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Pharmacology 3251 Clinical and Experimental

CLINICAL PHARMACOLOGY 1: Indications, Signs and Symptoms Objectives: 1. Understand the terms clinical pharmacology, indications, signs and symptoms Indication: A condition or problem that necessitates or advises a particular treatment Symptom: An abnormality observed by the patient and regarded as irregular: how do they feel? Sign: An abnormality revealed on analysis: how are they? -

Need and indiation

-

Open Questions

-

Testing and Monitoring

-

Evidence

-

Adverse effects

-

Risk assessment

-

Simplification and switching

 2. Be familiar with reliable sources of drug information for therapeutics -

Australian Medicines Handbook (AMH)

-

Therapeutic Guidelines (eTG)

-

NPS MedicineWise Product Information (MIMS)

-

Consumer Medicines Information (CMI) Professional and patient sources

3. Describe the mechanism of action and clinical pharmacology of opioid analgesics Opioids: opium derived pain relief medicine which do not induce unconsciousness Highly effect pain relief

1 

Cellular actions: -

Act on Mu(µ), Kappa(ϰ) and Delta(δ) receptors

-

Inhibit intracellular cAMP formation via adenylate cyclase inhibition

-

Inhibit Ca2+  channel openings and prevent neurotransmitter release

-

Hyper polarisation of membranes due to opening of K+ channels Ultimately this leads to the inhibition of neuropeptide release and transmission neurons while simultaneously exciting inhibitory pathways.

Necessity of opioid use: Indications of opioid use is determined by pain, however there is no arbitrary scale for pain hence many scales can be used - visual, verbal, questionnaire, numeric etc Pain understanding can vary due to the actual sensation and the reporting of pain: -

Home environment, Patient beliefs, coping skills, cultural background, concept of suffering, gender, placebo effect

 Opioid:

Bioavailability

Half life

Indication

Codeine(Weak)

~High

4-6 hours

Moderate pain

Oxycodone



2-3 hours

Moderate pain - Antitussive

Morphine

25% -Metabolites are active

2-4 hours

Moderate - Severe pain - Cancer / post operative

Methadone

85%

13-58 hours

Moderate - Severe pain - used to treat opioid dependency

Buprenorphine - Partial agonist

16%

6-9 hours

Moderate - withdrawal

Fentanyl - 50-100x Morphine

Usually IV

1hour

Severe pain

2 

Heroin (Diacetylmorphine)

Not used clinically passes BBB and metabolism in brain



Cancer related / terminal pain (UK)



CLINICAL PHARMACOLOGY 2: Contraindications and Side Effects Objectives: 1. Understand the terms contraindications and side effects Contraindication: a condition which precludes a specific treatment due to adverse effect or interaction that may cause harm - Absolute or relative Side effects: On target and off target effects and adverse drug reactions(ADR) ADRs: -

Type A - related to the therapeutic use of the drug and is dosage dependent and predictable - adjust dosage

-

Type B - unrelated to therapeutics and is unpredictable with high mortality - stop drug treatment - Due to disease states, age, Pharmacogenetics of pharmacokinetic related metabolism and pharmacodynamic targets

-



2. Outline opioid side effects and how they can be managed 3. Describe how contraindication and side effect can limit the use of therapeutic drugs

PHARMACOKINETICS 1: Single Compartment Modelling Objectives: 1. Define key pharmacokinetic parameters 2. Use key pharmacokinetic formulae 3. Describe the key features of a one-compartment pharmacokinetic model

PHARMACOKINETICS 2: Two Compartment Modelling 3 

Objectives: 1. Describe the key features of a 2-compartment pharmacokinetic model 2. Discuss the two phases (a & b) relating drug concentration changes with time in the central compartment 3. Understand the effect of a 2 compartment model on the calculation of Vd and related parameters 4. Discuss the kinetic order of reactions 5. Discuss the effect of genetic variability on key pharmacokinetic parameters

PHARMACOKINETICS ONLINE LESSON Drug Clearance: Plasma cleared of drug per unit of time -

Metabolism and Excretion

-

CLtotal = CLrenal + CLliver + CLother Other may be breathed out or by gastric metabolism or other routes of either metabolism or excretion

-

How effectively the drug is removed from circulation impacts how the drug is dosed, if cleared quickly, it requires more frequent dosage to achieve steady state

Steady state: Plasma concentration of drug to be maintained as an effective therapeutic below a particular side effect or toxic range -

Steady state occurs when: rate of elimination = maintenance dosage rate -

Where Maintenance dosage rate = CL * CPss

Calculating: CL = F * Dose/AUC CL = 0.693 * Vd/t½ Clearance is critical in monitoring both that a drug is effective and remains below toxic and is affected by: -

Age

-

Disease

-

Pharmacogenetics (Individual polymorphisms) and Pharmacogenomics (Population predisposition - Ethnicities)

-

4 

Enzyme induction or inhibition

Volume of distribution: The volume that the drug has been distributed in the body, relate amount of drug in the body to the concentration of the plasma -

Note assuming the concentration is equal to that of plasma, if a drug is distributed straight to a tissue by outside intervention, it will have a different distribution

Vd = Ab/Cp Higher Vd indicates higher lipophilicity of the drug and a tendency to distribute to the tissue Higher volume of distribution will affect necessary loading dose, or a dose required to reach therapeutic range quickly. Drug Half Life: The time taken for a concentration of drug to half -

Usually 4-5 half lives before steady state is reached, assuming no loading dose is used

-

Below 10% of steady state concentration will remain after a similar 4-5 half life range when ending a drug cycle

Dosage is usually made once every half life, however some half lives may preclude this practice: -

Compliance: will the patient take the drug if the half life is too long or short - practical doses are required - if too short, increase dosages at longer intervals or if too long, smaller doses at smaller intervals

-

Safety and efficacy

Bioavailability and Oral Availability: The portion of a drug that remains therapeutic following metabolism Since IV doses negate first pass metabolism, the Bioavailability of a substance is determined by the relative concentration to an IV dose F = AUCpo/AUCIV Absorption: determined by: concentration gradient, area and blood supply Drug lipophilicity and low ionization helps Small intestine greatest point of absorption

5 

Protein Binding: The affinity of the drug to bind protein in the plasma - only free drugs are available to receptors Three major binding proteins in plasma: -

Albumin -

-

-

Acidic

Lipoproteins -

Lipid or basic drugs

-

Absorb in to lipid layer rather than specific binding sites

Acid Glycoproteins -

Higher concentrations during inflammation

-

Basic

Other drugs can compete for protein binding and alter the fraction of unbound drug Fraction unbound is relative to total concentration and does not change with drug concentration. pH and Pharmacokinetics: the ionisation of a drug effects its relationship with metabolic and excretion The plasma is hydrophilic and cell membranes are lipophilic hence ionisation states effects distribution and excretion via membrane permeability pKa = 50% of the drug is protonated. If pH > pKa then more of the drug will be deprotonated. Acids are ions when deprotonated (pH > pKa) AH → A- + H+ Bases are ions when protonated (pH < pKa) BH+ → B + H+ Disease states: Disease states can affect how drugs interact with the body Renal: -

Affects filtration and elimination of drugs and potentially predisposing the patient to toxic effects at regular dosage

6 

Liver: Affects metabolic capability due to reduced enzymatic activity or reduced liver blood blood flow -

Increased oral availability -

Due to decreased first-pass metabolism

-

Drugs that undergo extensive first-pass metabolism are most likely to be affected

-

Dose reductions of these drugs may be required

Decreased clearance -

Drugs that undergo extensive clearance by hepatic metabolism are most likely to be affected

-

Dose reductions of these drugs may be required

Cardiovascular: As blood flow is required for drug absorption, movement and distribution throughout the body, and elimination, it is unsurprising that the pharmacokinetics of a drug may be altered in patients with cardiovascular disease. -

Decreased or prolonged absorption

-

Decreased volume of distribution

-

Decreased clearance 

RENAL PHARMACOLOGY: Diuretics Objectives: 1. List at least 3 indications for the use of diuretics -

Hypertension

-

Oedema

-

Glaucoma

-

Hypernatremia

-

Nephrolithiasis

-

Hypercalemia

2. Name at least one example of a drug from each of the 5 classes of diuretics

7 

-

C Carbonic anhydrase inhibitors

-

O Osmotic

-

L Loop

-

T Thiazides

-

P Potassium sparing agents

3. Outline the mechanism of action and identify the primary site of action in the nephron of each of the 5 classes of diuretics -

C Carbonic anhydrase inhibitors

-

O Osmotic

-

L Loop = Thick ascending limb and inhibit K/Na/Cl reabsorption by cotransporter inhibition

-

T Thiazides = Act on the distal convoluted tubule by inhibiting Na/Cl cotransporter reabsorption

-

P Potassium sparing agents

4. Outline the adverse reaction profile for each of the 5 classes of diuretics  Drug Type and name

Site of Action

Adverse reactions Ion Flow

Example

Carbonic anhydrase Inhibits CA, preventing inhibitors Na+ H+ exchange gradient

Proximal Tubule

Metabolic Less Acidosis and reabsorbed: Na+, HCO3-, K+ alkaline urine - Sulfonamid e

Acetazolamide

Osmotic

Increases osmotic gradient to the tubule reducing water reabsorption

Loop of Henle

Gastric upset

Less reabsorbed: Na+, Cl- 

Mannitol

Loop

Binds to Cl- on 2Cl/Na/K cotransporter, preventing reabsorption of that method - Most effective ~25% Na excreted

Thick ascending limb

Gastric upset, hypotension, hypovolemia dehydration, gout, ototoxicity, low salt

Less reabsorbed: Cl- , Na+ , Mg2+  , 2- + Ca , K 

Frusemide

Thiazide

Inhibits Na+ Cl- cotransport reabsorption

Distal Metabolic Less Convoluted alkalosis, Gastric reabsorbed: Tubule upset, Electrolyte, Cl, Na, Mg, K

8 

Mechanism

hydrochloroth iazide

hypotension, More renal impairment reabsorbed: Ca Potassium sparing

Competes with Collecting aldosterone, prevents K Duct secretion and Na reabsorption

Gynecomastia, hypokalemia, Hepatic

Less reabsorbed: Na Less secreted: K

Spironolacton e

 5. Name at least five concerns regarding the use of diuretics in the elderly -

Reduced Kidney function

-

Incontinence

-

Treatment compliance and safety - Water pill

-

Fluid retention on ending treatment

-

Monitor electrolytes

LIPID LOWERING DRUGS Objectives: 1. Describe the basic structure, function and metabolism of lipoproteins Lipoproteins: = Phospholipid and apoprotein spherical with unesterified cholesterol and triglycerides in the centre Chylomicrons = dietary Lipoproteins synthesised in small intestine, deposits fat through lipolysis at tissue and finally at the liver VLDL = Synthesized by liver for fat distribution, mainly Triglycerides IDL = VLDL after lipolysis LDL = IDL after further lipolysis HDL = Mainly cholesterol, returns to liver 2. Describe the role of lipoproteins in disease Hyperlipidemia and hyperglyceridemia = increased lipid FFA and cholesterol in plasma and liver leading to fatty liver

9 

-

Reduced Chylomicron lipolysis

-

Reduced VLDL lipolysis

-

Increased serum and liver TG

3. List the common drugs and mechanism of action used to regulate lipoproteins  Drugs

Mechanism

Adverse effects

Drug

Statins

Inhibits endogenous Cholesterol Synthesis by HMG CoA reductase inhibition

Myotoxic ity

Atorvastat in & Rosuvastat in

Fibrates

Reduce serum triglycerides by stimulation of Beta oxidation in peroxisomes and some mitochondria

Gastric intestina l upset

fenofibrat e

Bile acid Sequestrants

Prevent bile reabsorption and induce more biosynthesis of bile acids and usage of serum cholesterol

Rash and Cholestyra irritation mine

Nicotinic

Prevents release of TG from adipose tissue, lowers system VLDL synthesis

Gastric intestina l upset

Niacin



ANTI-HYPERTENSIVES 1) Understand the factors that control blood pressure Blood Pressure > 140 / 90 Multifactorial and many unknown mechanisms for essential hypertension BP = TPR * CO -

Increased hypertrophy of smooth and cardiac muscle 

-

Reduced lumen diameter Non pharmacological approach - lifestyle changes

2) Describe the possible pharmacological approaches to lowering blood pressure 3) Describe the mechanisms of action of beta adrenoceptor antagonists, alpha 10 

adrenoceptor antagonists, calcium channel blockers, drugs affecting the renin angiotensin system, centrally acting drugs understand the adverse effects of therapy  Drug

Mechanism

Adverse effects

Drug

Diuretics

COLTP





Beta antagonists

Binds to Beta 1 receptors on the heart attenuates Sympathetic

Bronchospasm, reduced triglycerides, fatigue

Propranolol

Alpha antagonists Dilates vessels and Postural Ca Channel blockers smooth muscle tone hypotension, regulation Oedema, Flushing

Prazosin & Nifedipine

RAS system

ACE Inhibition reduce Angiotensin II AT1 Antagonists

Hypotension, Renal failure, and hyperkalaemia - fetal malformation

Enalapril - ACE inhibitor Losartan - AT1 Antagonists

Centrally acting agent

Reduced sympathetic outflow by Alpha 2 agonist (CNS)

Sedation, Sleep disturbance, depression, dry mouth

Clonidine

 4) Appreciate the need for combination therapy to control blood pressure 50% of patients do not respond to monotherapy

HEART FAILURE 1) definition, causes CO = HR * SV Insufficient oxygen perfusion to body due to faulty heart

11 

-

Myocardial infarction

-

Ischaemic heart failure

-

Metabolic

-

Inflammatory

-

Hypertension

Compensatory mechanisms leading to detrimental effects, Heart hypertrophy - Renin & Angiotensin - High Sympathetic tone 2) rationale for drug therapy Drug treatment Factors affecting Cardiac output - targeted by drugs Preload - Stretch before contraction or the degree of filling with blood Afterload - degree of resistance faced in contraction Contractility - force of the cardiac muscle Heart rate - BPM 3) mechanisms, uses, and side effects = diuretics Vasodilators Beta blockers inotropic drugs: cardiac glycosides, catecholamines  Drug

Mechanism

Diuretics

COLTP  For heart failure Loop and Thiazides



Renin Angiotensin block

ACE inhibitors Renal impairment, AT1 antagonists hypotension, Prevents hyperkalaemia Aldosterone release Lowering fluid retention and preload, and vasoconstriction lowering afterload

Enalapril (ACE inhibition) Losartan (AT1 Antagonist)

Vasodilator

Alpha receptor antagonist, lower vasoconstriction, in arteries = lowering afterload, in veins = lowering preload - Nitrates = Venous

Nitrate = isosorbide dinitrate Hydralazine

12 

Adverse effect

Reflex tachycardia Hypotension flushing and headache

Drug

dilation by NO donation and cGMP production Beta blockers

Beta adrenoceptor Hypotension, Antagonism, Non fatigue, low specific antagonism triglycerides can help prevent alpha 1 vasoconstriction, increase stroke volume

Propranolol - B Carvedilol - A and B

Cardiac Glycosides

Inhibits Na/K atpase to secondarily act on Na/Ca exchanger, reducing Ca efflux - Positive inotropy - Slower chronotropy

Digoxin

PDE inhibitors

Phosphodiesterase GIT upset, inhibitor reduces hepatotoxicity, breakdown of cAMP Arrhythmia

Catecholamine - Sympathomimetic

Beta stimulation for Arrhythmia, fatigue Dobutamine increased contractility

Anorexia, Diarrhoea, psychosis, drowsiness, Arrhythmia

Milrinone

HAEMOSTASIS AND THROMBOSIS ●

Describe how platelet activation can be prevented using antiplatelet drugs

Haemostasis is the act of maintain physio...