte Aspirin 100mg1 tablet daily Colecalciferol 1000 units1 capsule daily Donepezil 5mg2 tablets mane Garlic Oil 1mg(Blackmores)1 capsule daily Ginkgo biloba 2000(Cenovis)1 tablet daily Hydrocortisone Cream 1% Hypromellose 3mg/g eye drops1-2 drops prn Memantine 10mg1 bd Oxybutynin 5mgHalf tablet tds Salbutamol 100microgram1 prn Tiotropium 1 capsule in the morning Vitamin E 2000 units1 in the morning .

CCF. She also complains of slight epistaxis periodically but she thinks it is due to her nasal spray. AF. OA Alcohol consumption: 1-2 standard drinks per day . Medical History: Type 2 diabetes. she just wants to move forward now. started celebrex yesterday as paracetamol was not effective. She also thinks she has pre-diabetes and would like some information on this.Sample case study 2 Miss G. She takes everything her naturopath suggests and finds the glucosamine helpful. is a 70-year-old widow who complains of a painful right knee.

and trace Zn. Magnesium 27mg. minerals and herbs) 1 daily OTC Fish Oil 1000mg1 daily OTC does not take these Bio ACE (Vitamin E 75IU. Variable frequency of use. zinc and folic acid)1 daily OTC Glucosamine sulphate (Natures Own) 1950mg1 daily OTC most days ChelaMin (Potassium 167mg. vitamin C. vitamin E. Calcium 67mg. Cu. I and Cr) 1 daily Celecoxib 200mg1 tds Pain Budesonide 64mcg/dose 1-2 sprays each nostril daily Hayfever . folic acid. B vitamins. Perindopril 5mg1 mane Heart Simvastatin 40mg1 at 6pm Cholesterol Blackmore’s Executive B Stress Formula multivitamin (B vitamins.25mcg. Vitamin D3 1. Fe.Medications Medication Dose (according to drug chart) Purpose/comments Atenolol 50mg1⁄2 in the morning Heart Digoxin 250microgram1 mane Heart Frusemide 20mg1 mane Diuretic Warfarin (Marevan) according to INR Prevent clots Paracetamol 500mg2 prn Pain.

LDL = 3. TC = 6. HDL = 1.8 – 5.6 mmol/L (<1.1 5 weeks ago INR=1.8 6 weeks ago INR=2.0).6 nanomol/L (0.5 mmol/L (>1.5 ).0) NB time of last dose not stated 1 month ago: TG = 2.0).2 .Relevant test results: 3 months ago: BGL (fasting) = 6.5) 2 months ago: Digoxin 0.6 – 1.8 mmol/L (<2.1 mmol/L (3.5) 4 weeks ago INR= 2.3 mmol/L (<4.

What are the potential drugrelated problems? And how could these be addressed or monitored? -Compliance -Polypharmacy -Undertreatment -Drug interactions -Potential Adverse reactions .


Acute Pain Management PHARMACOLOGY .

PAIN • Subjective experience • Sensory and emotional component .

PAIN • Protective mechanism • Learning experience • Important .

PAIN Pain is a subjective experience Not a simple “stimulus and response” process Role of placebos Inflammation =/= pain .

2.PAIN 1. anticonvulsants and sodium channel blockers. Neuropathic . Nociceptive • • Usually responds to traditional analgesics Has been noted to respond to non-traditional approaches such as antidepressants.

PAIN • How do we assess pain? • Believe the patient • Differentiate between – – – – Need Tolerance Dependency Addiction .

PAIN • Measuring pain – Bedside diaries – Pain scales .

Severe pain – Step 1 plus potent opioids . Mild pain – Non-opioid analgesic. with or without adjuncts and non-drug strategies.WHO Analgesic Ladder 1. Moderate pain – Step 1 plus weak opioids 3. 2.

• PRN prescribing: The term prn (pro re nata) means ‘when necessary’.Approach to management • The aim of management is to prevent pain • Pain is best treated early and effectively because once established it is more difficult to treat. Appropriate early treatment of acute pain will minimise the transition to chronic pain. • Multimodal management is common and may involve multiple drug and non-drug treatments. .


previously unknown cyclooxygenase enzyme COX3. and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. found in the brain and spinal cord.PARACETAMOL • The mechanism of action is still unclear. . which is selectively inhibited by paracetamol. but recent research has shown the presence of a new. It is now believed that this selective inhibition of the enzyme COX-3 in the brain and spinal cord explains the effectiveness of paracetamol in relieving pain and reducing fever without having unwanted gastrointestinal side effects.

PARACETAMOL • • • • Effective for acute pain Comes in multiple dosage formulations Duration of action about 4-6 hours Regular doses can reduce opioid requirements by 20-30% • Generally well tolerated .

PARACETAMOL • • • • Analgesic ceiling effect Maximum daily dose No anti-inflammatory effect Hepatotoxicity .

nerves and in the CNS. .NSAIDs • The effects of NSAIDs can be explained by their ability to inhibit the synthesis of prostaglandin in peripheral tissues. • The side effect profile is also due to the same mechanism.



• Prostaglandin
– Inflammation – Gastric mucosal protection – Renal tubular function – Intrarenal vasodilation – Endothelial prostacyclin

• Thromboxane
– Vasoconstriction – Platelet aggregation

NSAIDs • Choice of agent: – Side effect profile – Efficacy – Dosage form – Other medical conditions .

NSAIDs • Agents: – Ibuprofen: – Indomethacin: – Naproxen: – Ketorolac: Safest but least effective Strong NSAID but has more side effects Strong NSAID with fewer side effects Should only be used for up to 7 days – Diclofenac – Piroxicam .

NSAIDs • Considerations: – Renal function – Platelet function – Peptic ulceration – Aspirin exacerbated respiratory disease – Bone healing .

• Agents: – Meloxicam – Celecoxib – Parecoxib . and spare the constitutive COX-1.COX-2 inhibitors • Selectively inhibits the inducible cyclooxygenase enzyme. COX-2.


COX-2 inhibitors • Efficacy: – As effective as NSAIDs – Opioid sparing effect similar to NSAIDs • Considerations: – Renal function – Platelet function – Aspirin exacerbated respiratory disease – Bone healing – Gastrointestinal .

4. Aspirin and some NSAIDs increase the risk of reoperation for posttonsillectomy bleeding . Paracetamol is an effective analgesic for acute pain. 5. NSAIDs given in addition to paracetamol improve analgesia.Conclusions Key messages 1. With careful patient selection and monitoring. 3. 2. NSAIDs and COX-2 inhibitors are effective analgesics of similar efficacy for acute pain. the incidence of NSAID-induced perioperative renal impairment is low.

COX-2 selective inhibitors do not appear to produce bronchospasm in individuals known to have aspirin-exacerbated respiratory disease.Conclusions 6. COX-2 inhibitors and NSAIDs have similar adverse effects on renal function. Paracetamol. COX-2 inhibitors do not impair platelet function. 9. . NSAIDs and COX-2 inhibitors are valuable components of multimodal analgesia. 7. 8.

• Interpatient opioid requirements vary greatly and opioid doses therefore need to be titrated to suit each patient. .OPIOIDS • Opioids remain the mainstay of systemic analgesia for the treatment of moderate to severe acute pain.

kappa.OPIOIDS • Acts directly on opioid receptors in the brain and spinal cord (mu. . delta) and mimics the effects of endogenous opioid substances (endorphins and enkephalins).

differences in side effects or patient satisfaction. either in terms of better pain relief.OPIOIDS • Choice of agent: – All full opioid agonists given in equianalgesic doses produce the same analgesic effect. – Most available data do not suggest that any one opioid is superior to another. .

particularly for people at high risk of NSAID-induced adverse effects. .Weak OPIOIDS • Weak opioids have similar efficacy to NSAIDs and offer modest additional analgesic efficacy when added to paracetamol. • A weak opioid may be considered an alternative to a NSAID when paracetamol alone is inadequate.

.e. About 10% of Caucasian people and 1–2% of Asian people cannot metabolise codeine to morphine and so do not receive any analgesia only side effects i.Weak OPIOIDS • Codeine – Ensure that an adequate dose of codeine is used. it is generally accepted that doses below 30 mg are unlikely to be effective. increase nausea and constipation.

. However it should be used with caution because of the high incidence of side effects (up to one-third experience nausea.Weak OPIOIDS • Tramadol – Can be a useful alternative for people who cannot tolerate conventional opioids or who are at particular risk of opioid-induced respiratory depression. sweating. dizziness or hallucinations) and medication interactions (e.g. vomiting. SSRIs and MAOI antidepressants).

3% compared with paracetamol alone and increases the incidence of dizziness. respiratory and cardiac depression .Weak OPIOIDS • Dextropropoxyphene – It is often used in combination with paracetamol but this combination improves pain relief by only 7. – The major metabolite of dextropropoxyphene is nordextropropoxyphene which is renally excreted. accumulation of nordextropropoxyphene can lead to central nervous system (CNS).

2 – 0.8mg sublingual 60 – 70mg Unknown N/A 2.Strong OPIOIDS DRUG Suggested dose equivalent to 10mg sc/im morphine Therefore oral dose equivalent to 10mg oral morphine Approximate duration of action (hours) dependent on dose and route of administration Codeine Dextropropoxyphene Fentanyl Hydromorphone Methadone Morphine Oxycodone Pethidine Tramadol Buprenorphine 130mg im 200mg oral Unknown 100 – 150 mcg iv/sc 1.3mg 3-4 4-6 0.5-1 2-4 8-24 (chronic dosing) 2-3 (standard release) 12-24 (sustained release) 3-4 (standard release) 12-24 (sustained release) 2-3 3-6 (standard release) 12-24 (sustained release) 6-8 (tablets) .4mg im 0.2.5mg 6 – 7 mg 10mg 5 – 6 mg N/A 50mg 0.5 – 2mg sc/im 6-7.5mg oral 10mg sc/im 20mg oral 30mg oral 15-20mg oral 75-100mg im 100 – 120mg im/iv 150mg oral 0.

Strong OPIOIDS • Choice of agent: – Ease of use – Dose flexibility – Route of administration – Patient variables – Pharmacokinetic variables .

Therapeutic window Side Effects Therapeutic Window No effect Time .

Strong OPIOIDS • Adverse effects: – Respiratory depression – Nausea and vomiting – Pruritus .

nalbuphine and droperidol are effective treatments for opioid induced pruritus. 3. Naloxone. In the management of acute pain. Tramadol is an effective treatment in neuropathic pain.OPIOIDS Points: 1. 4. one opioid is not superior over others but some opioids are better in some patients. 5. patient age rather than weight is a better predictor of opioid requirements. Tramadol has a lower risk of respiratory depression and impairs gastrointestinal motor function less than other opioids at equianalgesic doses 7. The incidence of clinically meaningful adverse effects of opioids is dose-related 6. 2. Dextropropoxyphene has low analgesic efficacy. In adults. although there is a large interpatient variation. naltrexone. .

neural plasticity. via glutamate release from excitatory synapses. neural development. augments the propagation of nociceptive information and is linked to learning and memory. At the spinal level.Ketamine • NMDA antagonist. • N-methyl-D-aspartate (NMDA) receptors are sited peripherally and centrally. NMDA receptor activation results in the development of hyperalgesia and allodynia. as well as acute and chronic pain states. Activation of NMDA receptors. .

4. 3. Ketamine may reduce opioid requirements in opioidtolerant patients. Ketamine improves analgesia in patients with severe pain that is poorly responsive to opioids. . NMDA receptor antagonist drugs show preventive analgesic effects. 2.Ketamine 1. Ketamine has an opioid-sparing effect in postoperative pain although there is no concurrent reduction in opioidrelated side effects.

antidepressants are effective in the treatment of a variety of chronic neuropathic pain states. • There are very limited data on the use of TCAs in acute nociceptive pain. However. . Desipramine given prior to dental surgery increased and prolonged the analgesic effect of a single dose of morphine but had no analgesic effect in the absence of morphine.Antidepressants • There are no published data on the use of antidepressants in the management of acute neuropathic pain.

Antidepressants reduce the incidence of chronic neuropathic pain after acute zoster and breast surgery . In neuropathic pain. 2.Antidepressants 1. chronic headaches and chronic back pain. tricyclic antidepressants are more effective than selective serotonergic re-uptake inhibitors. 3. Tricyclic antidepressants are effective in the treatment of chronic neuropathic pain states.

anticonvulsants have been used to treat chronic neuropathic pain and various systematic reviews have shown their efficacy in a variety of neuropathic pain states. However.Anticonvulsants • There are only limited data on the treatment of acute neuropathic pain with anticonvulsant medications. .

. • Perioperative gabapentin leads to substantial reductions in both postoperative analgesic requirements and pain. sodium valproate is of no benefit.Anticonvulsants • In acute nociceptive pain after surgery.

intramuscular [IM].Alpha-2 Agonists • Systemic administration (oral. • Higher doses of clonidine result in a significant reduction in opioid requirements but a greater degree of sedation and hypotension. . IV) of single doses of the alpha-2 agonists clonidine and dexmedetomidine decreases perioperative opioid requirements in surgical patients.

Common questions • Should I take pain medication only when I have a lot of pain? – No. Don't wait until pain becomes severe to take pain medication. You should take your pain medication as prescribed. . Sometimes this means you will take medicine on a regular schedule and sometimes just when you need it. Pain is easier to control when it is mild.

Common questions • Will I become "addicted" to pain medications? – The risk of addiction is very rare. .

If it is not they can change the plan.Common questions • What if the pain doesn’t get better? – Don‘t worry about being a nuisance. Ongoing pain can be a sign that your condition has changed. They also need to know whether your pain control plan is working. and the medical and nursing staff need to know about it. . – If your hospital has an Acute Pain Service you may be referred to it for specialist advice.

Sometimes the body gets used to a certain medication. . This is called tolerance. Changing the dose or the medication itself often solves the problem.Common questions • Can pain medicines stop working? – Pain medicine does not stop working.

Questions? .


OBJECTIVES • To learn how Blood Clots are formed. • How the blood clots are broken down ? • What drugs can be used to regulate clotting ? .


which strengthen the platelet plug. respond in a complex cascade to form fibrin strands. Platelets immediately form a plug at the site of injury. this is called primary hemostasis. called coagulation factors or clotting factors. Secondary hemostasis occurs simultaneously: Proteins in the plasma. .THE CLOTTING PROCESS • A complex process of which blood forms a clot. Exposure of the blood to proteins such as tissue factor initiates changes to blood platelets and the plasma protein fibrinogen. a clotting factor. • Coagulation begins almost instantly after an injury or damage to the blood vessel or its lining.

THE CLOTTING PROCESS STEPS: Platelet Activation The Coagulation Cascade Intrinsic pathway Extrinsic pathway Final Common Pathway Fibrinolysis (Plasmin) .

VII.Activates IX. labile factor) Required for coagulation factors to bind to phospholipid (formerly known as factor IV) Co-factor of X with which it forms the prothrombinase complex VI VII (stable factor) VIII (Anti Hemophilic factor A) Unassigned – old name of Factor Va Pro Convertin . XI. X Co-factor of IX with which it forms the tenase complex . platelets Co-factor of VIIa (formerly known as factor III) Calcium V (proaccelerin. V. XIII. protein C.THE CLOTTING PROCESS Coagulation factors and related substances FACTOR FUNCTION I (fibrinogen) II (prothrombin) Tissue factor Forms clot (fibrin) Its active form (IIa) activates I. VIII.

THE CLOTTING PROCESS FACTOR IX (Anti Hemophilic Factor B or Christmas factor) X (Stuart-Prower factor) XI (plasma thromboplastin antecedent) XII (Hageman factor) XIII (fibrin-stabilizing factor) FUNCTION Activates X: forms tenase complex with factor VIII Activates II: forms prothrombinase complex with factor V Activates IX Activates factor XI. VII and prekallikrein Crosslinks fibrin .

IX and X.Vitamin K epoxide reductase. In adding the gamma-carboxyl group to glutamate residues on the immature clotting factors Vitamin K is itself oxidized. •Vitamin K is an essential factor to a hepatic gamma-glutamyl carboxylase that adds a carboxyl group to glutamic acid residues on factors II. VII. as well as Protein S. Calcium is also required at other points in the coagulation cascade. phenprocoumon. Calcium mediates the binding of the complexes via the terminal gamma-carboxy residues on FXa and FIXa to the phospholipid surfaces expressed by platelets. (VKORC) reduces vitamin K back to its active form. and dicumarol. . as well as procoagulant microparticles or microvesicles shed from them. Protein C and Protein Z.THE CLOTTING PROCESS COFACTORS •Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and prothrombinase complexes to function. Vitamin K epoxide reductase is pharmacologically important as a target for anticoagulant drugs warfarin and related coumarins such as acenocoumarol. Another enzyme.

by doing so. Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors.THE CLOTTING PROCESS REGULATORS Five mechanisms keep platelet activation and the coagulation cascade in check. inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and. Abnormalities can lead to an increased tendency toward thrombosis: Protein C is a major physiological anticoagulant. Antithrombin Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). which synthesizes cAMP. It also inhibits excessive TF-mediated activation of FIX and FX. activates adenyl cyclase. in turn. This. . Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation.

leading to the production of circulating fragments that are cleared by other proteases or by thekidney and liver. . is broken down.FIBRINOLYSIS Fibrinolysis is the process wherein a fibrin clot. the product of coagulation. Its main enzyme plasmin cuts the fibrin mesh at various places.

White in color Often associated with MI. Cancer. stroke and ischemia Venous Thrombosis : Develops in areas of stagnated blood flow (deep vein thrombosis).THROMBOSIS Arterial Thrombosis : Adherence of platelets to arterial walls . Red in color.Unwanted Clots . .Associated with Congestive Heart Failure. Surgery.



Do not inject IM (haematoma).c. • Half-life 1 .only IV or deep s.parenteral.haemorrhage .HEPARINS STANDARD / UNFRACTIONATED HEPARIN • • • • Heterogenous mixture of polysaccharide chains Molecular Weight 3k to 30k Active in vitro and in vivo Administration .antidote protamine sulphate .monitor APTT • Adverse effect .2 hrs .

HEPARINS STANDARD / UNFRACTIONATED HEPARIN Complications • Haemorrhage • Heparin-induced thrombocytopaenia (HIT) – Most common drug-induced thrombocytopenia3 – 1-5% patients on heparin develop thrombocytopaenia • Osteoporosis (long-term only) .

Protamine sulfate effectively reverses 60% of enoxaparin . Dalteparin • • • • • • Changed management of venous thromboembolism Standard (Unfractionated) heparin 3k to 30k LMWH contains polysaccharide chains MW 5k Enriched with short chains with higher anti-Xa:IIa ratio Dose based on weight and renal function.HEPARINS LOW MOLECULAR WEIGHT HEPARIN Enoxaparin.

HEPARINS Enoxaparin in VTE prophylaxis Knee replacement Hip replacement .

– APTT for UH • Higher bioavailability -90% vs 30% • Longer Plasma Half Life – 4-6 hours vs 0. more specific for Xa receptors.1-1 hour (renal clearance slower than hepatic clearance) • Less inhibition of platelet function. less anti-Iia activity. • Lower incidence of thrombocytopenia and thrombosis .HEPARINS Advantages of LMWH over UH • No need for laboratory monitoring.

Vitamin K-Dependent Clotting Factors Vitamin K VII IX X II Synthesis of Functional Coagulation Factors .

Vitamin K Antagonists Vitamin K Antagonism of Vitamin K VII IX X Synthesis of Non Functional Coagulation Factors II Warfarin .

Warfarin .

36 hrs •Delayed onset 8 .WARFARIN •Isolated from clover leaves •Structurally related to vitamin K •Inhibits production of active clotting factors •Absorption rapid .binds to albumin •Clearance is slow .do not use during late pregnancies .reversed by vitamin K infusion •Can cross placenta .12 hrs •Overdose .

Haemorrhage Factors that may influence bleeding risk: •Intensity of anticoagulation •Concomitant clinical disorders •Concomitant use of other medications •Quality of management Target INR •DVT.5 .WARFARIN Major Adverse Effect . Atrial Fibrillation: 2-3 •Artificial Cardiac Valve: 3-3. PE.

IV DABIGATRAN . the actions of direct thrombin inhibitors are limited to thrombin .ORAL DIRECT THROMBIN INHIBITORS Unlike other anticoagulants.Bivalirudin. Lepirudin .

Warfarin Dabigatran .

FACTOR Xa INHIBITORS RIVAROXABAN Rivaroxaban is a competitive reversible antagonist of activated factor X (Xa). Factor Xa is the active component of the prothrombinase complex that catalyses conversion of prothrombin (factor II) to thrombin (factor IIa). .

Warfarin Rivaroxaban Dabigatran .

500 patients from 39 countries undergoing total hip replacement (THR) or total knee replacement (TKR).Clinical Studies XARELTO Total Hip and Knee Replacement Surgery — RECORD Programme The RECORD clinical programme (REgulation of Coagulation in ORthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism) consists of 4 phase III clinical studies evaluating Xarelto® compared to enoxaparin in more than 12. Xarelto® was administered as one 10 mg tablet once daily and compared to subcutaneous enoxaparin . These studies evaluated the efficacy and safety of Xarelto® in the prevention of venous thromboembolism (VTE). Patients enrolled in the programme reflect a wide range of men and women whose age (18 to 93 years) and weight (33 to 190 kg) reflect the patient population commonly seen in clinical practice.

patients undergoing total hip replacement surgery who were treated with Xarelto® benefited from significantly lower rates of the primary efficacy endpoint (composite of any DVT. In RECORD3 and RECORD4. . This superior efficacy was accompanied by a good safety profile comparable to that of enoxaparin. and all-cause mortality) compared to enoxaparin. Xarelto® was associated with a significantly lower risk for the primary efficacy endpoint (composite of any DVT. non-fatal PE. non-fatal PE. and all-cause mortality) in head-to-head comparisons with enoxaparin when both drugs were given over the same time period (RECORD1 over 5 weeks) and when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin (RECORD2). together with a safety profile comparable to that of enoxaparin in patients undergoing TKR surgery.Clinical Studies THR: Xarelto® provided significant risk reduction and comparable safety In the RECORD1 and RECORD2 studies.

RECORD 1-3 .

RECORD 1-3 .

For total thromboembolism there was a statistically significant relative risk reduction of 30–70%. The near absence of 'major' bleeding is explained in part by a study definition which excluded wound-related bleeding unless it was fatal or led to re-operation . For major thromboembolism the risk reduction was 40–90% which was statistically significant in RECORD1 and RECORD3. 3 and 4. SAFETY The rates of major or clinically relevant non-major bleeding were similar with rivaroxaban and enoxaparin 40 mg once daily.XARELTO Clinical Studies EFFICACY Rivaroxaban was more effective than enoxaparin in RECORD 1. The apparent increases in bleeding were small and statistically insignificant. when used for a similar duration. An overview found that rates of wound infection and reoperation due to bleeding were low and comparable.


Clinical Studies PRADAXA • • • • RE-MODEL •(TKR Pradaxa 150 or 220mg daily vs Enoxaparin 40mg daily) RE-MOBILIZE •(TKR Pradaxa 150 or 220mg daily vs Enoxaparin 30mg BD) RE-NOVATE •(TKR Pradaxa 150 or 220mg daily vs Enoxaparin 40mg daily) RE-NOVATE II •(TKR Pradaxa 220mg daily vs Enoxaparin 40mg daily) .


compared with enoxaparin 40 mg once daily.PRADAXA Clinical Studies EFFICACY Both doses of dabigatran were statistically 'non-inferior' to enoxaparin in RENOVATE and RE-MODEL. but this was not statistically significant. An overview showed a slight excess of bleeding with dabigatran 220 mg once daily. . In RE-MOBILIZE the total rates of venous thromboembolism with the two dabigatran regimens were significantly higher than with twice-daily enoxaparin. BLEEDING The rates of major or clinically relevant non-major bleeding were similar with the two dabigatran regimens and with enoxaparin.



GI Medications .

GI Medications •Drugs for GORD and ulcer •Anti-emetics •Aperients .

This means the majority of secreted K+ and Na+ ions return to the cytoplasm. In addition. through the stimulation of the secretion of the hormone histamine from enterochromaffine-like cells (ECL). The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach. and is stimulated by small intestine distention. These cells are part of epithelial fundic glands in the gastric mucosa. The secretion of sodium bicarbonate from the pancreas is stimulated by secretin. cholecystokinin. The intestinal phase: the remaining 10% of acid is secreted when chyme enters the small intestine. The production of gastric acid in the stomach is tightly regulated by positive regulators and negative feedback mechanisms. The resulting highly acidic environment in the stomach lumen causes proteins from food to lose their characteristic folded structure (or denature). Chloride and hydrogen ions are secreted separately from the cytoplasm of parietal cells and mixed in the canaliculi. but almost exactly isotonic with other bodily fluids. Gastric acid production is regulated by both the autonomic nervous system and several hormones. The neutralization is described by the equation: HCl + NaHCO3 → NaCl + H2CO3 . Gastric acid is then secreted into the lumen of the oxyntic gland and gradually reaches the main stomach lumen. secreted hydrogen and chloride ions mix and are secreted into the lumen of the oxyntic gland. The parietal cell releases bicarbonate into the blood stream in the process. Chloride and sodium ions are secreted actively from the cytoplasm of the parietal cell into the lumen of the canaliculus. Gastric acid secretion happens in several steps.8. Four types of cells are involved in this process: parietal cells. Its secretion is a complex and relatively energetically expensive process. The highest concentration that gastric acid reaches in the stomach is 160 mM in the canaliculi. At the same time sodium ions are actively reabsorbed. This also blocks gastric enzymes that have their optima in the acid range of pH. The enzyme carbonic anhydrase catalyses the reaction between carbon dioxide and water to form carbonic acid. The pH of gastric acid is 2 to 3 in the human stomach lumen. many microorganisms have their growth inhibited by such an acidic environment which is helpful to prevent infection. The parasympathetic nervous system. This creates a negative potential of -40 mV to -70 mV across the parietal cell membrane that causes potassium ions and a small number of sodium ions to diffuse from the cytoplasm into the parietal cell canaliculi. Besides this. There are three phases in the secretion of gastric acid: The cephalic phase: 30% of the total gastric acid to be produced is stimulated by anticipation of eating and the smell or taste of food. which causes a temporary rise of pH in the blood. Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine and gastrin-releasing peptide. In the canaliculus. the acidity being maintained by the proton pump H+/K+ ATPase. This polypeptide hormone gets activated and secreted from so-called S cells in the mucosa of the duodenum and jejunum when the pH in duodenum falls below 4. Gastric acid activates pepsinogen into pepsin–this enzyme then helps digestion by breaking the bonds linking amino acids.0. and secretin all inhibit production. The gastric phase: 60% of the acid secreted is stimulated by the distention of the stomach with food. Plus. In the duodenum. known as alkaline tide. Parietal cells contain an extensive secretory network (called canaliculi) from which the gastric acid is secreted into the lumen of the stomach.How is Gastric Acid Secreted? Gastric acid is produced by parietal cells (also called oxyntic cells) in the stomach. Gastrin acts on parietal cells directly and indirectly too. The hydrogen ions leave the cell through H+/K+ ATPase antiporter pumps. digestion produces proteins.5 to 5. which causes even more gastrin production. gastric acid is neutralized by sodium bicarbonate. G cells. a process known as proteolysis. The lowest pH of the secreted acid is 0. This is about 3 million times that of arterial blood. by stimulating the release of histamine. the endings of the vagus nerve (X) and the intramural nervous plexus in the digestive tract influence the secretion significantly. Their action is both direct on parietal cells and mediated through the secretion of gastrin from G cells and histamine from enterochromaffine-like cells. both directly acting on parietal cells and indirectly. Its release is stimulated by gastrin and acetylcholine and inhibited by somatostatin. via the vagus nerve. Vasoactive intestinal peptide. This acid immediately dissociates into hydrogen and bicarbonate ions. and the hormone gastrin stimulate the parietal cell to produce gastric acid. D cells and enterochromaffinelike cells.[1] but the acid is diluted in the stomach lumen to a pH between 1 and 3.The chief cells of the stomach secrete enzymes for protein breakdown (inactive pepsinogen and renin). This exposes the protein's peptide bonds.

Meal stimulated acid secretion: stimulated by: Gastrin .Types of Gastric Acid 1. Nocturnal (basal) acid secretion: depends on histamine 2.

ACh PGE 2 Histami ne + H2 Gastr in Gastrin + recep tor Ca+ M 3+ _Ade PGE nyl receptorcycl Ca++ AT cAM ase P P + + + + K+ Protein Kinase + H+ (Activated) Proton pump Gastric Parietal Lumen of cell stomach .

ACh PGE 2 Histami ne Gastr in Gastrin + recep tor Ca+ H2 M PGE _Ade + 3 + recep nyl tor cycl Ca++ AT cAM ase P P + + + + Protein Kinase K+ H+ K+ (Activated) Proton pump Gastric Parietal Lumen of cell stomach .

•Esophageal defense: the lower esophageal sphincter, which prevents reflux of acidic gastric contents into the esophagus.

Gastric Defence Against Acids

•Stomach defense: (require adequate mucosal
blood flow because of the high metabolic activity

and oxygen requirements of the gastric mucosa)
a) Secretion of a mucus layer that protects gastric

epithelial cells. Mucus production is stimulated by

PHARMACOLOGY Antacids: Neutralizes Existing Acids ex. PPIs: Blocks the proton pump to inhibit . HCl + Al(OH)3 MgCl2 + H20 AlCl3 + H20 H2RAs: Indirectly decreases gastric acid production through histamine receptors. HCl + Mg(OH)2 ex.

Proton Pump Inhibitors OCH3 Omeprazole CH2CF3 -CH3 N H3- -CH3 Esomeprazole N N Lansopraz ole N CH2SO- CH2SONH NH OCH3 Pantoprazo le -OCH3 N CH2SONH O(CH2)3OCH3 -CH3 Rabeprazo le N N N CH2SONH .

half an hour before breakfast (require acid to convert to active form) Produce healing of duodenal and gastric ulcers poorly responsive to H2-antagonists No dosage adjustments are necessary in patients with renal impairment .Proton Pump Inhibitors Inhibit gastric acid secretion by irreversible blockage of the acid. hydrogen or ‗proton pump‘ of the gastric parietal cells Inhibit basal and stimulated gastric acid secretion The degree of inhibition of gastric acid secretion is related to the dose and duration of therapy Greater potency and longer duration of action than H2-antagonists Anti-secretory effect lasts more than 24 hours Swallowed whole Administered once daily.

lansoprazole 30mg. Usual doses for healing are omeprazole 2040mg. as a single daily dose. or pantoprazole 40mg a day. Relapse occurs within 3 months after stopping therapy in about 70% of patients .Proton Pump Inhibitors Produce rapid symptomatic relief and healing of oesophagitis in about 80% of patients when administered for 4 weeks.

Headache. constipation. and less commonly. similar to H2-antagonists. abdominal pain. flatulence. Drug Interactions: Clopidogrel? P450 enzyme drugs . nausea. fatigue.Proton Pump Inhibitors Adverse Effects: Very low incidence. diarrhoea.


ranitidine and cimetidine .H2RAs Structurally related to histamine Inhibit the action of histamine on the parietal cells of the stomach by blocking the H2 receptor Block both daytime and nocturnal basal acid secretion reduce gastric acid released in response to food famotidine is the most potent followed by nizatidine.

Standard doses produce symptom relief in about 60% of patients (cimetidine 400mg. nizatidine 150mg or ranitidine 150mg twice a day) Efficacy can be improved by doubling the standard dose .H2RAs Relieve symptoms and may promote healing of mild oesophagitis Decrease the volume of gastric fluid available for reflux. famotidine 20-40mg.

phenytoin. Headache.H2RAs Side Effects: are uncommon. nausea. reversible mental confusion (mainly cimetidine) Drug Interactions: Cimetidine has a high frequency of drug interactions and interferes with metabolism of many drugs. with few differences between available drugs. dizziness. constipation. including warfarin. diarrhoea. skin rash (rare). .

Antacids .

Neutralize excess HCl in the stomach (by the reacted part) 2.Effects of the products of the reaction .Effect of the unreacted part 3.Antacids Antacid effects 1.

oxethazaine. magnesium hydroxide. diarrhoea (magnesium compounds).Antacids Combinations of aluminium hydroxide. and/or magnesium trisilicate with/without additives such as simethicone. or alginate Reduce acid concentration by reacting with gastric acid Do not reduce gastric acid secretion Used for symptomatic relief of gastric hyperacidity Side effects include constipation (aluminium hydroxide). intestinal concretions and obstruction .

Antacids 1.Effect of the reacted part: rapid neutralization of the gastric HCL 2.Unreacted sodium bicarbonate could be absorbed causing metabolic alkalosis if given in high doses or in patients with impaired renal function.NaCl produced by the reaction could be absorbed causing fluid retention and aggrevating hypertension 4. 3.CO2 produced causes gastric distention and increased production of .

Effect of the reacted part: less rapid neutralization of the gastric HCL 2.Antacids 1.High doses given with dairy products can lead to hypercalcemia and renal insufficiency (milk-alkali .CO2 produced causes gastric distention and increased production of gastrin which causes rebound acidity 3.

Unabsorbed aluminum salts may cause constipation .Antacids 1.No metabolic alkalosis 3.Effect of the reacted part: slow neutralization of the gastric HCL 2.

Unabsorbed magnesium salts may cause osmotic diarrhea 4.Magnesium could be absorbed and excreted by the kidney and therefore should not be given to patients with renal insufficiency for a long time .Effect of the reacted part: slow neutralization of the gastric HCL 2.No metabolic alkalosis 3.Antacids 1.

2.stimulates mucosal prostaglandins and bicarbonate production . it forms a viscous paste that binds to ulcers or erosions for 6 hours forming a physical barrier against hydrolysis of mucosal proteins by pepsin.Mucosal Protective Agents Sucralfate (Carafate) Sucralfate = complex aluminum hydroxide + sulfate + sucrose Mechanism of action: acidic environment of the stomach.

allowing the ulcer to heal Binds bile acids and pepsins and may therefore reduce their injurious effect Also binds to acute gastric erosion sites produced by alcohol or other drugs eg aspirin Usual dose is 1g four times a day on an .Mucosal Protective Agents Sucralfate (Carafate) Aluminium salt of a compound similar to sucrose Antiulcerant Binds to the surface of both gastric and duodenal ulcers and protects the ulcer from acid.

Mucosal Protective Agents Sucralfate (Carafate) Is only minimally absorbed from the GI tract but binds to ulcer site for up to 6 hours used for the short-term (8 weeks) treatment of duodenal ulcer with similar efficacy to H2 antagonists. Efficacy in the treatment of gastric ulcer has not been established long-term use by patients with renal impairment may result in accumulation of aluminium and cause adverse effects .

cimetidine.Mucosal Protective Agents Sucralfate (Carafate) Adverse Effects: Constipation (2%). phenytoin. norfloxacin and ciprofloxacin and therefore should not be . respiratory difficulties and rhinitis have been reported. ranitidine. Hypersensitivity reactions such as urticaria. angioedema. theophylline. Drug Interactions: Reduces absorption of digoxin.

Anti-Emetics .

Anti-Emetics •Substance P Neurokinin-receptor antagonist •5-HT3 Antagonists •Corticosteroids •Dopamine Antagonists .

Anti-Emetics Mechanism: All except domperidone have central dopamine antagonist activity and as a result they may cause extra-pyramidal side effects (more likely in people <20 years) .

a. Metoclopramide (Maxolon®, Pramin®): Dopamine receptor antagonist and a prokinetic agent. It blocks the dopamine receptors in the chemoreceptor trigger zone and stimulates the motility of the upper GI tract, accelerating gastric emptying. Dose: Up to 2mg/kg, repeated at 4 to 6 hourly intervals up to a usual maximum daily dose of 10mg/kg. Side effects: Restlessness, drowsiness, dizziness, headache. EPSE in children and elderly, avoid use in Parkinson‘s disease and depression.

c. Prochlorperazine (Stemetil®, Stemzine®): An anti-psychotic with a strong antiemetic activity. Acts mainly on the chemoreceptor trigger zone by blocking dopamine receptors, however, it also has a blocking action on histamine and muscarinic receptors. Dose: Oral – initially 20mg, then 10mg after 2 hours, if still needed 5-10mg three times a day. IM/IV – 12.5 mg every 8 hours when needed. Rectal – 25mg followed by an oral dose (if possible) after 6 hours.

•Bulking agents

•Osmotic Laxatives
•Stool Softeners

•Stimulant Laxatives

small hard stools and long-term control .Aperients BULKING AGENTS Onset: Agents: sterculia 48-72 hours Ispaghula husk. Normacol Mechanism: Absorb water in the colon to increase faecal bulk which stimulates peristaltic activity. •Bulking agents are useful for mild constipation. Fybogel. psyllium and Metamucil.

Glycoprep.30 mins (PEG or Saline laxatives) 2-30mins pr Agents: Sorbilax. Movicol. Microlax. Lactulose. Fleet Enema. Duphalac.Aperients OSMOTIC LAXATIVES Onset: 24-72 hours (Glycerol. Sorbitol) 5-30mins pr 5 . Osmosis Picolax Mechanism: . Colonlytely.

sulfate and citrate. . There is a risk of electrolyte disturbance particularly in the elderly. phosphate. PEG laxatives also contain electrolytes to minimise electrolyte and water loss. They have a fast onset of action and are suitable for occasional use when rapid bowel evacuation is required. children and patients with renal impairment or cardiovascular disease. They have a fast onset of action and are generally used for faecal impaction and severe constipation unresponsive to other treatment.Aperients Glycerol can be used for rapid relief of constipation when stool is present in the lower rectum. They are not suitable for acute relief of constipation as they can take several days to have an effect. Lactulose and Sorbitol need to be taken regularly. Saline laxatives contain poorly absorbed ions such as magnesium.

liquid paraffin is a lubricant. The evidence for the efficacy of stool softeners when used alone for constipation is lacking. Agarol.Aperients STOOL SOFTENERS Onset: Agents: 24 . rectal 5 . Docusate and poloxamer are detergents.72 hours. Poloxamer Coloxyl. . Parachoc Mechanism: These agents soften the stool and ease its passage. Liquid paraffin.20 minutes Docusate.

May also cause accumulation of water and electrolytes in the colonic lumen. chronic neuromuscular disease and in people taking opioids.Aperients STIMULANT LAXATIVES Onset: 6 . Senokot.60 minutes Agents: Bisacodyl.12 hours. often used with other laxatives there is no convincing evidence that chronic use of stimulant laxatives is harmful to the colon stimulants . Sodium picosulfate Dulcolax. rectal 5 . Bisalax Mechanism: Act by direct stimulation of nerve endings in colonic mucosa to increase intestinal motility. •May be used long term for constipation in spinal damage. Senna.

Thank You Questions? .