Pharmacology

Michael Soriano Clinical Pharmacist

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

Pharmacology
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.

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

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

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

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

Pharmacokinetics -in the elderly

There are important age-related changes in body composition and functioning which are relevant to the pharmacokinetics of drugs. 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
ABSORPTION
Age-related changes lead to a decrease in small-bowel surface area and an increase in gastric pH, but these changes do not lead to clinically significant changes in drug absorption. Factors affecting drug absorption include patients comorbid illnesses, timing of drug administration and other accompanying products. 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, calcium, magnesium and vitamin B12) are poorly absorbed in the elderly. *the bioavailability of some drugs may also be increased by reduced first
pass liver metabolism in older people.

Pharmacokinetics
DISTRIBUTION
With ageing, 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). 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.
Water soluble drugs such as paracetamol, digoxin, cimetidine and ethanol have decreased distribution to tissues resulting in higher serum concentrations. Fat soluble drugs such as diazepam, chlordiazepoxide, chlormethiazole, 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.

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

Pharmacokinetics
ELIMINATION
Most drugs are eliminated by the kidney as either the parent compound or as a metabolite or metabolites. 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 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

0800

1200

1800

Pharmacodynamics
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.

Polypharmacy
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.

Polypharmacy
THE PRESCRIBING CASCADE
A new resident comes in with dementia, incontinence, glaucoma and insomnia. How many drugs would usually be prescribed in practice?

How many drugs should be in the patients regimen?

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

Polypharmacy
Various studies found that 2.9% to 31% of all hospitalisations of older people are attributable to medication-induced illnesses. The most frequent drug-related causes of hospitalisations in a Melbourne study were gastrointestinal bleeding, cardiac arrhythmias, blood dyscrasias and postural hypotension. The most commonly implicated drugs were NSAlDs, digoxin, warfarin and theophylline, prescribed mainly for joint pain, cardiac disease, prevention of thromboembolism and respiratory disease, respectively.

Sample case study 1

Mr T. is a 68-year-old male who is a new resident in your nursing home (4 weeks ago). 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). Medical History: Alzheimers disease, shingles, incontinence, dry eye syndrome, #NOF 5 years ago, # wrist last year, osteoporosis, COPD, eczema.

Medications
Medication Dose (according to drug chart) Purpose/comments
Osteoporosis Shingles Anti-platelet Osteoporosis Alzheimers dementia provided by family provided by family Eczema Dry eyes Alzheimers 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

Sample case study 2

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

Medications
Medication Dose (according to drug chart) Purpose/comments
Atenolol 50mg12 in the morning Heart Digoxin 250microgram1 mane Heart Frusemide 20mg1 mane Diuretic Warfarin (Marevan) according to INR Prevent clots Paracetamol 500mg2 prn Pain. Variable frequency of use. Perindopril 5mg1 mane Heart Simvastatin 40mg1 at 6pm Cholesterol Blackmores Executive B Stress Formula multivitamin (B vitamins, vitamin C, vitamin E, folic acid, minerals and herbs) 1 daily OTC Fish Oil 1000mg1 daily OTC does not take these Bio ACE (Vitamin E 75IU, B vitamins, zinc and folic acid)1 daily OTC Glucosamine sulphate (Natures Own) 1950mg1 daily OTC most days ChelaMin (Potassium 167mg, Calcium 67mg, Magnesium 27mg, Vitamin D3 1.25mcg, and trace Zn, Fe, Cu, I and Cr) 1 daily Celecoxib 200mg1 tds Pain Budesonide 64mcg/dose 1-2 sprays each nostril daily Hayfever

Relevant test results:

3 months ago: BGL (fasting) = 6.1 mmol/L (3.8 5.5) 2 months ago: Digoxin 0.6 nanomol/L (0.6 1.0) NB time of last dose not stated 1 month ago: TG = 2.6 mmol/L (<1.5 ); TC = 6.3 mmol/L (<4.0); HDL = 1.5 mmol/L (>1.0); LDL = 3.8 mmol/L (<2.5) 4 weeks ago INR= 2.1 5 weeks ago INR=1.8 6 weeks ago INR=2.2

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

PHARMACOLOGY TOPICS ACUTE PAIN MANAGEMENT ANTICOAGULANTS GI MEDICATIONS

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

PAIN
1. Nociceptive

Usually responds to traditional analgesics

Has been noted to respond to non-traditional approaches such as antidepressants, anticonvulsants and sodium channel blockers.

2. Neuropathic

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

PAIN
Measuring pain
Bedside diaries Pain scales

WHO Analgesic Ladder

1. Mild pain
Non-opioid analgesic; with or without adjuncts and non-drug strategies.

2. Moderate pain
Step 1 plus weak opioids

3. Severe pain
Step 1 plus potent opioids

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. PRN prescribing: The term prn (pro re nata) means when necessary.

PHARMACOLOGY
ARACHIDONIC ACID CASCADE
NSAIDs, COX-2 inhibitors

OPIOID RECEPTORS
Opioids

DAMAGED NERVES NERVE IMPULSE TRANSMISSION

Antidepressants, membrane stabilizers

CENTRAL PAIN CONTROL

Paracetamol, Ketamine

PARACETAMOL
The mechanism of action is still unclear, but recent research has shown the presence of a new, previously unknown cyclooxygenase enzyme COX3, found in the brain and spinal cord, which is selectively inhibited by paracetamol, and is distinct from the two already known cyclooxygenase enzymes COX-1 and COX-2. 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

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

PAIN

NSAIDs

NSAIDs
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

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

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

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

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

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

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

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, either in terms of better pain relief, differences in side effects or patient satisfaction.

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, particularly for people at high risk of NSAID-induced adverse effects.

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. About 10% of Caucasian people and 12% of Asian people cannot metabolise codeine to morphine and so do not receive any analgesia only side effects i.e. increase nausea and constipation.

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. However it should be used with caution because of the high incidence of side effects (up to one-third experience nausea, vomiting, sweating, dizziness or hallucinations) and medication interactions (e.g. SSRIs and MAOI antidepressants).

Weak OPIOIDS
Dextropropoxyphene
It is often used in combination with paracetamol but this combination improves pain relief by only 7.3% compared with paracetamol alone and increases the incidence of dizziness. The major metabolite of dextropropoxyphene is nordextropropoxyphene which is renally excreted; accumulation of nordextropropoxyphene can lead to central nervous system (CNS), respiratory and cardiac depression

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 1.5 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 0.4mg im 0.8mg sublingual

60 70mg Unknown N/A 2- 2.5mg 6 7 mg 10mg 5 6 mg N/A 50mg 0.2 0.3mg

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)

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

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

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

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

Antidepressants
There are no published data on the use of antidepressants in the management of acute neuropathic pain. However, 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. 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
1. Tricyclic antidepressants are effective in the treatment of chronic neuropathic pain states, chronic headaches and chronic back pain. 2. In neuropathic pain, tricyclic antidepressants are more effective than selective serotonergic re-uptake inhibitors. 3. Antidepressants reduce the incidence of chronic neuropathic pain after acute zoster and breast surgery

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

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

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

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. Pain is easier to control when it is mild. 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.

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

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

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

Questions?

ANTICOAGULANTS

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

THE CLOTTING PROCESS

THE CLOTTING PROCESS

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

THE CLOTTING PROCESS

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

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, V, VII, VIII, XI, XIII, protein C, platelets Co-factor of VIIa (formerly known as factor III)

Calcium
V (proaccelerin, 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 - Activates IX, X Co-factor of IX with which it forms the tenase complex

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

THE CLOTTING PROCESS

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

THE CLOTTING PROCESS

REGULATORS
Five mechanisms keep platelet activation and the coagulation cascade in check. 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). It also inhibits excessive TF-mediated activation of FIX and FX. Plasmin proteolytically cleaves fibrin into fibrin degradation products that inhibit excessive fibrin formation. Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked receptors. This, in turn, activates adenyl cyclase, which synthesizes cAMP. cAMP inhibits platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release of granules that would lead to activation of additional platelets and the coagulation cascade.

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

Unwanted Clots - THROMBOSIS

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

ANTICOAGULANTS
HEPARINS

VITAMIN K ANTAGONISTS
DIRECT THROMBIN INHIBITORS FACTOR Xa INHIBITORS

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

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)

HEPARINS
LOW MOLECULAR WEIGHT HEPARIN 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. Protamine sulfate effectively reverses 60% of enoxaparin

HEPARINS
Enoxaparin in VTE prophylaxis Knee replacement Hip replacement

HEPARINS
Advantages of LMWH over UH
No need for laboratory monitoring. APTT for UH Higher bioavailability -90% vs 30% Longer Plasma Half Life 4-6 hours vs 0.1-1 hour (renal clearance slower than hepatic clearance) Less inhibition of platelet function, more specific for Xa receptors, less anti-Iia activity. Lower incidence of thrombocytopenia and thrombosis

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

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

WARFARIN
Major Adverse Effect - Haemorrhage Factors that may influence bleeding risk: Intensity of anticoagulation Concomitant clinical disorders Concomitant use of other medications Quality of management
Target INR
DVT, PE, Atrial Fibrillation: 2-3 Artificial Cardiac Valve: 3-3.5

Bivalirudin, Lepirudin - IV
DABIGATRAN - ORAL

DIRECT THROMBIN INHIBITORS

Unlike other anticoagulants, the actions of direct thrombin inhibitors are limited to thrombin

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

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 12,500 patients from 39 countries undergoing total hip replacement (THR) or total knee replacement (TKR). 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. These studies evaluated the efficacy and safety of Xarelto in the prevention of venous thromboembolism (VTE). Xarelto was administered as one 10 mg tablet once daily and compared to subcutaneous enoxaparin

Clinical Studies
THR: Xarelto provided significant risk reduction and comparable safety
In the RECORD1 and RECORD2 studies, 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, 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). This superior efficacy was accompanied by a good safety profile comparable to that of enoxaparin. In RECORD3 and RECORD4, Xarelto was associated with a significantly lower risk for the primary efficacy endpoint (composite of any DVT, non-fatal PE, and all-cause mortality) compared to enoxaparin, together with a safety profile comparable to that of enoxaparin in patients undergoing TKR surgery.

RECORD 1-3

RECORD 1-3

XARELTO Clinical Studies

EFFICACY Rivaroxaban was more effective than enoxaparin in RECORD 1, 3 and 4, when used for a similar duration. For total thromboembolism there was a statistically significant relative risk reduction of 3070%. For major thromboembolism the risk reduction was 4090% which was statistically significant in RECORD1 and RECORD3. SAFETY The rates of major or clinically relevant non-major bleeding were similar with rivaroxaban and enoxaparin 40 mg once daily. The apparent increases in bleeding were small and statistically insignificant. An overview found that rates of wound infection and reoperation due to bleeding were low and comparable. 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

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)

PRADAXA Clinical Studies

EFFICACY Both doses of dabigatran were statistically 'non-inferior' to enoxaparin in RENOVATE and RE-MODEL. 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. An overview showed a slight excess of bleeding with dabigatran 220 mg once daily, compared with enoxaparin 40 mg once daily, but this was not statistically significant.

The FUTURE

GI Medications

GI Medications
Drugs for GORD and ulcer

Anti-emetics
Aperients

How is Gastric Acid Secreted?

Gastric acid is produced by parietal cells (also called oxyntic cells) in the stomach. Its secretion is a complex and relatively energetically expensive process. Parietal cells contain an extensive secretory network (called canaliculi) from which the gastric acid is secreted into the lumen of the stomach. These cells are part of epithelial fundic glands in the gastric mucosa. The pH of gastric acid is 2 to 3 in the human stomach lumen, the acidity being maintained by the proton pump H+/K+ ATPase. The parietal cell releases bicarbonate into the blood stream in the process, which causes a temporary rise of pH in the blood, known as alkaline tide. The resulting highly acidic environment in the stomach lumen causes proteins from food to lose their characteristic folded structure (or denature). This exposes the protein's peptide bonds.The chief cells of the stomach secrete enzymes for protein breakdown (inactive pepsinogen and renin). Gastric acid activates pepsinogen into pepsinthis enzyme then helps digestion by breaking the bonds linking amino acids, a process known as proteolysis. In addition, many microorganisms have their growth inhibited by such an acidic environment which is helpful to prevent infection. Gastric acid secretion happens in several steps. Chloride and hydrogen ions are secreted separately from the cytoplasm of parietal cells and mixed in the canaliculi. Gastric acid is then secreted into the lumen of the oxyntic gland and gradually reaches the main stomach lumen. Chloride and sodium ions are secreted actively from the cytoplasm of the parietal cell into the lumen of the canaliculus. 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. The enzyme carbonic anhydrase catalyses the reaction between carbon dioxide and water to form carbonic acid. This acid immediately dissociates into hydrogen and bicarbonate ions. The hydrogen ions leave the cell through H+/K+ ATPase antiporter pumps. At the same time sodium ions are actively reabsorbed. This means the majority of secreted K+ and Na+ ions return to the cytoplasm. In the canaliculus, secreted hydrogen and chloride ions mix and are secreted into the lumen of the oxyntic gland. The highest concentration that gastric acid reaches in the stomach is 160 mM in the canaliculi. This is about 3 million times that of arterial blood, but almost exactly isotonic with other bodily fluids. The lowest pH of the secreted acid is 0.8,[1] but the acid is diluted in the stomach lumen to a pH between 1 and 3. 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. The gastric phase: 60% of the acid secreted is stimulated by the distention of the stomach with food. Plus, digestion produces proteins, which causes even more gastrin production. The intestinal phase: the remaining 10% of acid is secreted when chyme enters the small intestine, and is stimulated by small intestine distention. Gastric acid production is regulated by both the autonomic nervous system and several hormones. The parasympathetic nervous system, via the vagus nerve, and the hormone gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal cells and indirectly, through the stimulation of the secretion of the hormone histamine from enterochromaffine-like cells (ECL). Vasoactive intestinal peptide, cholecystokinin, and secretin all inhibit production. The production of gastric acid in the stomach is tightly regulated by positive regulators and negative feedback mechanisms. Four types of cells are involved in this process: parietal cells, G cells, D cells and enterochromaffinelike cells. Besides this, the endings of the vagus nerve (X) and the intramural nervous plexus in the digestive tract influence the secretion significantly. Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine and gastrin-releasing peptide. Their action is both direct on parietal cells and mediated through the secretion of gastrin from G cells and histamine from enterochromaffine-like cells. Gastrin acts on parietal cells directly and indirectly too, by stimulating the release of histamine. The release of histamine is the most important positive regulation mechanism of the secretion of gastric acid in the stomach. Its release is stimulated by gastrin and acetylcholine and inhibited by somatostatin. In the duodenum, gastric acid is neutralized by sodium bicarbonate. This also blocks gastric enzymes that have their optima in the acid range of pH. The secretion of sodium bicarbonate from the pancreas is stimulated by secretin. 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 4.5 to 5.0. The neutralization is described by the equation: HCl + NaHCO3 NaCl + H2CO3

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

Gastrin

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. HCl + Mg(OH)2 ex. HCl + Al(OH)3 MgCl2 + H20 AlCl3 + H20

H2RAs: Indirectly decreases gastric acid production through histamine receptors.

PPIs:

Blocks the proton pump to inhibit

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

CH2SONH

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, 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

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

Proton Pump Inhibitors

Adverse Effects: Very low incidence, similar to H2-antagonists. Headache, diarrhoea, nausea, abdominal pain, and less commonly, fatigue, flatulence, constipation.

Drug Interactions: Clopidogrel? P450 enzyme drugs

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, ranitidine and cimetidine

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

H2RAs
Side Effects: are uncommon, with few differences between available drugs. Headache, dizziness, nausea, diarrhoea, constipation, skin rash (rare), reversible mental confusion (mainly cimetidine)

Drug Interactions: Cimetidine has a high frequency of drug interactions and interferes with metabolism of many drugs, including warfarin, phenytoin,

Antacids

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

Antacids
Combinations of aluminium hydroxide, magnesium hydroxide, and/or magnesium trisilicate with/without additives such as simethicone, oxethazaine, 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), diarrhoea (magnesium compounds), 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. 3- NaCl produced by the reaction could be absorbed causing fluid retention and aggrevating hypertension 4- CO2 produced causes gastric distention and increased production of

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

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

Antacids
1- Effect of the reacted part: slow neutralization of the gastric HCL 2- No metabolic alkalosis 3- 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

Mucosal Protective Agents

Sucralfate (Carafate)
Sucralfate = complex aluminum hydroxide + sulfate + sucrose Mechanism of action: 1- in acidic environment of the stomach, 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. 2- stimulates mucosal prostaglandins and bicarbonate production

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, 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)
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

Mucosal Protective Agents

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

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)

Anti-Emetics
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 Parkinsons disease and depression.

Anti-Emetics
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.

Aperients
Bulking agents

Osmotic Laxatives
Stool Softeners

Stimulant Laxatives

Aperients
BULKING AGENTS

Onset:
Agents: sterculia

48-72 hours
Ispaghula husk, psyllium and Metamucil, Fybogel, Normacol

Mechanism: Absorb water in the colon to increase faecal bulk which stimulates peristaltic activity. Bulking agents are useful for mild constipation, small hard stools and long-term control

Aperients
OSMOTIC LAXATIVES Onset: 24-72 hours (Glycerol, Lactulose, Sorbitol) 5-30mins pr 5 - 30 mins (PEG or Saline laxatives) 2-30mins

pr
Agents: Sorbilax, Duphalac, Movicol, Glycoprep, Colonlytely, Microlax, Fleet Enema, Osmosis

Picolax
Mechanism:

Aperients
Glycerol can be used for rapid relief of constipation when stool is present in the lower rectum.

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

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

Aperients
STIMULANT LAXATIVES Onset: 6 - 12 hours; rectal 5 - 60 minutes

Agents:

Bisacodyl, Senna, Sodium picosulfate

Dulcolax, Senokot, Bisalax

Mechanism: Act by direct stimulation of nerve endings in colonic mucosa to increase intestinal motility. May also cause accumulation of water and electrolytes in the colonic lumen.
May be used long term for constipation in spinal damage, chronic neuromuscular disease and in people taking opioids; often used with other laxatives there is no convincing evidence that chronic use of stimulant laxatives is harmful to the colon stimulants

Thank You
Questions?