Handouts 2014

School of Life Sciences
2013 2014
Clinical Pharmacology & Medical Pharmacology Module Handbook
Convenor: Dr Roberts email: richard.roberts@nottingham.ac.uk
06/01/2014
Clinical Pharmacology/ Medical Pharmacology Modules
Dr. Richard Roberts- Module Convenor
Aim of the Module: To provide background information about common drugs that may come across in clinical situation -Mechanism of action -Use -Side effects
What is pharmacology? Study of drugs: The effect of the drug on the bodypharmacodynamics. The effect of the body on the drugpharmacokinetics.
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Receptors Neurotransmitters and some hormones cannot cross the plasma membrane. Receptors: proteins in plasma membrane which bind these compounds. Binding causes activation of the receptor activates intracellular signalling cascades response in the cell.
eg noradrenaline released from sympathetic nerve endings acting on vascular smooth muscle cells.
Membrane
a adrenoceptor
contraction
Some receptors are intracellular eg nuclear receptors Steroids act at nuclear receptors to alter gene transcription. Can cross plasma membrane.
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Intracellular receptors
Steroid hormone Extracellular Medium
Cytoplasm Steroid hormone receptor
Dimer formation
Nuclear membrane
Steroid response element
Target Gene
Receptor Nomenclature Receptors are combined into families based on the agonists that activate them and function. eg adrenoceptor family Activated by noradrenaline and adrenaline adrenoceptors 1 a2 b-adrenoceptors b1 b2 b3
Contraction of smooth muscle
Relaxation of smooth muscle
Get different responses depending on proportion of receptor subtypes present
Different subtypes useful for therapy. Can generate compounds selective for 1 subtype over the other. eg Noradrenaline & adrenaline- act at a & badrenoceptors Isoprenaline- selective for b-adrenoceptors. BUT not b1 or b2-adrenoceptors Salbutamol- selective for b2-adrenoceptors
NA
Therefore can create selective drugs- selective effects
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Adrenoceptors- role in fight or flight
Drugs can be agonists ie activate a receptor eg b2-adrenoceptor agonist acting on airways
Or antagonists- block the receptor therefore preventing the agonist from having an effect. eg b1-adrenoceptor antagonist acting on the heart
eg noradrenaline released from sympathetic nerve endings acting on vascular smooth muscle cells.
Membrane
a adrenoceptor
x
contraction Antagonist binds to receptor, preventing agonist from binding.
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Competitive antagonist competes for the binding site with the agonist. If there is a high enough concentration of agonist, the agonist can displace the antagonist and the response recovers.
contraction
contraction
Non-competitive anatagonist Binds to the receptor in such a way that the agonist cannot displace it, no matter how much agonist is present.
Alteration of Neurotransmitter Function
NT
Agonist
R
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eg b-blockers
NT
Antagonist
R
Pre-synaptic receptor
Agonist or antagonist
eg Loperamide, Domperidone
NT
Increase or decrease
Reuptake inhibitor
eg SSRI, St Johns Wort, Sibutramine, Bupropion
NT
NT NT NT NT
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Pre-cursor
Synthesis
eg ACEis
NT
Hormone
NT
R
Metabolism
eg MAOIs
eg PDE inhibitors
eg calcium channel blockers
NT
Inhibitors Inhibitors or activators R Enzymes
Action through Chemical Properties (non-specific effect). eg antacids- reduce acidity because they are alkaline. Laxatives- irritation- stimulates bowel movements.
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Summary The majority of drugs act at receptors. There are different receptors. And different subtypes of these receptors. Drugs can be designed to act selectively at these receptors. Therefore have selective effects in the body, and reduce side effects. Drugs can be designed to activate (agonist) or block (antagonist) receptors (or enzymes/ transporters)
The Physiology and Pharmacology of Drug Abuse.

Which drugs are abused and why? Are common mechanisms involved? What are the costs to individuals and society? Can drug abuse be treated?
Famous Drug abusers

Cocaine: Stephen King, Sigmund Freud, Robert Louis Stevenson (wrote Dr Jekyll & Mr Hyde in six days and nights on a cocaine binge. "That an invalid in my husband's condition of health should have been able to perform the manual labour alone of putting 60,000 words on paper in six days, seems almost incredible," said his astonished wife, Fanny). Amphetamines: Charlie Parker, Lenny Bruce, Judy Garland, Anthony Eden, Adolf Hitler (couldn't function without daily methylamphetamine injections into his buttocks by his ever-diligent, physician, Doctor Morell). LSD: Timothy Leary, Jonathan Aitken, Aldous Huxley, Dr Kary Mullis (Nobel Prize Winner for Chemistry in 1993 and inventor of PCR, a method for detecting even the smallest amount of DNA. "Would I have invented PCR if I hadn't taken LSD? I seriously doubt it, I could sit on a DNA molecule and watch the polymers go by. I learnt that partly on psychedelic drugs.) Ecstasy: Shaun Ryder, Sting Fat Boy Slim, Eminem (takes half an E before every stage performance to "loosen up)
Heroin: River Pheonix, Thomas De Quincey, King George V, Charlie Parker, William Borroughs (.heroin, the ultimate merchandise. No sales talk necessary. The client will crawl through a sewer and beg to buy) Other abused drugs: cannabis, ethanol, nicotine, solvents, benzodiazepines
Addictive behaviours; eating, sex, exercise, Everton FC.
Definitions
Addiction; the compulsion to take a drug irrespective of any associated adverse consequences. Dependence; the need for continuing exposure to a drug (to avoid physical and/or psychological disturbances associated with abstinence (withdrawal syndromes)). Many abused drugs not associated with withdrawal symptoms; many therapeutic drugs are!
Tolerance; the need to increase drug dose to maintain the same effect.
All compulsive drug taking now considered to have an element of drug-seeking behaviour.
Abused drugs have very different structures; can they have a common mechanism in promoting reward?
Nerves communicate by releasing neurotransmitters that are recognised by receptors
Brain Reward Pathways

Many essential behaviours are pleasurable (rewarding).
Activity in some neuronal pathways in the brain are associated with reward. For example; rats will self-administer some drugs and these drugs activate reward pathways. Much attention on the meso-limbic dopamine pathway (cell bodies in ventral tegmental area, VTA, terminate in the nucleus accumbens).
Many drugs of abuse, opiates, nicotine, amphetamine, cocaine, ethanol, cannabis, ecstasy, PCP, barbiturates, caffeine increase dopamine release in the nucleus accumbens.
Dopamine release in the nucleus accumbens is a common response to drugs of abuse
Drugs of abuse enhance release of dopamine from VTA neurones. GABA inhibits neuronal activity.
Functional Magnetic Resonance Imaging (FMRI) for measurement of human brain activity
Can be used to measure regional blood flow in the brain by BOLD technique. Increases in neuronal activity increase oxygen requirement, accompanied by changes in local blood flow. Changes ratio of haemoglobin to oxyhaemoglobin (have different characteristics in magnetic field). Can, therefore, detect which areas of the brain are activated by different drugs. Administration of opiates, amphetamine and cocaine to humans enhances blood flow in dopamine-rich areas such as the nucleus accumbens and the VTA.
Does taking drugs recreationally do you any harm?
Heroin
Short-term effects appear soon after a single dose and disappear in a few hours. After an injection, the user reports feeling a surge of euphoria ("rush") accompanied by a warm flushing of the skin, a dry mouth, and heavy extremities. Following this initial euphoria, the user goes "on the nod," an alternately wakeful and drowsy state. Mental functioning becomes clouded due to the depression of the central nervous system. Unwanted effects; respiratory depression (fatal in overdose), constipation. Chronic users may develop collapsed veins, infection of the heart lining and valves, abscesses, cellulitis, and liver disease. Pulmonary complications, including various types of pneumonia, may result from the poor health condition of the abuser and respiratory depression. Nutritional status tends to be poor. Danger of HIV and hepatitis from injecting. Withdawal precipitates craving, restlessness, muscle and bone pain, insomnia, diarrhea and vomiting, cold flashes with goose bumps ("cold turkey"), kicking movements ("kicking the habit"). Major withdrawal symptoms peak between 48 and 72 hours after the last dose and subside after about a week. Sudden withdrawal by heavily dependent users who are in poor health is occasionally fatal, although heroin withdrawal is considered less dangerous than alcohol or barbiturate withdrawal.
Cocaine
The powdered, hydrochloride salt form of cocaine can be snorted or dissolved in water and injected. Crack is cocaine that has not been neutralized by an acid to make the hydrochloride salt. This form of cocaine comes in a rock crystal that can be heated and its vapours smoked. Crack" refers to the crackling sound when it is heated. Cocaine blocks the re-uptake of monoamine neurotransmitters in the peripheral and central nervous systems. Physical effects include constricted blood vessels, dilated pupils, and increased temperature, heart rate, and blood pressure. The duration of cocaine's immediate euphoric effects, which include hyperstimulation, reduced fatigue, and mental alertness, depends on the route of administration. The faster the absorption, the more intense the high. On the other hand, the faster the absorption, the shorter the duration of action. The high from snorting may last 15 to 30 minutes, while that from smoking may last 5 to 10 minutes. Increased use can reduce the period of time a user feels high and increases the risk of addiction.
Cocaine cont.
Some tolerance, but sensitisation possible. Binges, during which the drug is taken repeatedly and at increasingly high doses, may lead to a state of increasing irritability, restlessness, and paranoia; can result in full-blown paranoid psychosis. Cardiovascular complications, arrhythmias, heart attack, stroke. Appetite reduction leading to malnourishment.
Ecstasy (MDMA (3,4 methylenedioxymethamphetamine);

releases monoamine neurotransmitters (5HT, noradrenaline, dopamine). Acts as both a stimulant and psychedelic, producing an energizing effect, as well as distortions in time and perception and enhanced enjoyment from tactile experiences.
In high doses, MDMA can interfere with temperature regulation. On rare but unpredictable occasions, this can lead to severe hyperthermia, resulting in liver, kidney, and cardiovascular system failure, and death. ( Leah Betts died from drinking too much water). Cardiovascular risks similar to cocaine. In animal studies (adolescents more susceptible) MDMA is neurotoxic. MDMA meets many of the accepted diagnostic criteria for addiction, as evidenced by continued use despite knowledge of physical or psychological harm, withdrawal effects, tolerance and almost 60 percent of people who use MDMA report withdrawal symptoms, including fatigue, loss of appetite, depressed feelings, and trouble concentrating.
Cannabis: (active agent THC) mimics effects of small endogenous

lipid messengers (e.g. anandamide) , inhibits wide range of neurotransmitter release in the brain and periphery. Mild euphoric effect in moderate doses; dysphoria in high doses particularly nave users. Context dependent.
Very low acute toxicity but some concerns about precipitation of schizophrenia in chronic heavy users.
Stimulates appetite through actions on feeding centres in the the hypothalamus and possibly gut.
Alcohol
CNS depressant (excitatory effects due to disinhibition). Large doses irritate stomach (nausea, dyspepsia). Inhibits anti-diuretic hormone causing dehydration (hangover). Involved in many accidents; alcohol use a major factor in 25% males admitted to UK hospitals Long term drinking leads to: neuropathies (peripheral and central e.g. Wernickes encephalopathy (psychosis)); myopathies (most seriously primary caridomyopathy); hepatotoxicities (cirrhosis most common), haematological disorders. Alcoholics often obese (high calorific intake) but malnourished, particularly vitamin deficient. Suicide very common in alcoholics: 80x higher than non-alcoholic. Up to 30% alcoholics die by suicide and up to 50% all suicide attempts in UK made by alcoholics Severe withdrawal syndrome associated with alcoholism; most severe form delirium tremens. Confusion, delusions, tactile and visual hallucinations, convulsions, cardiovascular collapse (15-50% mortality)
How common is the use of abused drugs?
Self-reported drug use (ever in lifetime) in 17-18 year old US students, 2005: Heroin, 1.5%; Cannabis, 45%; Ecstasy, 5.4%; LSD, 3.5%; Solvents 11.4%; Amphetamines, 4.5%; Steroids 3.4%;
Cigarettes 23% (in last 30 days),
Drug abuse costs society up to 18.8bn a year - or more than 300 per person - in England and Wales including the costs of crime, social security and bringing drugs offenders to justice, as well as the bill to the NHS. Annual costs per user; young recreational and older regular
users: less than 20; Class A users, 2,030; Problem users, 11,000
For every 1 spent on treatment, at least 5 is saved on health service and criminal justice costs.
Pharmacological approaches to treatment of drug abuse

(Not effective without psycho-social support). Substitution e.g. methadone treatment for opiate abuse. Long-acting synthetic opiate agonist administered orally for sustained period at dose sufficient to prevent opiate withdrawal, blocks effects of illicit opiate use, and decreases opiate craving. Patients stabilised on adequate, sustained dosages of methadone can hold jobs, avoid crime and violence of the street culture, reduces exposure to HIV by stopping injecting.
Nicotine replacement
Nicotine-containing gum and sub-lingual tablets provide slow buccal absorption avoiding bolus obtained by smoking, reduces withdrawal syndrome. Clinical trials evidence mixed: little use in reducing cigarette consumption, craving significantly reduced but one year quit rates unaffected (around 20%). Nicotine patch results similar: little effect on quit rates irrespective of nicotine dose or patient population. Nicotine nasal sprays also available.
Antagonist treatments
Naltrexone therapy for opiate addiction Long-acting synthetic opiate antagonist; all the effects of selfadministered opiates, including euphoria, are completely blocked. Few side effects, taken orally either daily or three times a week for a sustained period of time. Individuals must be medically de-toxified and opiate-free for several days before naltrexone can be taken to prevent precipitating opiate abstinence syndrome. Best used in outpatient settings after medical detoxification in a residential setting. Theory is that the repeated lack of the desired opiate effects, as well as perceived futility of using the opiate, will break the habit of opiate addiction. Naltrexone itself has no subjective effects or potential for abuse. Patient non-compliance is major problem.
Nicotine Antagonists
Mecamylamine: nicotinic acetylcholine receptor antagonist. Blocks rewarding actions of nicotine and (apparently) cueinduced craving. Interestingly, mecamylamine also reduces craving and anxiety associated with handling paraphernalia in cocaine addicts. Since smoking is more common amongst cocaine users and nicotine enhances cue-induced cocaine craving, some argue that the link supports gateway theory.
Peripheral antagonists
General approach to produce circulating antibodies that bind drugs of abuse in the bloodstream. Extension of this is to use enzymes or engineered antibodies that bind to and metabolise drugs. Can be overcome by increasing dose of drug. Cocaine fragments bound to a protein carrier have been used to generate an antibody (Cantab Pharmaceuticals) now in clinical trial. A nicotine vaccine has also been developed.
Anti-craving medicines
Acamprosate (Ca2+salt of N-acetyl-homotaurine); registered for use as adjunct in maintaining abstinence in alcohol-dependant patients (666mg tds). Reduces alcohol consumption in alcohol-preferring rats! Reduces neuronal excitability that occurs during alcohol withdrawal. Naltrexone in addition to role in opioid dependence also reduces alcohol craving by interfering with positive reinforcement and possibly alcohol-conditioned cues. Possibly acts by blocking endogenous opioid disinhibition of GABA neurones in VTA thereby reducing firing of dopamine releasing neurones.
Afebutamone/buproprion (Zyban)
Registered as adjunct to smoking cessation. Old antidepressant drug; mixed NA/5HT uptake inhibitor. Significantly reduces craving and extends quit rates. Mechanism of action unknown. Other antidepressants reported to have beneficial effects in alcohol craving but differences between individual SSRIs indicates complex mode of action. Contraindicated in seizure-prone patients.
Acomplia (rimonabant, SR141716A)

Cannabinoid receptor antagonist; blocks the effects of natural cannabinoids (endocannabinoids) such as anandamide in the brain. Cannabis increases appetite; Acomplia reduces appetite & aids weight loss. Also (apparently) reduces craving in smoking cessation. Early days; might block other useful endocannabinoid effects (e.g. ability to forget, anxiolysis, anti-cancer etc).
Curing addiction
Ibogaine, an hallucinogenic alkaloid found in the root bark of the African shrub Tabernanthe iboga. Claimed to be a complete cure for heroin, cocaine, alcohol etc, addiction. Has a complex pharmacology; reduces reward in experimental animals but also somewhat neurotoxic.
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Antibiotics, antifungals, & antivirals
Learning Objectives: To understand the mechanisms of action of commonly-used antibiotics, anti-fungals and antivirals.
Peptidoglycan Precursor molecules & ATP Amino acids & nucleotides Proteins RNA DNA
Cell Wall
Cell membrane
Inhibiting these processes will prevent bacteria growing and dividing
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Aim: Selectivity for bacteria over mammalian processes. Target processes only in bacteria eg synthesis of cell wall. Make pores in cell wall. Inhibit DNA/RNA synthesis.
Antibiotics Beta-lactam antibiotics 1. Penicillins 2. Cephalosporins and cephamycins 3. Carbapenems and monobactams Interfere with synthesis of peptidoglycan which makes up bacterial cell wall - not present in humans Inhibits formation of cross-linking between peptide chains.
Peptidoglycan Formation
Tetrapeptide Side-chain Peptide crosslinks
b-lactams
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Penicillins -Oral or iv -Widely used -Can cause hypersensitivity reactions eg skin rashes -GIT disturbances eg amoxicillin, ampicillin
Cephalosporins & Cephamycins -can be given orally, but most given parenterally, IM or IV -septicaemia, pneumonia, menigitis, UTI. - Can cause hypersensitivity reactions.
Resistance Penicillins and cephalosporins contain beta-lactam ring. Beta-lactamases produced by bacteria break this ring. O R1 C H N O N COOH S CH3 CH3
Penicillin
b-lactamase Carbapenems and monobactams developed to deal with b-lactamase producing bacteria
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Flucloxacillin- b-lactamase resistant penicillin.
Antibiotics affecting Bacterial Protein Synthesis Tetracyclines -Protein synthesis occurs in ribosomes -Tetracyclines compete with tRNA (translational RNA) prevent binding to ribosome, prevents protein synthesis. -Selective for bacterial ribosome. -Bacteriostatic -Wide spectrum of activity -eg tetracycline, minocycline, doxycycline -Resistance due to induction of proteins promoting efflux of drugs from bacterium.
Chloramphenicol -Prevents peptide chain elongation -Reserved for serious infections due to toxicity -Resistance through production of chloramphenicol acetyltransferase
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Aminoglycosides eg gentamycin, streptomycin, neomycin -Given by IV eg septicaemia -Cause misreading of message- bactericidal -Resistance by inactivation by enzymes. -Can cause ototoxicity
Peptide chain
tRNA
Chloramphenicol prevents chain elongation
Tetracyclines prevent tRNA binding 50S subunit
Aminoglycosides: misreading of message
30S subunit
Macrolides eg erythromycin, clarithromycin -Prevent peptide chain extension. -Used in penicillin-sensitive patients. -Given orally -Side effects- GIT disturbances -eg H. pylorri, Legionnaires disease, diptheria -Resistance due to an alteration of the binding site on the bacterial ribosome.
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Antifungal Drugs Amphotericin Macrolide antibiotic. Binds to cell membranes- forms a pore in membrane Selective for fungi. Given topically Can cause renal toxicity
Griseofulvin Fungistatic Interferes with division/ growth Given orally
Azoles eg ketoconazole, fluconazole, itraconazole Inhibit fungal cytochrome P450 3A enzyme. Prevents formation of sterol used in fungal membrane. Alters fluidity of membrane - net effect impairs replication. Liver toxicity (rare) with ketoconazole.
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Antiviral Drugs Viruses- essentially nucleic acid contained in protein coat DNA Viruses- eg smallpox, herpes viruses DNA translated into mRNA by host RNA viruses- eg influenza, measles, mumps, rubella RNA acts as mRNA Retroviruses- DNA copy made of RNA by reverse transciptase. DNA then integrated into host cell DNA
Reverse transcriptase
Proteins
Transcription
HIV replication in host cell
Anti-HIV Drugs (anti-retroviral drugs) -Reverse transcriptase inhibitors. -Prevents copying of viral RNA into DNA. Hence prevents replication. -Nucleoside Reverse Transcriptase Inhibitors -eg zidovudine (azidothymidine, AZT) -Analogues of nucleosides. eg AZT analogue of thymidine. -Competes with host nucleosides for reverse transcriptase- causes chain termination.
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Reverse RNA Transcriptase DNA AZT ACGTCCTGC ACGTCCTGCT AZ More nucleosides cant attach
Associated with a number of unwanted side effectscan effect DNA replication in host. Therapeutic response of zidovudine wanes with time due to mutation of the virus and hence resistance.
Non-Nucleoside Reverse Transcriptase Inhibitors Bind to reverse transcriptase near catalytic site and denature it. eg Nevirapine & Efavirenz
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Protease Inhibitors HIV mRNA- transcribed into 2 polyproteins These are converted into structural proteins by a virus-specific protease. Protease inhibitors prevent this eg saquinavir (SQV) nelfinavir (NFV) indinavir (IDV)
Can cause GIT disturbances and metabolic abnormalities (eg insulin resistance).
Combination Therapy Changed prognosis of HIV. Highly Active Antiretroviral Therapy (HAART). 2 Reverse transcriptase inhibitors with one or more protease inhibitor. HIV replication is inhibited. Patient survival is prolonged. But many unwanted side effects. Lifelong treatment as virus not eradicated.
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Other Antiviral Drugs Acyclovir Treatment of herpes simplex (cold sores, genital infections) and Varicella-Zoster viruses (shingles & chickenpox). Guanosine derivative. Inhibits DNA polymerase- inhibits chain formation. 30x more specific for virus DNA polymerase
Neuroaminidase Inhibitors Neuroaminidase (or sialidase) -surface glyocoprotein (enzyme) -required for replication of influenza virus -Allows release of virus from infected cells -Zanamivir (Relenza) -Oseltamivir (Tamiflu) Reduce duration of influenza if given within 36 (Z) or 48 (Os) hours of infection.
Summary -Multiple ways of inhibiting bacteria. -Bacterial resistance is a growing problem. -Fewer antifungal and antiviral drugs. -Increased knowledge of HIV has allowed new targets to be identified and hence new drugs. -Antiviral drugs inhibit replication, but do not eradicate.
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RESPIRATORY PHARMACOLOGY
Dr. Richard Roberts
Objectives
Understand the pathophysiology of asthma and COPD Be familiar with the pharmacological targets of the drugs used Be familiar with current treatment recommendations Have a knowledge of the adverse effects of the drugs used
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Lung Structure
Trachea Main Bronchi Increased surface area
Bronchi
Bronchioles
Alveoli
Structure
Alveoli
Epithelial Cells
LUMEN Mucous secreting globlet cells cilia Epithelial cells Smooth muscle cells
Mucous traps particles and cilia help to move these particles out of lung NB cystic fibrosis- thick mucous
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Innervation of the airways

Pathways involved: Sympathetic: circulating adrenaline - act on 2-adrenoceptors on bronchial smooth muscle to cause relaxation - - inhibition of mediator release from mast cells 2-adrenoceptors also on mucous glands to inhibit secretion Increased clearance of mucous.
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Adrenoceptors
b adrenoceptors: Subtypes
b1 adrenoceptors eg sino atrial node and ventricles in heart- rate and force of contraction eg airway smooth musclerelaxation eg skeletal muscle, adipose tissue
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b2 adrenoceptors b3 adrenoceptors
Parasympathetic Innervation: Release Acetycholine (ACh) activates muscarinic M3 receptors Bronchoconstriction increase mucous secretion Sensory nerves local reflexes, respond to irritants Cause coughing, bronchoconstriction and increased mucous secretion
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Muscarinic Receptors
Subtypes:
M1 CNS, salivary glands, gastric glands M2 Heart- rate of contraction, GI smooth muscle contraction, CNS M3 Salivary glands, smooth muscle (GI, airways) M4 CNS M5 CNS
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Role of Sensory Nerves in Local Control: Potential Role in Exercise-Induced Asthma

Water loss from airways in exercise thought to stimulate release of mediators and activates sensory nerves:
Thanai Pongdee , James T. Li Annals of Allergy, Asthma & Immunology Volume 110, Issue 5 2013 311 - 315
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Sensory Nerves
Sensory nerves: up-regulated by inflammationare sensory nerves hypersensitive in asthmatics? Other local control eg Cold Receptors: Detect changes in temperature May be involved in cold-induced asthma
Refs: TRPM8 mediates cold and menthol allergies associated with mast cell activation Cho et al. (2010) Cell Calcium 48, 202-208 TRPM8 mechanism of autonomic nerve response to cold in respiratory airway . Xing et al. (2008). Molecular Pain
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Normal v Obstructive
eg COPD, asthma- cannot expel all air quickly
Obstructive Normal FEV1 (4.0L) FVC (5.0L) FEV1 (1.3L) FVC (3.1L)
FEV1 = 32% of Normal FEV1:FVC= 0.42
FEV1 is lower as air comes out slower. FVC may be normal if all air can be expelled. COPD- may drop if all air cannot be expelled
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Peak Flow Meter

Way of patients keeping an eye on their lung function Small, hand held device. Measures flow of air out of lungs. PEF- rises rapidly during forced expiration, then drops. Constriction of airways reduces peak flow.
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Asthma
Affects 5-10% of population Reversible increases in airway resistance, involving broncho-constriction and inflammation Decreases in FEV1 and the FEV1:FVC ratio Value of < 70% suggests increased airway resistance. If it is asthma this should be reversed by a b2-adrenoceptor agonist.
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Asthmatic attack
Genetic predisposition, provoked by: allergens cold air viral infections smoking exercise
Genetic component associated with atopy (hayfever, eczema)
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Phases of an Asthmatic Attack

Allergen Mast Cell histamine PGD2 LT C4 LTD4 Bronchoconstriction
Early Phase
Chemokines eg ILs Chemotaxins
Late Phase Leukocytes eg T cells neutrophils basophils
Late Phase
Occurs at a variable time after initial stimulus. Chemotaxins (Leukotriene B4, PAF) attract monocytes & eosinophils (leukocytes) Cause airway inflammation & airway hypersensitivity
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ASTHMA THERAPY
Two main categories: 1 Relief of symptoms bronchodilators
Block early phase of asthma attack caused by bronchoconstriction. 2 Prevention of attack - anti-inflammatory agents
Prevents late phase caused by release of cytokines.
BRONCHODILATORS
Reverse bronchospasm Rapid relief 2-adrenoceptor agonists eg. Salbutamol (ventolin) Agents of 1st choice
Increase FEV1 Act on 2-adrenoceptors Given by inhalation Longer acting agents (e.g. salmeterol) given for long term prevention. bronchodilation
Salbutamol
Gs
Adenylyl cyclase cAMP Relaxation of airway tone
ATP
2-adrenoceptor agonists
-adrenoceptors also on mast cells Increase in cAMP prevents release of eg histamine Also effects on mucous secretion
Long Acting -adrenoceptor agonist (LABA)

eg salmeterol, formoterol (2x daily) Indacaterol (1x daily) Salbutamol (SABA) 4x daily Reason why they are long acting not clear Current theory- absorbed into lipid bilayer of cells Slowly released over time to activate receptor
Adverse effects
2 Adrenoceptor agonists
Tremor, palpitations, hypokalaemia (high doses e.g. nebulisers)
Regulation of cAMP by PDEs

Salbutamol
Gs
Adenylyl cyclase cAMP ATP Phosphodiesterase (PDE) 5 AMP
PDE Isoform PDE1 PDE2 PDE3 PDE4 PDE5 PDE6 PDE7 PDE8 PDE9 PDE10 PDE11
Metabolises cAMP & cGMP cAMP & cGMP cAMP cAMP cGMP cGMP cAMP cAMP cGMP cAMP & CGMP cAMP & cGMP
Phosphodiesterase Inhibitors
Roflumilast (PDE4) inhibitor (Daxas) COPD Reduces inflammation Potential for enhancing -AR effects
Muscarinic M-receptor antagonists
Block parasympathetic bronchoconstriction e.g. ipratropium (non-selective antagonist) Given by inhalation- no systemic side effects Also inhibits mucous secretion Tiotropium- long-acting
Adrenaline
ACh
Gq
cAMP
Ca2+
Bronchodilation
Contraction
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Side Effects
Non-selective therefore block muscarinic receptors around the body: Dry mouth (salivation) Nausea/ headache (CNS) Atrial fibrillation & tachycardia & palpitation (cardiac) Constipation (GI) Urinary retension Blurred vision (accommodation)
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Xanthines
eg theophylline (doxofylline, enprofylline) Bronchodilators, but not as good as b-adrenoceptor agonists (2nd line use) Oral (or i.v. aminophylline in emergency) Historically- phosphodiesterase inhibitors- increase cAMP, but not at clinically relevant concentrations Adenosine receptor antagonist? Anti-inflammatory effects
Aminophylline
Mix of theophylline and ethylenediamine (2:1 ratio) Improves solubility Monitor plasma levels- toxicity
Side effects:
Tremor, palpitations, nausea CNS stimulation (sleep disturbance, overactivity) Drug interactions: inhibition of metabolism increases risk of toxicity eg cimetidine induction of metabolism reduces plasma levels eg smoking (NB smoking cessation will lead to increase in plasma levels!)
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ANTI-INFLAMMATORY AGENTS
Preventative; do not reverse an attack
Corticosteroids: Act at intracellular glucocorticoid receptor. Inhaled:

Beclometasone Budesonide Ciclesonide Fluticasone Mometasone
ANTI-INFLAMMATORY AGENTS
Oral: Prednisolone eg acute asthma attack OR IV Hydrocortisone eg life-threatening acute asthma
Intracelular receptors
Steroid hormone Extracellular Medium
Cytoplasm Steroid hormone receptor
Dimer formation
Nuclear membrane
Steroid response element
Target Gene
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Mechanism
Leads to altered gene transcription: results in decreased cytokine and chemokine production eg TNF, IL-1, IL-2, IL-3, IL-6 Upregulation of anti-inflammatory genes eg annexin A1 (also known as lipocortin). Annexin A1 appears to act through formyl peptide receptors (FPR) oInhibits release of histamine from mast cells oInhibits cPLA2- PGs
AnnexinA1: inhibits synthesis of PGs and LTs: Corticosteroid Membrane

Annexin A1
PLA2 Arachidonic acid
Leukotrienes
Prostaglandins
Side effects of corticosteroids: throat infections (inhalation) and adrenal suppression (oral)
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Side effects
Corticosteroids Throat infections or oral candidiasis with inhaled Osteoporosis (diet/risk factors, bisphosphonates for prevention) Adrenal suppression in children Use lowest effective dose of steroid and not exceed max. Monitor height Indigestion (oral) Chicken pox severe (avoid contact)- immune response Withdrawal effect (reduce oral steroids gradually if >3 weeks)
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Steroid Resistance
COPD is a chronic inflammation BUT, steroids largely ineffective at reducing inflammation in COPD Suggests: steroid resistance May be due to alteration of glucocorticoid receptor.
CysteinylLeukotriene receptor antagonists e.g. montelukast, zafirlukast Allergen Mast Cell histamine PGD2 LT C4 LTD4
Bronchoconstriction Early Phase
Chemokines Chemotaxins
Late Phase Leukocytes
CysteinylLeukotriene receptor antagonists e.g. montelukast, zafirlukast
Block LT receptors block inflammatory actions of cysteinylleukotrienes (cystLTs) Leukotrienes also cause bronchoconstriction, therefore this also blocked Leukotriene synthesis inhibitors-block synthesis of leukotrienes and LTB4. eg zileuton, ZD-2138, Bay X 1005, and MK-0591 (not licensed)
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Side effects
Headache, rash Nausea, jaundice or other signs of liver toxicity Mood disorders/ suicidal thoughts reported with montelukast
Omalizumab (Xolair)
Severe, allergic asthma that cannot be controlled by steroids. Monoclonal antibody against free IgE Prevents IgE from binding to immune cells thus preventing allergen-induced mediator release s.c. injection every 2-4 weeks
Cromones
Sodium cromoglicate
Preventative (both early + late) May be of benefit in exercise-induced asthma Inhalation Uncertain action: mast cell stabiliser?
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Treatment of Asthma Initially identify and avoid the triggers for an asthmatic attackDust, animals, smoke, cold air etc
Lifestyle changes- weight reduction. Breast feeding of babies may prevent development of asthma
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British Thoracic Society Guidelines for the management of asthma in adults Step 1 Occasional bronchodilator (eg short acting b2 adrenoceptor agonist). If this is required frequently (> twice/week)- move up to step 2: Step 2 Add regular inhaled Steroid. Step 3 Step 2 plus trial of: long acting b2 adrenoceptor agonist Theophylline Leukotriene receptor antagonist Step 4 As above, but consider increasing concentration of steroid or adding 4th drug eg leukotriene receptor antagonist Step 5. Add oral steroid to existing therapy
47
If inhaled therapy isnt working, may need to check the patient is using the inhaler properly!
48
16
Acute severe asthma Treatment

Oxygen Nebulised 2 adrenoceptor agonist Oral prednisolone or i.v. hydrocortisone Life-threatening: + Nebulised Ipratropium s.c. 2 adrenoceptor agonist i.v. aminophylline
49
Bronchoconstriction as an adverse drug reaction

~ 15% of Asthmatics NSAIDs - inhibit COX More AA Leukotriene production adrenoceptor antagonists
- especially non-selective e.g. propranolol - selective e.g. atenolol also contraindicated in asthma/COPD except extreme circumstances (specialist only)
Drug allergy e.g. penicillins, cephalosporins, dipyridamole, tramadol, excipients (tartrazine)
Non-steroidal Anti-Inflammatory Drugs (NSAIDs) May provoke asthma in a number of sensitive patients Increased production of leukotrienes
Membrane PLA2 Arachidonic acid
Lipoxygenase Cyclo-oxygenase
NSAIDS
Leukotrienes
Prostaglandins
Increased inflammation/ spasm
17
Chronic obstructive pulmonary disease (COPD)

Comprises both chronic bronchitis + emphysema Loss of lung function. 80-90% of deaths related to smoking. Typically disease of late onset. High energy demand and difficulty eating e.g. use inhalers before a meal By 2020, projected to be 3rd leading cause of death worldwide. 5% of deaths in UK
52
http://www.nhs.uk/Conditions/Chronic-obstructivepulmonary-disease/Pages/Lynnsstory.aspx
53
COPD
Airflow limitation that is not fully reversible
Mild Moderate Severe FEV, 80% 50-79% 30-49% % predicted Smokers cough - little/no breathlessness Breathless on moderate exertion Breathless at rest/mild exertion Usually with wheeze and cough
Very severe
<30%
Prognosis depends on severity. Generally poor with progressive deterioration.
54
(NICE 2010)
18
Destruction of parenchyma- emphysema Remodelling and thickening of airways- small airways disease Mucus hypersecretion- chronic bronchitis
55
COPD- aim of treatment

Improve respiratory function 1) Stop smoking- reduces progressive decline in lung function 2) Tend to be less responsive to bronchodilators. A combination of bronchodilators is better than one on its own. Mild COPD may be helped by short-acting b2 adrenoceptor agonist More severe- a regular inhaled antimuscarinic blocker should be added (eg ipratropium)
56
BTS Guidelines for treatment of COPD

Mild bronchodilator drugs (b2-adrenoceptor agonist or anti-muscarinic) bronchodilator drugs (poss. in combination) plus trial of corticosteroids regular bronchodilators, a trial of steroids consider nebuliser at home.
Moderate
Severe
Long-term oxygen therapy (24-28%, 15 hours/day) is only treatment known to improve outlook in severe COPD
57
19
3) Corticosteroids - relatively ineffective in most patients on own.
BUT some evidence that combinations of steroids with b2-AR agonists beneficial.
58
Mucolytics
eg carbocysteine Erdosteine Mecysteine
Antioxidants Break up thick mucous Used in COPD
Smoking
Contents of cigarrette smoke: Particulate matter and tar- effects on lungs Tar- solid material inhaled. Forms sticky brown residue. Oxidative stress Benzene benzo(a)pyrene- DNA damage Arsenic Acrolein- mitochondrial damage Cyanide CO Heavy metals eg Cadmium
60
20
Smoking
About 120,000 people die because of smoking in the UK each year. Smoking causes one-third of all cancer deaths. Half of long-term smokers will die prematurely as a result of smoking.
61
Decline in lung function with smoking
Time
62
Cystic fibrosis
Inherited disorder of ion transport in epithelial cells Respiratory, hepatobiliary, gastrointestinal and reproductive tracts and pancreas affected Defect in chloride transporter (CFTR) leading to reduced Na+ and H2O transport
Thicker secretions with obstruction and destruction of exocrine glandular ducts Recurrent infections
63
21
CF- disease characteristics

Pancreatic exocrine insufficiency
Reduced or absent secretions
PERT- pancreatin. Inactivated by gastric acid therefore given with food.
Patients living longer- developing other complications:

Diabetes (20%) Liver Disease Osteoporosis
64
Management of CF
Aim: to clear viscous mucous from airways, treat respiratory infection, improve respiratory function
Lung disease Physiotherapy Antibiotics Corticosteroids Bronchodilators Dornase alfa administered using nebuliser
synthetic version of enzyme which cleaves extracellular DNA
Digests extracellular DNA released from dying neutrophils in the airway which contributes to increased mucus viscosity.
65
Further Reading
Disease Management- Randall & Neil Pharmacology- Rang et al. BNF National Institute for Clinical Excellence (NICE) Website British Thoracic Society Website
66
22
Cardiovascular Drugs And Diseases

Richard Roberts
Contents
Hypertension Hypercholesterolaemia Ischaemic Heart Disease & MIs Chronic Heart Failure
Hypertension
A blood pressure which is associated with significant cardiovascular risk
Cause of essential hypertension is not known but may be multifactorial 2o hypertension:

Caused by disease: eg renal disease, Cushings syndrome, hyperthyroidism Or pregnancy Or drugs
Stage 1 hypertension bp measurement >140/90 mmHg. Patient given ambulatory blood pressure monitoring (ABPM) or home blood pressure monitoring (HBPM) in the daytime over 1 week. Hypertension if average ABPM or HBPM bp >135/85 mmHg. Stage 2 hypertension bp measurement >160/100 mmHg & ABPM average or HBPM average bp is >150/95 mmHg. Severe hypertension bp measurement >180 mmHg or diastolic bp >110 mmHg.
Who to Treat?
Stage 1 hypertensive if evidence of organ damage or renal disease or diabetes. Otherwise- lifestyle interventions Anyone with Stage 2 hypertension.
Goals of treatment
Reduce blood pressure The BHS target: SBP < 140mmHg and DBP < 85mmHg (80mmHg in diabetics). Reducing bp will:
cardiovascular damage. prevent renal damage. prevent LVH. prevent CAD. reduction risk of stroke and MIs.
Treatment of Newly Diagnosed Hypertension (NICE 2011)

< 55 yrs ACEI (or AT1 antag) > 55 yrs or black pt Ca2+ channel blocker STEP 1
ACEI + Ca2+ channel blocker
STEP 2
ACEI + Ca2+ channel blocker + thiazide
STEP 3
Add further diuretic, alpha-blocker, or beta blocker
STEP 4
ACE Inhibitors
ACE: Angiotensin converting enzyme - found mainly in lungs Renin ACE
Plasma protein Angiotensinogen
AI
AII
Renin- proteolytic enzyme from kidneys

Vasoconstriction
Stimulates Aldosterone secretion
ACEIs
e.g. captopril, enalapril, lisinopril, perindopril, ramipril Inhibition of ACE leads to: angiotensin II, which
Reductions in arterial and venous vasoconstriction Reduced aldosterone production leads to reductions in salt and water retention Also potentiate bradykinin cough
May increase potassium interaction with salt substitutes
AT1 receptor antagonists

e.g. candesartan, irbesartan, losartan, valsartan Block the action of angiotensin II at the AT1 receptor. Have similar consequences as ACEIs but do not give rise to a cough.
Calcium channel blockers

e.g. diltiazem, verapamil & DHPs (felodipine, nifedipine) Verapamilheart rate cardiac output Dihydropyridines inhibit VOC on VSM, vasodilatation and a reduction in BP.
Smooth muscle cell
Calcium channel blocker
Contraction
Diuretics Thiazides (e.g. bendroflumethiazide) Inhibit Na+/Cl- reabsorption in distal convoluted tubule Reduction in circulating volume- reduce workload of heart Hypokalaemia (decrease K+) Vasodilatation
Loop Diuretics
Thiazides Na+
-Cl
K+ Na+ Cl-
DCT
Na+
+
Aldosterone
Loop of Henle
Beta-Blockers
e.g. atenolol, propranolol Block action of Noradrenaline (and adrenaline) on heart. 1 ARs in sino-atrial node- blockers decrease rate of contraction 1 ARs in ventricles muscle and atriablockers decrease force of contraction cardiac output
Vasodilators
Alpha-blockers e.g. doxazosin, prazosin Last choice These are competitive receptor antagonists of a1-adrenoceptors Wide spread side effects, which makes them poorly tolerated.
Adverse effects
Thiazides Urination! Diabetogenic Alter lipid profile Hypokalaemia Beta-blockers Bronchospasm Reduce hypoglycaemic awareness ACEIs Cough Severe first dose hypotension Calcium channels blockers Peripheral oedema Postural hypotension Constipation (some) Alpha-blockers Widespread Postural hypotension
Lifestyle changes: ALCOHOL Weight reduction Reducing fat and salt intake Increasing fruit and oily fish in the diet Increasing exercise Stopping smoking.
Hypercholesterolaemia and Atherosclerosis

Hypercholesterolaemia: elevated plasma cholesterol, leads to: Atherosclerosis: focal lesions (plaques) on the inner surface of an artery.
Risk factors for atherosclerosis

Genetic Hypercholesterolaemia (raised LDL-C or lowered HDL-C) Hypertension* Smoking* Obesity* Hyperglycaemia* Reduced physical activity*
* Can be altered by lifestyle changes
Hypercholesterolaemia
Major risk factor for atherosclerosis. Total plasma cholesterol > 6.5mmol/l Ideal cholesterol <5.2mmol/l 25-30% middle aged population have hypercholesterolaemia (TC>6.5mM) Especially important is high LDL-C component or low HDL-C
Management
Modify risk factors
Stop smoking Treat HT/DM Exercise Low cholesterol diet but only 25-30% of cholesterol comes from diet
The Statins
HMG-CoA Reductase Inhibitors Hydroxymethylglutaryl coenzyme A reductase which catalyses: Hydroxymethylglutaryl
HMG-CoA reductase Mevalonate Cholesterol (ultimately) HMG-CoA reductase is the 1st committed step in cholesterol synthesis
Statins
e.g. simvastatin, pravastatin, atorvastatin, fluvastatin Reduce plasma cholesterol cholesterol synthesis hepatic LDL receptors, promoting LDL-C uptake Statins are hepatoselective the liver is the main site of cholesterol synthesis 1st pass metabolism: 5% reaches systemic circulation
Cholesterol synthesis greater at night therefore statins taken at night
Effects of statins
4S trial (Scandinavian Simvastatin Survival Study) : Over 5 years, 30% reduction in mortality, 42% reduction in death from CAD Some evidence that statins may lead to regression of atherosclerosis Treatment for 2 years with 40 mg rosuvastatin per day caused a reduction in size of atheroma in 75% of patients (ASTEROID study, 2006)
Trials
Heart Protection Study (2002) Lancet 360, 7-22 40 mg simvastatin to high risk patients (CHD, stroke, diabetes, hypertension) Substantially (25%) reduced MI / Stroke / revascularisation / in all patients even with low / normal cholesterols Consider statins for all high risk patients irrespective of cholesterol? Statin + aspirin + b-blocker + ACEi : independently and additively reduce risk in secondary prevention. Total of 75% reduction in risk.
Adverse Effects of statins

Cautions: use with care in liver disease, monitor liver function May cause rhabdomyolysis Risk : 1 in 1,000 to 10,000. Cerivastatin withdrawn Aug 2001 because of reports of fatal rhabdomyolysis. No evidence of muscle pain in Heart Protection Study actually being due to simvastatin.
OTC Statins
What are the implications? 10mg simvastatin without cholesterol test without prescription For pts at high risk
All males over 55 Males 45-55 and females over 55 with
Family history of IHD Smokers Overweight S Asians Indian subcontinent) ethnicity
But treatment might not be documented with GP
Bile acid binding resins

Colestyramine Used in addition to statin Binds bile salts in intestine and prevents reabsorption and cycling of cholesterol Leads to incorporation of endogenous cholesterol into bile salts. Also increases LDL receptors 13% fall in plasma cholesterol 20-25% fall in CAD Reduce absorption of fat soluble vitamins
Fibrates
eg Bezafibrate, clofibrate, gemofibrozil Activate: PPAR-a, alters lipoprotein metabolism through gene transcription (increase lipoprotein lipase) Promote breakdown in VLDL (with small reductions in LDL-C and increase in HDL). Also reduce triglycerides used with statins when TGs (+ cholesterol) raised Decrease glucose, use in DM Reduce incidence of IHD
Cholesterol Absorption Inhibitors

e.g. Ezetimibe Prevents cholesterol absorption May benefit patients with low synthesis but high absorption Vytorin- combination of simvastatin & ezetimibe
10
Others
Sterols/Stanols Present in Benecol margarine Prevents absorption of cholesterol Reduces LDL cholesterol by 10-15% Helpful add on to dietary restrictions and statin therapy
ISCHAEMIC HEART DISEASE
IHD
IHD: angina or MI Can lead to CHF. IHD associated with atherosclerosis within the coronary artery - impaired blood flow or thromboembolic occlusion. Coronary blood flow does not match demand, leading to ischaemia, which provokes the symptoms.
11
Risk Factors
Male gender Family history Smoking* Diabetes mellitus* Hypercholesterolaemia* Hypertension* Sedentary lifestyle* Obesity *
Angina pectoris Management

Lifestyle
Stop smoking Exercise Diet Weight
Coronary Artery Bypass Grafting Percutaneous transluminal coronary angioplasty & stenting (open up CA)
Pharmacological Management
Nitrates eg GTN Via release of NO Venodilatation, leading to a decrease in preload and a reduction in cardiac work Coronary vasodilatation
NO Guanylate cGMP cyclase PDE5 PKG Viagra dilation
Smooth Muscle Cell
12
b-blockers
First choice drugs for prevention HR & force cardiac work and preventing symptoms.
Slowing HR increases diastolic period, as will the time for coronary blood flow.
Calcium channel blockers

Vasodilatation and improve coronary blood flow, so preventing symptoms. Verapamil- effects on HR so reducing cardiac work.
ACEIs
vasodilatation HOPE trial indicated that ramipril reduced mortality in patients with IHD reduction in MI & stroke
13
Potassium channel activators

Nicorandil: combined NO donor and activator of ATP-sensitive K-channels. The target is the ATP-sensitive K+channel (KATP):
K Smooth Muscle Cell
Increased K+ pumped out of cell
Hyperpolarization
Antiplatelet drugs
Low dose Aspirin (75mg) Used to prevent MI in patients who have previously had an MI Prevents clot formation Reduces incidence of stroke Inhibits cyclo-oxygenase (irreversible):
Arachidonic Acid in membrane
PLA2
Free AA
Aspirin
Cyclo-oxygenase Endoperoxides
PGI2
Endothelium
Prostaglandins
Thromboxane
Platelets
14
Favours PGI2 production over TXA2 because
COX AA PGI2
Endothelial cell
Platelets
AA COX
TXA2
AA
X
COX
Endothelial cell
PGI2
Aspirin
AA
X
COX
TXA2
mRNA COX AA PGI2
Endothelium
Nucleus
AA
X
COX
TXA2
15

Platelets have no nuclei - cant produce any more cyclo-oxygenase (COX) - no more TXA2 - until new platelets synthesised (7 days) Endothelial cells have nuclei - can produce more COX (2 hours) - get PGI2 produced!
Anti-platelet drugs
Clopidogrel & Prasugrel
ADP receptor antagonist Equally effective Used in pts who can not receive aspirin Or used with aspirin
Other Anti-Platelet Drugs

Dipyridamole
PDE inhibitor inhibition of adenosine uptake into platelets leading to increased inhibition of platelet aggregation by adenosine
Abciximab- antibody targetting glycoprotein receptor on platelets
16
Drug Choice
Low dose aspirin and/or clopidogrel. Reduce BP to a target of < 140/85 mmHg (antihypertensive drug) Reduce Hypercholesterolaemia (statin). For symptomatic relief or occasional treatment, a GTN spray or sublingual tablets.
Drug Choice - prevention

In terms of continuous, preventative treatment: 1st choice: b-blockers. Oral long-acting nitrates might be added. 2nd choice: if a b-blocker is ineffective or contra-indicated, then verapamil (or diltiazem) would be used
Myocardial Infarction
MI: thromoembolism or rupture of plaque
17
Thromboembolism leading to MI
INFARCTION Thrombus formation
Immediate Treatment: Thrombolysis

Dissolves the clot, with reperfusion, salvages the cardiac muscle Fibrinolytics convert plasminogen to plasmin- degrades fibrin If indicated, the earlier the better damage is irreversible 6h post MI. Only really effective in 1st 12h.
Discharge
Aspirin and/or clopidogrel b-blocker (or Ca-channel blocker if bblocker contraindicated) ACEI Statin All lower risk additive
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Chronic/ Congestive Heart Failure (CHF)
Heart Failure
Failure of the heart as a pump to meet the circulatory needs
Heart Failure
May be due to failure of the heart muscle or failure of the heart valves May be chronic or acute (post MI) Often secondary:
Hypertension IHD Cardiomyopathies (alcohol, viral) Lead to adaptation of heart muscle or damage of heart muscle
19
Also Precipitated by
Pregnancy Anaemia Hyper & hypothyroidism Fluid retaining drugs:
glucocorticoids NSAIDS
Neurohormonal adaptation
Reduced cardiac output:Body attempts to compensate for reduced circulation get activation of:
Sympathetic nervous system Renin-angiotensin-aldosterone system
But this leads to: A vicious circle develops which further impairs the pump activity of the heart. Neurohormonal activation leads to myocyte dysfunction Get maladaptation of heart. Fibrosis & stiffening due to increased aldosterone
Pre-load & After load
Work load On heart
Cant cope HF CO
Circulating volume Sympathetic NS Renal blood flow
Na+/water retension aldosterone lungs oedema
AII
20
CHF
Left-sided Failure Most common Associated with pulmonary oedema Right-sided failure Both sides
Signs & Symptoms

Fatigue, listless Poor exercise tolerance (determines grade) Cold peripheries Low blood pressure? Reduced urine flow Weight loss Breathlessness- pulmonary oedema
Diagnosis
Symptoms Echocardiogram: Ejection fraction <45% Chest X-ray cardiomegaly (enlarged heart), pulmonary oedema
21
Prognosis
Poor Median survival in mild/moderate failure of 5 years
Goals of treatment
Identify / treat any cause (valvular disease; IHD) Reduce cardiac workload Increase cardiac output Counteract maladaptation Relieve symptoms Prolong quality life reduce hospitalization
Pre-load & After load
Work load On heart
Cant cope HF CO
Circulating volume Sympathetic NS Diuretics b blockers Na+/water retension aldosterone lungs oedema Spironolactone AII Renal blood flow
ACEIs
22
Pharmacological Management: ACEIs

See earlier Reduce arterial (after load) and venous (preload) vasoconstriction Reduce salt/water retention, hence reduce circulating volume Inhibits RAS, prevents cardiac remodelling? Inhibition of aldosterone production aldosterone causes fibrosis & stiffening of heart
AT1 Receptor antagonists

e.g. Candesartan, losartan,valsartan, Oppose actions of AII at the AT1 receptor Equally effective as ACEIs But dont cause the cough Dual blockade with ACEIs?
Diuretics
Mainstay Prevent water retention Thiazides (bendroflumethiazide) used in mild failure or in elderly Loop diuretics (furosemide) esp pulmonary oedema
23
Spironolactone
Spironolactone aldosterone receptor antagonist Now being used as an effective agent which reverses the LVH ? Inhibits effects of aldo on heart fibrosis? (stiffens heart + arrhythmias)
b-blockers
Used to be contraindicated in CHF.. Now a central role Now known to reduce disease progression, symptoms and mortality Use in stable or moderate failure Reduce sympathetic stimulation, heart rate and O2 consumption Antiarrhythmic activity reduces sudden death Symptoms may get worse at 1st.
Digoxin
+ve inotrope by inhibiting Na+/K+ ATPase, Na+ accumulates in myocytes, promotes Ca2+ entry leading to increased contractility. Impairs atrioventricular conduction and increases vagal activity (via CNS). Leads to Heart block and bradycardia- beneficial in heart failure with atrial fibrillation as it controls ventricular rate. Digoxin reserved for failure with atrial fibrillation Reduces rate at which contraction passes from atria to ventricles. Allows time for ventricles to fill with blood.
24
A-V node
Atrial Fibrillation (AF)

Atrial fibrillation Common consequence of CHF. Impaired ejection of blood dilation of left atrium impaired rhythm of contraction of atria AF: stasis of blood, leading to thrombi which may dislodge and move to cerebral circulation need for prophylaxis, warfarin or aspirin.
Warfarin
Warfarin: Wisconsin Alumni Research Foundation arin Warfarin: Vitamin K antagonist Blocks unwanted coagulation Vitamin K essential for production of prothrombin and Factors VII, IX and X
25
Factors are glycopoteins with glutamic acid residues at N-terminal end of peptide chain Glutamic acids converted to carboxyglutamic acids after synthesis of the chain- dependent on vit K Warfarin blocks Vitamin K reductase, needed for Vit K to act as a cofactor: vit K needs to be in reduced form
Post-translational modification
Carboxylation of glutamic Acid residues
New factor
Vit K-dependent
Warfarin inhibition
X
WARFARIN
Vit K-dependent
26
Warfarin
Also used to prevent thrombosis
in patients with replaced heart valves atrial fibrillation Pulmonary Embolism DVT Several days to act- existing clotting factors need to be used up.
Warfarin- specific advice vitamin K antagonist If increase amount of vit K in diet, then reduce effectiveness of warfarin (large amount of green veg, green tea). Avocado & soya bean products may also reduce effects Cranberry products/juice should be avoided (CSM warning)- possible increase in metabolism
27
Diabetes Mellitus
Dr Richard Roberts
Diabetes Mellitus
TYPE 1 TYPE 2 Insulin dependent (IDDM) insulin production impaired Non-insulin dependent (NIDDM) body not as sensitive to insulin
Gestational DM Consequences of XS GH XS cortisol Rare genetic disorders
Clinical features of DM
Direct consequences of high blood glucose levels Polyuria, nocturia, polydipsia (osmotic diuresis) Visual disturbance (osmotic changes to intra-ocular pressure) urinogenital infections Metabolic consequences of impaired glucose utilization Lethargy, weakness, weight loss (intracellular glucose deficit) Ketoacidosis (increased fat metabolism) Long-term complications of hyperglycaemia and hyperlipidaemia Cardiovascular disease, nephropathy, neuropathy, retinopathy, infections, arthropathy (stiffness)
Diagnosis
Consider risk factors e.g. family history, obese Vigilant for symptoms
Persistent thirst (polydipsia) Nocturia, polyuria Recurrent infections e.g. cystitis, thrush (glycosuria) Weight loss (type 1) Lethargy
Test urine Blood glucose >7 mmol/L fasting or >11.1 mmol/L random
Treatment of diabetes
Aim: Improve glycaemic control -Reduce hyperglycaemia without hypoglycaemia Reduce co-morbidities\complications Trials (Diabetes Control & complications (Type I) & (UK Prospective Diabetic Study (Type II) found: Improving glycaemic control prevented or delayed complications of DM But in type I this is often at expense of increased incidence of hypoglycaemia
Managing Type 2 Diabetes
Dietary Advice
Blood Glucose Lowering Therapy
Managing Cardiovascular Risk
Managing longterm complications
Nephropathy
Retinopathy
Neuropathy
Dietary aspects - treatment

Fat
Low saturated fat and total fat
CHO - 55-60% energy intake

Low simple sugars High complex CHO (low G.I.)
Weight control - especially - Overweight\Obese Type 2 Recent onset type 2 - Dietary change may be enough
Pharmacological Treatment of Type 2: Oral antidiabetic drugs

Biguanides: metformin Sulphonylureas: gliclazide, tolbutamide Meglitinide analogues: nateglinide, repaglinide Glucosidase inhibitor: acarbose Glitazones (thiazolidinediones): rosiglitazone, pioglitazone Newer therapies
Biguanides (metformin) Action not clear. Proposed: Increased uptake of glucose into muscle Reduced uptake of glucose from GI tract Decreased gluconeogenesis Combine to decrease blood glucose and increase utilisation Favoured as not associated with weight gain (reduces appetite) Avoided in renal impairment Initial problem with diarrhoea (transient)
Sulphonylureas (gliclazide, tolbutamide) Rely on the fact that b cells still produce insulin Inhibit ATP-sensitive potassium channels (KATPchannels), causing depolarisation Increase insulin secretion from b-cells Short acting: tolbutamide, gliclazide Long acting (glibenclamide, chlorpropamide) avoided in elderly due to hypoglycaemic effects
Sulphonylureas Meglitinides KATP channel
Islet b cell
X
Glucose Glut-2 ATP Insulin K+ Ca 2+
Meglitinide analogues (nateglinide, repaglinide) Act on b-cells to close KATP-channels- release insulin Shorter acting- given at mealtimes to stimulate insulin release Nateglinide only licensed for use with metformin Repaglinide licensed for monotherapy for patients not overweight or metformin contraindicated or not tolerated
Glucosidase inhibitor (acarbose) -Inhibition of alpha-glucosidases in small intestine - reduces production of glucose in GI tract -Problem of flatulence and osmotic diarrhoea- may decrease in time -Used alone or in combination with sulphonylurea or metformin
Glitazones (thiazolidinediones) e.g. pioglitazone enhance glucose utilisation by tissues, reducing insulin resistance - PPAR- agonists- gene expression- insulin-like effects. Slow effect- takes 1-2 months for max. effect. hepatic glucose output; glucose transporters in skeletal muscle- increased glucose utilisation; promotion of fatty acid uptake into adipose cells
- Not first line due to risk of liver toxicity (troglitazone withdrawn), monitoring - add on to sulphonylurea OR preferably metformin - NICE recommend for patients unable to take sulphonylurea with metformin combination or failure of this combination
Cardiovascular safety: Rosiglitazone and pioglitazone should not be used in patients with heart failure. Increased risk of heart failure when combined with insulin. Rosiglitazone not recommended for use in patients with ischaemic heart disease- increased risk, particularly with insulin. MHRA warning increased risk with rosiglitazone compared to pioglitazone (July 2010).
Adipose tissue, skel muscle, liver

Glitazones
GLUT-4 PPARg Protein
Glucose
Fatty acid Transporter protein
FAs
Newer treatments: Glucagon-Like Peptide Receptor Agonist Exenatide -GLP-1 Receptor Agonist -stimulates insulin release from b cells in a glucose-dependent mechanism. -Lower risk of hypoglycaemia Used in combination with metformin or a sulphonylurea. S.C. Injection Reports of acute pancreatitis.
Islet b cell
KATP channel
X
GLP-1 agonist GLP1-R K+ Ca 2+
Insulin
Sitagliptin & Vildagliptin GLP-1 broken down by dipeptidylpeptidase-4 (DPP4) Dipeptidylpeptidase-4 inhibitors prevent metabolism Increase insulin secretion. Used in combination with metformin or sulphonylurea or a glitazone.
IDF Guidelines for Treatment of Diabetes Lifestyle changes
1st Line- Metformin
2nd Line- Add sulphonylurea
3rd Line- Add insulin OR a-glucosidase inhibitor OR DPP4 inhibitor OR TZD
Insulin may be required

Particularly during illness Added to oral treatment
Treatment of Type 1
Replacement of insulin Polypeptide hormone with role in regulation of CHO, fat and protein metabolism inactivated by GI enzymes subcutaneous injection (can also be given iv or im for more rapid effect), Human, porcine or bovine insulin Insulin requirement increased by stress, infection, puberty (GH effect), accidental or surgical trauma, 2nd and 3rd trimesters of pregnancy Risk of hypoglycaemia: sweating, tremor, tachycardia, confusion, drowsiness
Insulin
Insulin has a short plasma half-life unless complexed with protamine (isophane) and/or zinc to reduce absorption. Short acting
soluble insulin 6-8 hr effect Peak response 2-5 hr Given 15-30 min before meals
Intermediate -isophane insulin and insulin zinc suspension
Long-acting crystalline insulin zinc suspension New product- insulin glargine- human insulin analogue given once a day Biphasic -Combination of short & long-acting insulin Insulin pumps continuous subcutaneous infusion, expensive, reserved for poorly controlled diabetes
Insulin regimens
Regimens adapted to suit individual. Insulin requirements may alter eg depending on level of exercise eg Short-acting mixed with intermediate twice a day before meals Short-acting mixed with intermediate before breakfast; short acting before evening meal; intermediate at bedtime Short-acting 3 times a day before each meal; intermediate at bedtime
Treatment of diabetes may result in hypoglycaemia: Enhanced sympathetic activity tremor, pallor sweating, shivering, palpitations anxiety Neuroglycopenic - reduced CNS glucose delivery drowsiness, disorientation, confusion aggression, inappropriate behaviour apparent drunkenness convulsions, coma, brain damage, death Other effects - multiple or indirect pathogenesis hunger, salivation, weakness, blurred vision
Hypoglycaemia
Hypoglycaemia unawareness - risk factors: Alcohol- may mask effects Sleep- NB hypoglycaemia common at night Exercise- may require reduction of insulin dose before exercise Treatment of hypoglycaemia Oral CHO (drink, food) i.m. glucagon i.v. glucose
Ketoacidosis
In the absence of insulin- increased breakdown of triglycerides - form ketone bodies Results in acidosis - diuresis- also causes depletion of Na+, K+, PO4 Sweet smell of ketones on breath
Managing Type 2 Diabetes
Dietary Advice
Blood Glucose Lowering Therapy
Managing Cardiovascular Risk
Managing longterm complications
Nephropathy
Retinopathy
Neuropathy
10
Management of cardiovascular risk factors

Statin Low dose aspirin BP control reduces risk of cardiovascular disease ACEi (benefit in nephropathy) Increased risk of new-onset diabetes with thiazide and -blocker combination- use with caution b-blockers (atenolol) can mask hypoglycaemic symptoms
Summary of treatment
Patient with type 2 could have:
1-2 oral hypoglycaemic drugs 2 antihypertensives Statin Low dose aspirin Requirement for lifestyle changes
Other Drugs Used in Diabetic Patients
11
Treatment of neuropathy
Diabetic neuropathy- common secondary complication Reduced sensory (& motor) neurones Loss of sensation- ulceration
Painful neuropathy: Optimal diabetic control to prevent neuropathy 1st step: paracetamol/aspirin- mild to moderate pain 2nd step: low doseTricyclic antidepressants (shown to be of use in some patients) 3rd step: anticonvulsants eg phenytoin, carbamazepineshooting or stabbing pains Chronic pain- opiates
Adverse Drug Reactions

Diarrhoea with metformin
reassurance according to severity and duration Should improve with time
Liver toxicity with glitazones:

Urgent referral for nausea & vomiting, abdominal pain, fatigue, dark urine, jaundice
Hypoglycaemia
If recurrent and on insulin- alternative regimen/diet/education Sulphonylureas (meglitinide analogues)- dose?
Weight gain
Sulphonylurea, glitazones
12
References
BNF Disease Management, Randall and Neil Stockleys Drug Interactions
13
06/01/2014
PHARMACOLOGY OF THE GASTROINTESTINAL TRACT
Dr Richard Roberts
First Part
Acid secretion, GORD, Peptic Ulcers Treatment options Warning symptoms COX-2 inhibitors Case study
Overview of the GI Tract
Upper Respiratory Tract
Oesophagus Abdominal aorta Stomach Spleen Pancreas Small intestine
Liver Gall bladder Duodenum Colon Ileum Appendix Rectum
06/01/2014
Gastric Pharmacology
The stomach is a major site of disease and drug action.
Neuronal and Hormonal Control of the GIT Neuronal Control Autonomic NS: Parasympathetic (ACh) Sympathetic (NA) Hormonal Control Endocrine (secreted into blood) eg gastrin Paracrine (local hormones) eg histamine
Involved in: Gastric secretion Vomiting Motility of the GIT Formulation and excretion of bile
06/01/2014
Gastric Secretion Hydrochloric Acid (HCl) Mucus Bicarbonate ions (trapped in mucosa) Others: Intrinsic Factor (uptake of vit B12) Pepsinogen (protease) Protect mucosa
Control of Acid Secretion.

Parietal cells release gastric acid following stimulation of:
Histamine receptors (H2) Muscarinic receptors (acetylcholine) Gastrin receptors (secreted by mucosa)
Contain a proton pump which exchanges intracellular H+ for extracellular K+- acid secretion
Vagus Nerve
ACh M
ECF-like Histamine H2
GR
Enterochromaffin -like cell Gastrin
ACh
M1 Inhibits
GR
PGs
PG R PP H+ K+
Parietal Cell
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Pharmacological Control of Acid Secretion
H2 receptor antagonists Proton pump inhibitors Prostaglandin analogues
H2 histamine receptor antagonists cimetidine (Tagamet) ranitidine (Zantac) famotidine (Pepcid). Low dose OTC for short term relief High doses POM.
Histamine H2 receptors : coupled via adenylyl cyclase to increase cAMP which activates the proton pump
H2 Histamine receptor antagonists competitive antagonists at the H2 histamine receptor antihistamines are H1 receptor antagonists reduce gastric acid secretion provide symptomatic relief in the long term promote ulcer healing (relapse on discontinuation).
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Proton pump inhibitors (PPIs) e.g. omeprazole, lansoprazole irreversible inhibition of the proton pump (H+/K+ATPase): PPIs activated by acid pH Inhibit H+ secretion by >90%, may lead to achlorhydria. Increase risk of Campylobacter infection (food poisoning).
Prostaglandin Analogues: eg Misoprostol Inhibits release of acid & stimulates mucus & bicarbonate secretion
Vagus Nerve
ACh M
GR H2 receptor antagonist
ACh
M Inhibits
GR
Misoprostol PG R
Parietal Cell PP
PPI H+
K+
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Neutralising Acid
Antacids : - anti-acid; widely available (OTC) and act to raise pH. Provide relief Sodium bicarbonate : simplest HCO3- + H+ CO2 + H20 Magnesium hydroxide and Aluminium hydroxide also used: Al(OH)3 + 3HCl Mg(OH)2 + 2HCl AlCl3 + 3H2O MgCl2 + 2H2O
Some types of antacids in common use Simple antacids Soluble (more than about 10% of the dose is absorbed) e.g. calcium carbonate, chalk, sodium bicarbonate Insoluble (less than 5% of the dose is absorbed) e.g. Aluminium hydroxide, aluminium and magnesium mixtures (co-magaldrox in Maalox & Mucogel), magnesium trisilicate, aluminium-magnesium complexes e.g. hydrotalcite (Altacite), magnesium carbonate
Alginates : Antacids may be combined with Alginates eg Gaviscon Double Action Mucopolysaccharides. The alginic acid combines with saliva to form a viscous foam.
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Dyspepsia (indigestion) Symptoms: Heart burn Acidity Nausea Acid reflux Symptoms can often be confused with cardiac problems- need to rule these out. Also need to rule out carcinoma
Dyspepsia can occur as a result of: GORD: gastro-oesphageal reflux disease, leading to oesophagitis
Peptic ulceration (gastric and duodenal) erosion, damage, bleeding (anaemia?) Gastritis Drug (NSAID and oral steroids) - induced damage
GORD Reflux of contents of stomach into the oesophagus Causes pain- heartburn. Sometimes back/shoulder pain Sometimes wheezing or cough Caused by: Increased abdominal pressure- pregnancy, obesity, overeating Incompetence of gastro-oesophageal sphincter caused by hiatus hernia Can lead to tightening of oesophagus- difficulty swallowing
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Hiatus hernias
Management of GORD Lifestyle: Weight reduction, reduce fatty foods, stop smoking, avoid tight clothes Pharmacotherapy: Initially antacids or antacids + alginates Sometimes H2 antagonists- but not as effective as: Proton pump Inhibitors- most effective agents. Remove symptoms & allow healing.
Peptic Ulceration Gastric & duodenal ulcers Erosion of inner lining Perforation of lining- serious problem OR erosion of blood vessel- vomit blood Symptoms: Gastric pain Hunger pain- relieved by eating Night pain- relieved by milk or food or antacids nausea 80-95% ulcers due to Helicobacter pylori infection
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H. Pylori & Peptic Ulcers
Early 1980s Robert Warren & Barry Marshall found H. pylori in cultures from peptic ulcer sufferers. Not believed bacteria could live in stomach. 1984 Barry Marshall drank culture of H. pylori. Developed gastritis- cured by antibiotics.
Treatment: Decrease acid (antacid) Decrease acid production (H2 antagonist or PPI) Kill H. pylori (antibiotics) Remove NSAIDs
Treatment of Peptic Ulceration: H. Pylori Infection Infection identified by serology (antibodies to H. pylori) or urea breath test Triple Therapy Proton pump inhibitor + 2 antibiotics for 1 week Associated with 90% eradication PPIs may be required for 4-8 weeks to promote healing
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Treatment of peptic ulcers (cont.) If eradication failure: PPI + Bismuth Chelate + tetracycline + metronidazole
Bismuth chelate- kills H. pylori, coats the ulcer, & absorbs pepsin. prostaglandin secretion acid secretion & neutralises acid by increasing bicarbonate secretion
Vagus Nerve
ACh M
GR H2 receptor antagonist
ACh
M Inhibits
GR
PGs
PG R PP PPI H+
K+
Parietal Cell
Bismuth chelate
NSAID-Induced Ulcers
Oral NSAIDS commonly associated with peptic damage/ulceration (includes low dose aspirin). Ibuprofen low incidence of GI side effects. Paracetamol not ulcerogenic
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Prostanoid pathway: Arachidonic acid (membrane) NSAIDs AA (free)

COX
Leukotrienes
Prostaglandins
Inhibits H+ secretion COX-1 - gastric? COX-2 - inflammation COX-2 selective inhibitors (celecoxib) may have less GI-side effects, but only reserved for certain patient groups.
NSAID-Induced Ulceration- Treatment If possible switch to paracetamol or stop NSAID For healing use PPI or H2 receptor antagonist If NSAID required, then prophylaxis with PPI may be needed
Use COX-2 inhibitor eg rheumatoid arthritis???
NSAIDs Used in treatment of inflammation, pain & increased body temperature. eg aspirin, ibuprofen, naproxen, diclofenac Inhibit cyclooxygenase and therefore prostaglandins. Non-selective inhibit COX-1 & COX-2 production of
COX-2 responsible for production of prostaglandin mediators of inflammation.
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COX-2 inhibitors
Anti-inflammatory drugs with lower GI side effects e.g. celecoxib BUT: COX-2 inhibitors are associated with small increased risk of CV effects (MI or stroke) Rofecoxib (Merck) voluntarily withdrawn 2004 (lawsuits) Other Problems: Valdecoxib (Pfizer) withdrawn 2005 due to serious skin reactions Lumiracoxib (Novartis) withdrawn Nov 2007 due to hepatotoxicity
CSM guidance: - COX-2 inhibitors should be used in preferance to standard NSAIDs only in patients with high risk of GI problems AND after assessment of cardiovascular risk
Non-selective NSAIDs Inhibit COX-1 & COX-2. Concerns that they may also cause CV events June 2006- paper indicating moderate increase in cardiovascular risk with ibuprofen and diclofenac at highest doses used on a daily basis MHRA guidance (October 2006): NSAIDS and COX-2 inhibitors should be used at lowest possible dose and shortest duration
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Minimize GI irritation by Avoid NSAIDs e.g. try paracetamol first Giving NSAIDs with food Prescribe only 1 NSAID at a time (includes low dose aspirin) Use less toxic NSAID first-line ibuprofen<diclofenac<naproxen Use lowest effective dose Give in combination with PPI or misoprostol Encourage patients to report warning symptoms
Warning symptoms for Upper GI problems

Unexplained weight loss Dysphagia Anaemia Vomiting Upper abdominal pain Evidence of GI blood loss Patient on long-term/high dose NSAIDs and taking Gaviscon OTC
Case study
Mr DU 67 year old smoker (>20 per day) Medical history: Hypertension Osteoarthritis COPD Complains of stomach pains & heart burn First step? Check medication-
Medication includes: Celecoxib (osteoarthritis) Low dose aspirin (anti-platelet) Also H.Pylori negative
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What could be the cause of stomach problems? Celecoxib & aspirin- both NSAIDs Change to paracetamol & clopidogrel Or aspirin + PPI Lifestyle effects? Smoking can cause GORD- heartburn Other comments on current medication? COX-2 inhibitor & cardiovascular disease! COX-2 inhibitors shouldnt be given to patients at risk of CVD
NAUSEA & VOMITING
Nausea and Vomiting

Stimulated by: Toxins: bacterial poisons, alcohol (15%) Smells Motion sickness Migraine Pregnancy Drugs- many, particularly: - Chemotherapy Opioids e.g morphine
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Physiology of vomiting
Highly co-ordinated physiological response: 1. 2. 3. 4. 5. 6. 7. 8. Discomfort, dry mouth, salivary inhibition. Yawning sympathetic distress Reappearance of saliva Pyloris closes Tone of stomach increases Deep breath Contraction of abdominal muscles to force food out Forced expiration to prevent inhalation
Under central control, where most anti-emetics act:
Reflex Mechanism of Vomiting Central regulation of vomiting occurs in the vomiting centre & the chemoreceptor zone (CTZ). CTZ sensitive to chemical stimuli- main site of anti-emetic drugs Output from the CTZ stimulates the vomiting centre, leading to the initiation of vomiting Neuronal signals from GIT feed in to CTZ and vomiting centre
Neurotransmitters Involved in Nausea & Vomiting Histamine Acetylcholine Dopamine 5-HT Blocking these receptors in the brain prevents nausea & vomiting
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Chemotherapy-Induced Nausea & Vomiting Some chemotherapy agents stimulate release of 5-HT from enterochromaffin cells. Acts at vagal afferents. Feeds into CTZ & vomiting centre.
Dopamine & 5-HT3 antagonists Drugs, toxins Stimuli from GIT Visceral Afferents Nucleus of the Solitary Tract CTZ Vomiting Centre
Muscarinic antagonists
5-HT3 antagonists
H1 antagonists
Anti-emetics
H1- Histamine receptor antagonists e.g. promethazine.
Effective in motion sickness. Also have anti-muscarinic actions. Produce drowsiness.
Anti-muscarinic agents e.g. hyoscine, prochlorperazine

Effective in motion sickness. Also reduce gastric motility (see later). Anti-muscarinic side effects (eg dry mouth). Produce drowsiness.
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Anti-emetics 2
Dopamine antagonists e.g. domperidone, metoclopramide.
Act in CTZ but has unwanted CNS effects. Effective against anticancer drug-induced emesis. Also stimulates gastric emptying reduce nausea
5-hydroxytryptamine antagonists e.g. ondansetron

blocks 5-HT at 5-HT3-receptors in gut and CNS - particularly effective against anti-cancer drugs. Act in CTZ.
Cannabinoid receptor agonist nabilone licensed for chemotherapy- action unclear
Newer Agents: Neurokinin Receptor Antagonists NK1 Receptor activated by Substance P NK1 receptor antagonists suppress nausea & vomiting. eg Aprepitant used in chemotherapy-induced N&V in combination with 5-HT receptor antagonist.
Steroids eg dexamethasone also have anti-emetic action. Used in chemotherapy-induced N&V Mechanism unknown.
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Standard Prescription for chemotherapy N&V: 5-HT3 receptor antagonist + steroid + NK1 receptor antagonist
LOWER GI PHARMACOLOGY
Constipation
Persistent,
difficult, infrequent or seemingly incomplete defecation
Causes: Dietary changes (reduced NSP and fluid intake) Stress Immobility e.g. due to illness ADR e.g. Opioids, calcium channel blockers, muscarinic antagonists Dehydration Irritable Bowel Syndrome Common in elderly due to reduced mobility, poor diet/ low fluid intake
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Diverticular disease
Occurs in ~ 80% of elderly Caused by long-term constipation- straining Diverticula- small sacs/ pouches that can form in the wall of the large intestine Diverticulitis- occurs when these become inflammed/ infected or strangulated (cuts off blood supply) May cause abdominal pain or altered bowel habits Pain results from muscle spasms
Weak area of gut. Pouches form Food can get stuck Infection
Management of constipation
Determine the cause e.g diet, lifestyle, medication, underlying condition eg. intestinal obstruction Best approach is diet with NSPs and fluid Could add bulking agents eg ispaghula husks Laxatives
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Treatment of constipation
Bulk-forming: Ispaghula husk (Fybogel), methylcellulose, sterculia, unprocessed wheat bran May take several days to work ADRs: flatulence, abdominal distension Increase faecal mass, retain water- stimulates peristalsis.
Laxatives- Osmotic Work by increasing water in faecal matter Lactulose (disaccharide of galactose and fructose) Colonic bacteria convert it into lactic and acetic acid raise fluid volume osmotically Delayed effect approx. 48 hours Good fluid intake required Flatulance, abdominal cramps, discomfort Macrogols (Movicol, Idrolax) Sequester fluid in bowel Insufficient evidence to recommend established, cheaper products
over
well-
Magnesium sulphate & magnesium hydroxide - Remain in lumen & retain water
Stimulant laxatives
For use when required rather than regular use. Usually taken at night to produce effect next morning. Senna extracts Enter the colon & metabolised to anthracene derivatives. Stimulate GIT activity by irritation. Dantron Also a GIT irritant. Limited for terminal care only due to potential carcinogenicity Bisacodyl Usually taken as suppository. Rapid effect (1-2 hours) Stimulate rectal mucosa- causes peristaltic action
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Faecal softeners/lubricants
Docusate sodium Detergent-used to soften stools & ease defecation Docusate also has weak stimulant activity
Other drugs that increase GI Motility (prokinetic)

Domperidone & Metoclopramide Dopamine D2 receptor antagonists. Stimulation of dopamine receptors inhibits gastric motility. Leads to postprandial bloating & pain, nausea & vomiting. Dopamine antagonists block this. Prucalopride: 5-HT4 agonist which increases GI motility (used when others have failed).
Dopamine
D2
Inhibits ACh
X
M
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Dopamine
Prucalopride
D2
Domperidone
Inhibits ACh
5HT4
Stimulates
X
M
5-HT (Serotonin) 5-hydroxytryptamine Tryptophan
5-hydroxytryptophan
5-hydroxytryptamine (5-HT)
5-HT Receptors- Numerous subtypes 5-HT1 5-HT2 5-HT3 5-HT4 5-HT5 5-HT6 5-HT7 5A & 5B 1A 2A to to 1F 2C
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Prucalopride selective serotonin 5-HT4-receptor agonist chronic constipation in women
NICE guidance Prucalopride for constipation in women (December 2010) treatment of chronic constipation in women for whom treatment with different laxatives has failed Prucalopride should be prescribed only by clinicians experienced in the treatment of chronic constipation. www.nice.org.uk/TA211
Dopamine Receptor Antagonists

- Anti-emetic action through effects on CTZ - increase gut motility Closes gastro-oesophageal sphincter- benefit in GORD Increases gastric emptying duodenal peristalsis Can prevent bloating. and increases
central side effects (metoclopramide only): drowsiness, fatigue. 10-20% syptoms can restlessness, experience insomnia, Parkinsons
Domperidone- doesnt cross BBB (NB but can act in CTZ)
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Gastroparesis- delayed gastric emptying Symptoms- nausea, vomiting, bloating, pain. Due to post-viral syndrome, diabetes mellitus, post surgery or unknown. Dopamine receptor antagonists beneficial by increasing gastric emptying and anti-emetic effects.
Diarrhoea
Common, debilitating and can be life threatening (5 million deaths world wide due to dehydration). Causes: Often bacterial or viral infection. Rotaviruses cause damage to small bowel villi
Adhesive enterotoxigenic bacteria : adhere to brush border and increase Cl- and Na+ secretion followed by water. amoebae & giardia also cause diarrhoea
Travel broadens the mind and loosens the bowels Gorbach, 1987
Often bacterial or viral infection. Rotavirus: damages small bowel villi Invasive bacteria: damage epithelium. Cytotoxins: damage muscosa e.g.Campylobacter Adhesive enterotoxigenic bacteria: adhere to brush border, increase cAMP leading to Cl- and Na+ secretion followed by water:
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Diarrhoea can also be caused by drugs: antibiotics can alter gut flora leading to superinfection e.g. clostridium difficile which may lead to colitis Orlistat pancreatic lipase inhibitor used in obesity Misoprostol via cAMP causing secretory diarrhoea PPIs suppress acid secretion too much allowing infection
Metformin (type 2 diabetes)
Treatment of diarrhoea
Many GIT infections are viral- can only treat symptoms Antibiotics may be of use in eg ingestion of contaminated food Oral rehydration therapy (ORT) Diarrhoea: dehydration with electrolyte disturbances. Therefore rehydration is a must: Electrolytes e.g. Dioralyte. + Glucose- allows transport of Na via a specific cotransporter on epithelial cells (H2O follows) Young & old are particularly at risk of dehydration. Also patients on concurrent diuretic treatment
Water Absorption
Na+ Symporter Glucose
Na+
Osmosis
H 2 O2
Water
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Drugs that Reduce GIT Motility
Neurotransmitters & Receptors:

Acetylcholine (ACh) stimulates muscarinic or nicotinic receptors on cholinergic neurons Muscarinic ACh receptors involved in the contraction of smooth muscle of the GIT (and the control of vomiting) Enkephalins via opioid receptors involved in GI motility
Treatment of diarrhoea
Opiates eg loperamide gut motility. Reduce motility of lower GIT allowing reabsorption of water and reducing water stools Allows bowel control and normal daily activities Symptomatic relief
Loperamide
Opioid receptor
Inhibits
X
M
ACh
Ca2+
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NB:
Codeine - a derivative of morphine. - Also used as an analgesic. - Anti-tussive agent (cough medicines). - Constipation is an ADR for reasons outlined. - All opioids eg morphine can cause constipation
Methylnaltrexone peripherally acting opioid-receptor antagonist treatment of opioid-induced constipation in patients receiving palliative care used on top of existing laxative therapy. No central effect therefore no effect on analgesic effect of opioids.
Antimotility agents Opioids (e.g. loperamide, codeine) & antimuscarinic agents Opioids reduce tone and peristaltic movement Inhibit acetylcholine release act at muscarinic receptors
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Antimuscarinic agents
Anti-muscarinic agents act directly at muscarinic receptors eg atropine, buscopan (hyoscine) Rarely employed as primary therapy for diarrhoea due to effects at muscarinic receptors around body. Inhibits secretions- dry mouth, dry eyes & dry skin (reduced sweating) Causes tachycardia (increase heart rate) Mild restlessness at low doses- agitation at higher dosesCNS effects
Anticholinergics and opioids ADR All patients prescribed long-term opioids should receive laxative- constipation Anticholinergic effects with TCAs, antipsychotics, sedating antihistamines
IRRITABLE BOWEL SYNDROME (IBS)

This is a common, long-standing disorder Present for at least 12 weeks within 1 year Pain, bloating - relieved by defecation Episodes of diarrhoea and/or constipation. Cause not understood. May have a psychological association- stress or depression
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Treatment of IBS
-Treat symptoms as appropriate eg constipation- NSPs to diet or laxative Diarrhoea- opioid as required -For bloating/ pain: -Anti-spasmodic agents such as anti-muscarinics eg buscopan eg dicycloverine- reduces smooth muscle tone in lower GIT -OR Mebeverine -Causes direct relaxation of GIT smooth muscle -PDE inhibitor?
Treatment of IBS (2nd line)

Tricyclic Antidepressants eg amitriptyline -Used at low dose -Analgesic effect -Also constipating (antimuscarinic effects)
Linaclotide Peptide guanylate cyclase-C receptor agonist Acts on guanylyl cyclase C receptor on epithelial cells receptor for endogenous hormones guanylin and uroguanylin Increases intestinal fluid secretion and transit Reduces pain GI selective- not absorbed Used in irritable bowel syndrome with constipation
Pharmacologic Properties, Metabolism, and Disposition of Linaclotide, a Novel Therapeutic Peptide Approved for the Treatment of Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipations
http://jpet.aspetjournals.org/content/344/1/196.full.pdf+html
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Lubiprostone Cl- channel activator Increases intestinal fluid secretion Constipation
Inflammatory Bowel Disease

Ulcerative Colitismucosal inflammation in the colon. Cause unknown- possible role of colonic bacteria. Causes bloody diarrhoea. Severe attack is potentially life-threatening. Less nutritional consequences than:
Crohns Disease Transmural inflammation. Can effect anywhere in GIT (mouth to anus) Cause unknown Pain, diarrhoea, weight loss due to impaired absorption and increased losses. Fatigue Micronutrient deficiencies. Protein-energy malnutrition in 20-80% of patients. Strictures can cause GI obstruction. 70-80% of patients require surgery at some point. Exacerbations and remission.
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Treatment of inflammatory bowel disease

Drugs used are intended to reduce the inflammatory response 5-aminosalicylates All these compounds are aminosalicylic acid (5-ASA). broken down to 5-
5-ASA inhibits leukotriene & prostanoid synthesis, scavenge free radicals, & decrease neutrophil chemotaxis eg Sulfasalazine- metabolised to 5-ASA. Mesalazine- pH changes yield 5-ASA
Questionable use in Crohns but some effect in Ulcerative collitis
Treatment of IBD (cont)

Corticosteroids e.g oral prednisolone anti-inflammatory, immunosuppressive actions. eg budesonide - poorly absorbed so far less systemic side effects. Used to induce remission, particularly in more severe disease Enemas used for more distal or rectal inflammation e.g. Predfoam
Treatment of IBD..
Immunosuppressants
e.g. Azathioprine and methotrexate- Inhibit purine synthesis and hence DNA. Reduces inflammatory cell proliferation Cyclosporin- inhibits IL-2 induced gene expression Used in refactory disease or for steroid-sparing
Infliximab
- monoclonal antibody for severe, active Crohns - Neutralises inflammatory cytokine TNF-a, implicated in Crohns Associated with risk of TB
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Summary
Peptic ulcers and GORD require reduction in acid secretion. H.pylori is responsible for 80-90% of peptic ulcers NSAIDs are associated with gastrotoxicity and require close monitoring Drugs that alter gastric motility can be used to treat constipation and diarrhoea. Nausea & vomiting are controlled by the CNS- CNSacting drugs
Summary
Irritable Bowel Syndrome- treatment of symptoms Ulcerative Collitis & Crohns- treatment with immunosupressants.
References
BNF Rang, Dale, Ritter & Moore. Pharmacology. Randall & Neil, Disease Management. Chapter 8 Clinical guidelines for treatment of disease: www.prodigy.nhs.uk/Clinical%20Guidance/ReleasedGui dance/ British Society for Gastroenterology Guidelines: www.bsg.org.uk/pdf_word_docs/ibd.pdf National association for Colitis and Crohns disease www.nacc.org.uk
www.npc.co.uk/MeReC_Bulletins/
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Summary
Drugs that alter gastric motility can be used to treat constipation and diarrhoea. Can also be a side effect of drugs Ulcerative Collitis & Crohns- treatment with immunosupressants.
References
BNF Rang, Dale, Ritter & Moore. Pharmacology. Randall & Neil, Disease Management. Chapter 8
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Psychopharmacology;
Diseases of the brain and their treatment
Neurodegenerative disorders
Parkinsons, Huntingdons, Alzheimers, Motor Neuron diseases
Disordered thought and perception

Schizophrenia
Mood disorders
Depression, Bipolar disease, Anxiety
Neurodegenerative diseases of movement
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Parkinsons Disease;
Progressive disease of movement (mainly in elderly) Symptoms; tremor at rest (pill rolling), muscle rigidity, suppression of voluntary movement (hypokinesia) comprising inertia in motor system. Patients walk with shuffling gate, finding starting, stopping, changing direction difficult. Cause not known; might follow cerebral ischemia, viral encephalitis or other brain damage. Can be drug-induced; reserpine (depletes dopamine), anti-psychotic drugs (block dopamine receptors). Rarely genetic link (2 gene mutations; synuclein & parkin). Neurotoxin MPTP, contaminant in designer drug, causes destruction of nigro-striatal dopaminergic neurones and Parkinsonian symptoms.
Organisation of extrapyramidal motor system
Dopamine-inhibitory; ACh (acetylcholine) excitatory; GABA (gamma amino butyric acid) inhibitory
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In Parkinsons disease there is a progressive degeneration of dopaminergic neurones in the substantia nigra. Symptoms not evident until very substantial loss has occurred.
Synthesis of catecholamine neurotransmitters; dopamine, noradrenaline and adrenaline
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Drug therapy:
No drug reverses neurodegeneration. Aim to reverse effects of dopamine deficiency in basal ganglia or block excitatory effect of acetylcholine (on muscarinic receptors). Most effective drug is levodopa (L-DOPA), brain permeable dopamine precursor. Co-administered with carbidopa (inhibits DOPA-decarboxylase peripherally) and sometimes entacapone (inhibits catechol-o-methyl transferase) to prevent breakdown. Levodopas efficacy usually wanes after about 2 years. Side effects are involuntary movements and unpredictable on-off behaviour Other useful drugs include bromocriptine (DA agonist), amantadine (DA releaser) & benztropine (muscarinic antagonist).
Attempts to cure Parkinsons disease include foetal stem cell transplantation, sub-thalamic lesions & deep brain stimulation.
DBS leaves electrodes in place in the brain to deliver continuous stimulation. The electrodes are powered by a programmable stimulator (like a pacemaker), which is implanted in the chest wall. Some positive effects on tremor reported.
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Huntingtons disease (Huntington's chorea)

Inherited disorder resulting in progressive brain degeneration. Characterised by excessive, abnormal movements (dancing-like), also progressive dementia. Protein encoded by the HD gene (huntingtin) interacts with range of regulatory proteins causing excitotoxicity and neuronal apoptosis. 75% reduction in GABA content in striatum; produces hyperactivity of dopaminergic transmission (converse of PD). Drugs that alleviate the symptoms include neuroleptics (e.g. chlorpromazine) and the GABA receptor agonist baclofen.
Alzheimers disease (AD)

Age-related dementia distinct from ischemia-related conditions. Can involve 75% loss of (particularly cholinergic) neurones in forebrain causing memory loss and language difficulties. Characteristic amyloid plaques and neurofibrillary tangles.
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Amyloid plaques consist of excessive (neurotoxic) amounts of A fragment of amyloid precursor protein (APP) a normal cell membrane constituent. Neurofibrillary tangles are aggregates of highly phosphorylated form of Tau (another normal neuronal protein); role in neurotoxicity not clear. Most AD of unknown cause (sporadic). Familial AD (rare) due to mutations in genes for APP and unrelated presenilin; both cause increased A formation. Treatment Anticholinesterases (preserve released ACh) e.g. tacrine are of some limited benefit. Anti-inflammatory drugs might retard neurodegeneration (some evidence that long term NSAID consumption associated with lowered risk of developing AD; not proven).
Motor neurone disease (MND); Also known as amyotrophic lateral sclerosis (ALS), affects movement due to progressive degeneration of the motor nerves connecting the spinal cord to the skeletal muscles. Only 10% cases have a genetic component. Sufferers eventually lose all control over voluntary movements, even processes like swallowing and eye movements, although it does not affect mental ability (Stephen Hawking !). No effective drug therapy although modest success in slowing progression claimed for riluzole; inhibits release and action of glutamate.
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Nutrition and neurodegenerative disease;

Alzheimers disease is often accompanied and worsened by malnutrition. Weight loss can be progressive; loss of 4% body wt. in 1 y (about one third of patients) or severe loss of > 5 kg in 6 months (about 10%). Disease severity a risk factor. Nutritional interventions indicated for severe groups. Up to 80% Parkinsons patients suffer constipation. Related to reduced water intake (dont feel thirst) throughout life.
Complication in some with PD is oropharyngeal dysphagia, a symptom complex recognized by difficulty in transfer of a food bolus from mouth to oesophagus. Dysphagia is also major problem in motor neuron disease. Gastrostomy feeding tubes are being inserted more frequently in MND patients but not associated with increased survival times. Median survival from tube insertion 146 days; 1 month mortality after gastrostomy was 25%. Body mass index should be used with caution for the evaluation of the nutritional status of patients with MND. Experimental evidence that dietary restriction is neuroprotective in PD and AD models.
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Schizophrenia; a disease of disordered thought & perception
Criteria for schizophrenia (DSM IV); 2 or more of each present for significant time during 1 month period; Positive symptoms: Delusions Hallucinations Disorganised speech (frequent derailment or incoherence) Grossly disorganised or catatonic behaviour Negative symptoms: Flattening of mood and lack of volition Only one of these required for diagnosis if delusions are bizarre or hallucinations consist of voice running a commentary on patients behaviour or thoughts, or 2 or more voices conversing with each other.
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Typically equally affects men and women in late teens/early 20s Incidence about 0.2 per 1000 in UK (~12,000) Genetic component identified but concordance amongst identical twins only 50%. Pathology; cause unknown but dopamine hypothesis partly based on similar symptoms following some drugs that increase dopamine levels or stimulate dopamine receptors (e.g. amphetamine, cocaine, apomorphine). Suggested hyperactivity in the mesolimbic system, dopaminergic tract originating in the ventral tegmental area and projecting to nucleus accumbens, ventral striatum, amygdala, hippocampus and other parts of the limbic system (involved in emotion and memory). Supported by PET studies showing reduced mesolimbic blood flow in schizophrenics.
Human dopaminergic pathways cognition movement
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Treatment;
Drug therapy can lead to remission and re-integration into society Drugs used referred to as neuroleptics or anti-psychotics Typical anti-psychotics (e.g. chlorpromazine, haloperidol)
Antagonise dopamine D2 receptors reducing dopaminergic activity in mesolimbic and mesocortical pathways. Major side effect; extra-pyramidal symptoms, Parkinsonianlike, due to blockade of D2 receptors in nigro-striatal pathway.
As D2 receptors become supersensitive, Parkinsonian symptoms reduce. After months/years 20% patients develop tardive dyskinesia; repetitive, involuntary stereotyped movements resembling Huntingtons chorea. Atypical antipsychotics; e.g. clozapine, olanzapine, risperidone. Fewer side effects, poor correlation between D2 antagonism and efficacy.
clozapine
Antagonists at D4 receptors; located in frontal cortex, medulla and midbrain i.e.areas not involved in movement control. However, atypicals have affinity at other receptors (5HT2, alpha1 and alpha2 adrenoceptors, histamine H1, muscarinic) and D4 blockade probably not complete explanation of activity.
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Nutritional implications of schizophrenia: Schizophrenics make poor dietary choices, Likely to engage in less physical activity than normals. Atypical antipsychotic drugs produce weight gain; average of between 4.5 and 7 kg in the 3 months following commencement of olanzapine. Good take up with free fruit and vegetable programmes. But, consumption fell to pre-intervention levels 12 months after the intervention stopped. No differences at any time in blood micronutrients, body mass index, physical activity or risk of heart disease compared with controls.
Depression
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Major Depression Lifetime prevalence of 9-15% (up to 20% in women). Reactive depression has link to stressful life events; endogenous, no clear trigger. Some evidence of genetic component (identical twin studies) but no gene defect identified. A major depressive episode is present if five or more of the following nine symptoms are present during the same two-week period. At least one of the five symptoms must be either a depressed mood or loss of interest or pleasure (anhedonia).
Depressed mood for most of the day Disturbed appetite or change in weight Disturbed sleep Psychomotor retardation or agitation Loss of interest in previously pleasurable activities; inability to enjoy usual hobbies or activities (anhedonia) Fatigue or loss of energy Feelings of worthlessness; excessive and/or inappropriate guilt Difficulty concentrating or thinking clearly Morbid or suicidal thoughts or actions
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Noradrenaline and serotonin (5HT) pathways in the brain.
Raphe nuclei
Locus coeruleus
Synthesis of catecholamines
Metabolism via monoamine oxidase (MAO) and catechol-o-methyl transferase (COMT)
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Synthesis of 5HT
Metabolised by MAO
Reuptake and metabolism of noradrenaline
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Monoamine theory of depression: Reserpine (old anti-hypertensive drug) depletes nerves of monoamines and caused depressive symptoms. 1st generation antidepressant drugs (ADs; tricyclics e.g. imipramine) block monoamine reuptake (increase synaptic levels). Suggested (1965) that depression due to deficiency of brain MA. Problems Increased synaptic [MA] happens immediately but benefit from ADs takes weeks to appear. Some drugs that increase MA availability (e.g. cocaine) are not antidepressant.
Neurotrophic hypothesis Stress causes over-activity of hypothalamic-pituitary-adrenal (HPA) axis.
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Increased hormones (glucocorticoid, ACTH, CRH) cause atrophy of stress-vulnerable neurones (e.g. hippocampus) and reduction in neurogenesis. Imaging studies demonstrate shrinkage of some brain areas in depressives. ADs increase the expression of protective neurotrophic factors such as brain-derived neurotrophic factor (BDNF) reversing stress-induced damage. Treatment; Despite problems with monoamine theory, most effective ADs do interact with monoamine neurotransmission.
Antidepressant drugs:
Tricyclics e.g. imipramine Inhibit NA & 5HT re-uptake. Delayed effects, inhibit variety of receptors, dangerous in overdose (cardiac dysrhythmias), many drug interactions. Monoamine oxidase inhibitors (MAOI) e.g. phenelzine
Reduce intracellular MA metabolism. Delayed efficacy; major problem of cheese effect (preserve dietary tyramine, a sympathomimetic). Can cause fatal cerebral hypertension. Must not be given with other ADs.
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Selective serotonin re-uptake inhibitors (SSRI) e.g. fluoxetine
Currently most widely prescribed ADs. Safer in overdose; no more effective or rapid in action than older drugs. Side effects include nausea, anorexia, insomnia, reduced libido, ejaculation failure. Other MA uptake inhibitors Inhibit uptake by noradrenaline selective (e.g. reboxetine) or nonselective (e.g. venlafaxine). No more effective but less side effects and safer in overdose that TCAs. Electro-convulsive treatment Patients anaesthetised and muscle relaxant given. Mechanism unknown but can be life saving in refractory depression. Some short term memory loss.
Bipolar disorder (manic depression) Patients cycle between depression and mania Some famous manic depressives (mixed nuts);
Buzz Aldrin, astronaut; Napoleon Bonaparte; Jim Carrey, actor; Dick Cavett, writer, media personality; Agatha Christie; Winston Churchill; Rosemary Clooney, singer; Francis Ford Coppola, director; Patricia Cornwell, writer; John Daly, athlete (golf), Ray Davies, musician;Emily Dickinson; Patty Duke, actor, writer; T S Eliot, poet; Robert Evans, film producer; Carrie Fisher, writer, actor; Edward FitzGerald, Robert Frost; F Scott Fitzgerald, author; Connie Francis, actor, musician; Sigmund Freud, physician; Cary Grant, actor; Victor Hugo, poet; Jack London, author; Robert Lowell, poet; Marilyn Monroe, actress; Mozart, composer; Spike Milligan, comic actor, writer; Ilie Nastase, athlete (tennis), politician; Isaac Newton, scientist; Plato, philosopher, (according to Aristotle); Edgar Allen Poe, author; Charley Pride, musician; Graham Greene, writer; Abbie Hoffman, writer, political activist; Gordon Sumner (Sting), musician, composer; St Francis; St John; St Theresa; Rod Steiger, film maker; Robert Louis Stevenson; Liz Taylor, actor; Mark Twain, author; Vincent Van Gogh.
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Treatment; Mood stabilising drugs used to control mood swings. Lithium is most common; recently, anti-epileptic drugs, (e.g.carbamazepine) proved useful and less toxic. Lithium is toxic in overdose (confusion, convulsions & cardiac dysrhythmias) and has narrow therapeutic window (plasma levels monitored and kept between 0.5 and 1.0 mmol/L). Given prophylactically, both phases reduced. Takes 3-4 weeks to work. Mechanism not clear. Neuroleptics used to manage acute mania. Some patients prefer to avoid treatment, preferring possibly creative manic phase at expense of depression.
Anxiety
Normal fear response to threat comprises various components; defensive behaviour, autonomic reflexes, arousal, alertness, corticosteroid release, negative emotions. In anxiety states, these occur in an anticipatory manner, independent of imminent danger. Difficult to distinguish normal from pathological anxiety. More than 10% western populations regularly use anxiolytic drugs. Anxiety disorders include: Generalised anxiety (excessive anxiety with no clear focus); panic disorder (marked somatic symptoms); phobias; post-traumatic stress disorder (anxiety triggered by insistent memory of past stressful event).
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Anxiolytic and hypnotic drugs Main drugs used are benzodiazepines, e.g. diazepam Potentiate action of major inhibitory neurotransmitter, GABA. Benzodiazepines with short half-lives used mainly as hypnotics (e.g. midazolam) but problems with dependence. Longer acting drugs (e.g. flurazepam) preferred as anxiolytics. Benzodiazepines obliterate memories of events experienced under their influence (use in minor surgery) and are anti-convulsant. Risk of dependence! Buspirone; 5HT1A receptor agonist is non-sedative anxiolytic. Takes weeks to work so ineffective in panic. Beta-adrenoceptor antagonists (e.g. propranolol) used to control physical symptoms of anxiety (palpitations, sweating etc). No effect on emotional component.
Alcohol; short term effectiveness, side effects all too familiar. Anxiety commonly co-exists with depression. Can treat acutely with benzodiazepine prior to ADs taking effect. Some disorders with anxiety component treated with other drugs; e.g. GAD and obsessive compulsive disorder treated with SSRIs or TCAs.
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Nutrition and mood disorders: 50% depressed patients overweight and 20% obese. Women with depression have more abdominal fat and are more at risk of CVD than non-depressed. Depressed patients do not value modest weight loss; one study reported that one third of patients thought that 10% loss in body weight required for benefit and were prepared to risk death to achieve this. SSRIs have common GI side effects (nausea, vomiting, dyspepsia, diarrhoea, constipation!), anorexia with weight loss (but increased appetite and weight gain also reported). Weight gain major reason for non-compliance.
Eating disorders
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Eating disorders:
The main types of eating disorders are anorexia nervosa and bulimia nervosa. A third type, binge-eating disorder, has been suggested but has not yet been approved as a formal psychiatric diagnosis. Eating disorders frequently co-occur with other psychiatric disorders such as depression, substance abuse, and anxiety. Females are much more likely than males to develop an eating disorder. 5 to 15 % of people with anorexia or bulimia and about 35% with binge-eating disorder are male. Syndromes are complex and treatments require psycho-social as well as medical intervention. SSRIs can contribute to treatment regime.
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Obesity
MP3 L10 1 IAM
WHAT IS OBESITY?
Too much body fat Too much fat in the wrong place Caused by chronic positive energy balance: Results from: too much energy intake or too little energy expenditure or a combination of both??
Learning objectives- to:

define obesity Discuss the treatment options for patients with obesity
How do we assess obesity?

Body Mass Index BMI= weight (kg)/height2 (m2) <18.5 18.5-24.9 > 25 25-29.9 30-34.9 35-39.9 40 and above underweight healthy overweight pre-obese grade I grade II grade III Risk of co-morbidity average increased moderate severe very severe (WHO)
Prevalence of obesity, adults aged 16-64, 1986/87 - 2004, England

30
Men
25
Women
20
% BMI over 30
15
10
0 1986/87 1991/92 1994 1996 Year 1998 2000 2002 2004
www.heartstats.org
Foresight model: by 2050 60% men, 40% women
Consequences of Obesity Obesity is a major risk factor for CHD Also: Increases bp Increases plasma cholesterol levels Increases risk of type II diabetes additional risk factors for CHD Increase cost to NHS est. 45.5 billion by 2050
Cancer WCRF Report 2007- systematic review of literature Increased risk of certain cancers with increased body fat Adult weight gain also associated with increased risk of cancer- even within healthy range of BMI Adult weight gain due to increase in fat http://www.dietandcancerreport.org/
WCRF Report 2007- Systematic Review Risk

Exposure Cancer
Risk
Exposure Body fatness Cancer Oesophagus Pancreas Colorectal Breast (postmen) Endometrium Kidney Colorectal Gall bladder Pancreas Breast (postmen) Endometrium Breast (postmen)
Convincing
Abdominal Fat Probable Body fat Breast (premen) Body fatness Abdominal Fat
Adult weight gain
Waist Circumference
Apples or pears- waist:hip ratio Apples- greater risk of complications
MEN Waist circumference Odds ratio for 1 or more risk factors 94-102cm >102cm 2.2 4.6 WOMEN 80-88cm 1.6 >88cm 2.6
Risk of:
high total cholesterol (> 6.5 mmol/l) low HDL cholesterol (< 0.9 mmol/l) High b.p.(>160 diastolic or >95 mmHg systolic)
Han et al. BMJ, 311, 1995
Weight Loss Target: An achievable target should be set5-10% of original weight Max weekly weight loss of 0.5-1 kg May still have BMI > 25 kg/m2
Dietetic Treatment Based on energy balance equation Energy input- energy consumption = energy balance In order to lose weight energy balance must be negative
Current Prescription Only Medicines Orlistat Sibutramine- Suspended Jan 2010 Rimonabant- marketing authorisation suspended Oct. 23rd 2008. Dexfenfluramine, fenfluramine and phentermine associated with valvular heart disease and pulmonary hypertension. No longer recommended.
Orlistat Tetrahydrolipostatin. Synthesised derivative of lipostatin, (a metaolic product of Streptomyces toxytricini) - Inhibits Gastric and Pancreatic lipase - minimal absorption - Needs to be taken before each main meal - ~ 30% inhibition of lipases at normal therapeutic doses (lose 200kcal per day) -Needs to be combined with a low fat diet reinforces the need to restrict fat intake
Side effects Steatorrhea- fatty, foul smelling faeces - may actually help to reduce fat intake Reduced absorption of fat therefore need to monitor fat soluble vitamin status- supplements?
Meta Analysis of Clinical Trials (Rucker et al BMJ Online & Padwal et al Cochrane Database, 2003) 16 clinical trials (10,631 subjects) Orlistat for 1 year reduced weight by 2.9kg more than placebo. With calorie-reduced diet. BUT Controlled trials are not always mirrored in Clinical Practice.
Prescribing guidelines To be combined with reduced calorie diet. BMI > 30 kg/m2 or BMI > 28 kg/m2 if other risk factors eg type 2 diabetes, hypercholesterolaemia, hypertension Should only be continued after 12 weeks if weight loss exceeds 5%
Dose 120 mg taken immediately before, during or 1 hr after each main meal Max. 360 mg daily Miss dose if meal contains no fat
OTC Orlistat (Alli) Reduced dose- 60mg tds Max 6 months Combined with reduced fat diet BMI > 28 Review after 12 weeks Dietary approaches and physical activity should be tried before Orlisat
http://www.rpsgb.org/pdfs/otcorlistatguid.pdf
Sibutramine (suspended) Combined NA and 5HT uptake inhibitor-CNS Appetite suppressant.
Side effects Increases SNS activity, can raise BP BUT offset by weight reduction Increases heart rate slightly.
Rimonabant (Acomplia) -CB1 receptor antagonist -Licensed for use in EU July 2006 -NICE guidelines issued June 2008 -European Medicines Agency suspended marketing authorisation Oct. 23rd 2008. -Review found that benefits do not outweigh the risks.
Blocks central and peripheral CB1 receptors Decreased motivation to eat palatable food Anorexigenic effects Stimulation of satiating signals in GIT Inhibition of lipogenesis (adipose and liver)
Phentermine- US Not licensed in UK. Increases catecholamine levels in brain. Also peripheral effects- increase hr, bp, palpitations. Qnexa- phentermine + topiramate 42% > 10% weight loss FDA rejected- Oct 2010- side effects Qsymia- Licensed in US 2012
Bariatric Surgery
Roux-en-Y gastric bypass (RYGB) results in 2040% weight loss maintained over at least 15 years.
Laparoscopic adjustable gastric banding (LAGB) results in 1530% weight loss.
From OBrien et al. Obes Surgery vol 16 pp1032-1040
Surgery can lead to major, sustained weight loss. Not possible with drugs Increases satiety and reduces appetite Therefore patients dont want to eat as much.
Bariatric Surgery reduces mortality and morbidity in morbidly obese patients: Improves type 2 diabetes Reduces hyperlipidaemia Reduces hypertension Improves sleep apnoea
Buchwald, H. et al. JAMA 2004;292:1724-1737.
Risk?- risks associated with surgery ~ 1% early mortality after RYGBP surgery ~ 0.4% early mortality after banding Cost?- cost effective as reduces impact on Health service of co-morbidities
Control of Appetite and Future Treatments
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Brain ARC NPY/ AgRP POMC/ CART
Insulin PYY Leptin Adipose tissue
Ghrelin Vagus
CCK Pancreas GIT
Leptin (Greek: thin) Peptide hormone secreted from adipose tissue Mutations causing absence of leptin leads to severe obesity Many obese people have increased levels of leptinLeptin resistance?
Ghrelin Produced from GIT. Secreted on anticipation of food Hunger at certain times of day- Ghrelin
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B L
D Ghrelin
Insulin
Leptin
Cummings et al., 2001
Ghrelin levels peak before meal. Stimulates hunger in humans. Ghrelin antagonists/ synthesis inhibitors in development for treatment of obesity.
NPY as a Drug Target NPY orexigenic therefore blocking receptorsdecrease appetite? Inhibition of NPY synthesis suppresses food intake. Energy homeostasis may be altered through NPY Y1, Y2 and Y5 receptors in the brain. Y1 antagonist- inhibits NPY-induced feeding in rats
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Reward Centres also involved Appetite linked to reward processes in the brain. eg opioid receptors (endorphins) Cannabinoid receptors Dopamine Reinforcement of motivation to find and consume foods of high incentive/energy content?
Dopamine & Reward Feeding is associated with dopamine release in the dorsal striatum. Degree of pleasure correlates with the amount of dopamine released.
Evidence from Other Drugs Bupropion (Zyban) Anti-depressant and smoking cessation (cf rimonabant). Link to reward and dopaminergic system? NA and dopamine reuptake inhibitor Weight loss in obese patients being treated for depression. Weight gain after smoking cessation less in patients taking bupropion.
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Clinical Trial Patients BMI>30 Placebo- 24 weeks, 600kcal/day deficit- ~5% weight loss 400mg/day bupropion- 24 wks, 600kcal/day deficit ~10% weight loss No increase in adverse effects compared to placebo.
(Anderson et al (2002) Obesity Research vol 10, pp633-641)
Empatic- bupropion + zonisamide 8.6 % weight loss after 24 weeks.
5-HT Receptor System (serotonergic) 5-HT (serotonin)- number of different receptor subtypes. 5-HT1B, 5-HT2c, 5-HT6 all cause weight loss in rodents. Serotonergic compounds alter expression of neurotransmitters in hypothalamus: POMC mRNA NPY mRNA -
5-HT 5-HT1B 5-HT2c
NPY AgRP
POMC CART
ARC
Food Intake
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Lorcaserin (APD356) 5-HT2c receptor agonist Phase II clinical trials- greater weight loss than placebo. After 84 days- 3.5kg weight loss (moderate) (May not be as good as sibutramine) Phase III clinical trials Other compounds targeting these receptors in pipeline. FDA approved Oct 2012
Tesofensine Phase II clinical trials Triple reuptake inhibitor (5-HT, NA, dopamine) cf sibutramine 15% weight loss over 22 weeks
A natural way to help speed up weight loss
Contains: Fucus- kelp Boldo Dandelion root Butternut
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Drug Metabolism Adverse Drug Reactions Drug Interactions

Dr Richard Roberts
Objectives
To understand the basic principles of pharmacokinetics including drug Absorption Distribution Elimination Understand how this relates to drug dosing Be aware of drugs commonly associated with adverse drug reactions and other risk factors involved Understand the mechanisms of drug interactions
Pharmacology- the study of what a drug does to the body & what the body does to a drug Pharmacodynamics- what the drug does to the body Pharmacokinetics- what the body does to the drug Involves: Absorption ADME Distribution Metabolism Excretion Contribute to: Interindividual variation in response to drug
Absorption
ADME
The passage of a drug from its site of administration into the plasma Absorption is important for all routes of administration except i.v.
Main routes of administration are: oral sublingual eg glycerol trinitrate rectal transdermal inhalation injection subcutaneous intramuscular intravenous intrathecal (brain or s.c.)
Oral Dose
Bioavailability: Proportion of drug that reaches systemic circulation
Circulation
Drug is taken by mouth & swallowed
Tablet dissolves
1st pass metabolism
. .. ... ...
Enters small intestineabsorbed
GIT Absorption dependent upon: Rate of travel to small intestine- altered by: gut motility - some disorders decrease gut motility - Presence of food decreases gut motility Particle size- dependent on tablet formulation
eg. Capsules may be designed to stay intact for several hours to delay absorption Or formulations designed to give gradual release over time
GIT Absorption dependent upon:
Physicochemical Properties eg -tetracycline (antibiotic) binds to Ca2+ . Milk inhibits absorption.
Drug interactions
Altered Absorption Altered pH: antacids Binding: colestyramine with digoxin, warfarin (binds bile salts) Altered gut motility: anticholinergics or opioids Alcohol- inhibits absorption of erythromycin
Food can Affect Drug Absorption Antifungals: griseofulvin, itraconazole Absorption of griseofulvin doubles if taken with fatty meal- solubility Itraconazole capsules- improved bioavailability if taken after a meal Itraconazole solution-bioavailability higher in fasted state! Aspirin: Food decreases absorption rate. If rapid absorption required, take without food. BUT food may also protect gut mucosa from aspirin.
SINGLE ORAL DOSE Availability over time
Time to peak plasma concentration determined by dissolution of tablet & rate of absorption
Plasma concentration
Toxic level Excretion
Therapeutic level
Time
Half-lifetime taken to reach half-max. concentration in plasma. Can be short (mins) or long eg mefloquine 30 days (1x week dose)
Distribution
ADME
Defined as: Movement of drug from circulating blood to sites of action, binding, and elimination Rate and extent of distribution depends on: relative arterial blood perfusion rate of different organs permeability characteristics of barriers eg Blood-brain barrier prevents some drugs reaching brain binding in blood (eg albumin) or tissues (eg fat)
METABOLISM AND EXCRETION
ADME
Like any compound taken into the body, drugs are excreted. Most drugs are excreted in urine. Some through lungs (eg gaseous anaesthetics) Lipophilic drugs require metabolism to polar metabolites in order to be excreted.
General Features of Drug Metabolism Enzymes arose either to handle endogenous compounds or eliminate toxic compounds Enzymes non-selective Enzymes exist in isozymic forms A single substrate may be metabolised though several different pathways Majority of metabolism occurs in liver.
METABOLISM AND EXCRETION 2 Routes of Drug Metabolism 2 phases of drug metabolism: Phase I- Cytochrome P450 enzymes Phase II conjugation- attachment of a substituent group. Increased water solubility. eg Glucuronidation Sulphation Glycine conjugation Acetylation
Prodrugs Some drugs require metabolism to form active drug e.g. acetylsalicylic acid (aspirin) metabolised to salicylic acid Codeine morphine
Toxic Metabolites Metabolism can also produce active, but toxic metabolites eg paracetamol- see later
COOH
Aspirin
OCOCH3
Phase 1
COOH
Salicylic Acid
OH
Phase 2
COOH O- glucuronide
Interindividual Variation in Metabolism Genetic variability in some P450 enzymes. -differences in metabolism of certain drugs. -reduced excretion & increased toxicity. -Or reduced concentrations of active drug eg. Proguanil (antimalarial) metabolised to cycloguanil (active form). Genetic polymorphismpoor metabolisers- less of active form. Also codeine CYP2D6. Poor metabolisers- no pain relief morphine
Alterations in drug metabolism is important site of drug-drug interactions. Also, environmental factors can alter drug metabolism eg nutrients Alcohol and cigarette smoke can alter drug metabolism
Drug-Drug Interactions Induction Induction of drug metabolism eg phenytoin, ethanol Decrease plasma levels of drugs eg Chronic heavy drinking reduces phenytoin concs Warfarin Continuous heavy drinking stimulates hepatic enzymes leading to increased metabolism.
Inhibition Inhibition of drug metabolism eg. erythromycin, cimetidine, fluconazole Increased plasma levels of drugs-toxic
Antibiotics & Antifungals with Alcohol Metronidazole & ketoconazole- flushing & gastric pain Inhibition of alcohol dehydrogenase? Disulfiram-like reaction Most other antibiotics fine.
Drug Metabolism Smoked or barbacued foodContain polycyclic aromatic hydrocarbons. Potent inducers of CYP1A1 & CYP1A2. Regular consumption of these foods can reduce plasma concentrations of drugs. Brassicas- brussels sprouts, cabbage etc regular consumption decreases plasma levels of some drugs by 50% Broccoli every day induces CYP 450 enzyme activity. Decrease plasma levels of drugs
Effects of Nutrients on Drug Metabolism Grapefruit juice- phytochemicals increase bioavailability of certain drugs- inhibition of CYP450 enzymes. Transient effect. Interactions with: Simvastatin: Avoid concomitant use Dihydropyridine calcium channel blockers (nifedipine, nicardipine)
Grapefruit and pills mix warning By James Gallagher Health and science reporter, BBC News Nov 2012
Effects of Herbal Medicines on Drug Metabolism Cytochrome P450 induction St Johns Wort (herbal medicine) Stimulates CYP450 enzymes eg oral contraceptives Increased metabolism and reduced levels of drug
Effects of Vitamins on Drug Metabolism: Folic Acid: Increases hepatic metabolism of phenytoin. NB As a result, phenytoin also decreases plasma levels of folic acid Vit B6: required for conversion of levodopa to dopamine in brain. However, if vit B6 levels are high (< 10mg od), get conversion to dopamine outside of brain.
Drug-Drug Interactions- Excretion Competition for renal excretion e.g methotrexate with NSAIDs Consequence- increase methotrexate levels- toxic
Metabolism of paracetamol
Paracetamol is non-toxic at normal doses Overdose- hepatotoxicity & death
Normal doses Toxic doses Saturated Glucoronidation Sulphation Glutathione conjugate Excretion Removal of toxic compound Death Oxidation NAPBQI NAPBQI GSH becomes depleted
Cell damage
Paracetamol Toxicity Serious liver damage at 150mg/kg (~10g for 70kg) 5g or more can cause liver damage in some patients eg existing liver damage, gluthionine depleted. Standard dose: 1g, 4 x per day. 4th most common cause of death due to self poisoning in UK Treatment with acetylcysteine or methionine increase GSH levels and reduces mortality
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Plasma concentrations- relationship to elimination

Plasma concentration of a drug determined by rate of absorption and rate of elimination. Determines how often a drug needs to be given to maintain plasma levels within therapeutic dose BUT below toxic dose
Single IV Injection
Injection- rapid rise in plasma concentration. Gradual decline in concentration due to elimination
T im e
Injection
Single Oral dose:

Absorption Elimination
Time
Dose
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REPEATED ORAL DOSES
Dosing rate depends on rate of absorption & elimination
Dose every 12 hours Gradual increase in plasma conc. Until steady state ie absorption = excretion
Repeated oral doses

drugs with long half lives (i.e. long time to be excreted) take longer to reach steady state. Also longer for drug to be washed out of body, therefore side effects may persist for a while. Altered elimination: age, renal or hepatic impairment or drug interactions result in reduced dose or dosage interval
IV INFUSION Aim- to produce steady plasma concentration. Rate In = Rate out

Infusion
May need to give bolus dose to start off with before continuous infusion
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Individual Variation in Response to Drug Individuals vary in their response to a drug due to: differences in absorption - genetic factors - presence of food/ drugs - age/ disease difference in distribution - other drugs - plasma binding proteins difference in metabolism - genetic - disease - environmental etc difference in excretion - genetic - disease - age
Factors influencing drug response: ethnicity age pregnancy genetics disease drug interactions
Interindividual variation can determine whether a drug is effective at the concentration used, or is toxic.
Adverse Drug Reactions (ADRs) ADRs or side effects? Side effect - secondary effect of a medicine, often predictable sometimes desirable (e.g. sedation with antihistamines in OTC sleep medicine) sometimes undesirable (e.g. sedation with antihistamines used in allergy relief) ADR side effect which is always undesirable
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Therapeutic Index- ratio of toxic dose: effective dose ie benefit: risk ratio OTC medicine- high benefit: low risk of ADR/toxicity However, anti-cancer/HIV treatment may be able to put up with narrower therapeutic index (more risk of ADR)
Toxic level
Therapeutic Index
Therapeutic level
Time
Examples of ADRs:
NSAIDS ulcers
Antibiotics (severe diarrhoea due to Clostridium difficile) Anticoagulants- bleeding/anaemia Digoxin- toxicity Diuretics- dehydration/electrolyte disturbances Anti-diabetic agents- hypoglycaemia

Some drugs can affect food intake: Reduced appetite: digoxin, fluoxetine (SSRI) (nausea?) Weight gain: corticosteroids, oral contraceptives, TCAs (increased appetite?) Taste disturbance: terbinafine (anti-fungal), allopurinol (gout), metronidazole (anti-bacterial), metformin (anti-diabetic) Dry mouth: anticholinergic effects e.g. antihistamines, TCAs
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Nausea & Vomiting: Many, particularly chemotherapy, SSRIs Dyslipidaemia: -blockers, thiazide diuretics Hyperglycaemia: corticosteroids, thiazide diuretics Malabsorption from the duodenum: colestyramine, liquid paraffin consider supplementing fatsoluble vitamins
No. of factors that may predispose a patient to an ADR:

Polypharmacy
drug interactions e.g cytochrome P450 inducers or inhibitors Drugs with narrow therapeutic index warfarin, lithium, digoxin, theophylline Extremes of age Mildly impaired renal function in most elderly patients Concurrent disease Altered pharmacokinetics e.g. renal, hepatic disease
Polypharmacy-Drug Interactions
i.e. interactions of the effect of two or more drugs on the body May result in an ADR but may be beneficial (e.g. atenolol + thiazide combine to reduce b.p. further) Can alter uptake/metabolism or oppose or enhance action of drug
15
Drug Interactions
Pharmacodynamic interactions Similar pharmacological targets eg. b-adrenoceptor agonists for asthma & badrenoceptor antagonists (beta-blockers) for CVD (opposing actions)
Similar or opposing pharmacology Warfarin and vitamin K Ca2+ channel blockers (verapamil) and Ca2+ (osteoporosis) Possible interaction Alcohol and sedative agents (sedative antihistamines, BDZ)- increased sedative effect
Disturbances of the equilibrium of fluid and electrolytes eg K+ sparing diuretics, ACEIs and K+ - hyperkalaemia Anticoagulants Theophylline garlic (anti-coagulant properties) caffeine (same action)
16
Specific Information for Dieticians

Some of the components of enteral and parenteral feeds may interfere with drugs. The next two slides contain general points for use of enteral and parenteral feeds with drugs.
Drugs & Enteral Feeds General points: Never put drugs into feed. If nasogastric tube is to be used for drug administration: Always stop feed and wash tube with water before and after drug admin. If possible, separate feed and drug by 2 hours Consider drug-nutrient interactions Consider other routes of administration.
Drugs & Parenteral Feeds General points: Drugs should never be given down IV lines Drugs are not generally added to TPN Stability occasionally heparin, insulin, H2 antagonists, corticosteroids Caution vitamin K and warfarin interaction Bioavailability of theophylline reduced by high protein feeds
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Further reading
British National Formulary! Pharmacology, Rang, Dale, Ritter & Moore Disease Management, Randall and Neil Stockleys Drug Interactions
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Herbal Medicines Dr Richard Roberts
Objectives
Herbal Medicines Licensing issues and health claims Herbal preparations and common uses Toxicity of herbal preparations and drug interactions
UK study: people > 50 use 2.26 prescription drugs 5.91 herbal & nutritional supplements 2.66 herbal supplements
Licensing issues
Most herbal medicines not controlled under the Medicines Act No sale restrictions Product Licence not required therefore rigorous clinical trials not required and controls re. dosage, labelling, purity, levels of ingredient not as strict as for medicines
Medicinal/Health claims
Herbal Medicines cannot make medicinal claims e.g. cannot claim to cure, treat or prevent a disease However, can have health claims e.g. for a healthy nervous system
Public perception-herbal medicines are safer than conventional medicines because they are natural. 40% of people think herbal medicines are safe because they are natural However, conventional medicines need to go through rigorous trials to determine safety. Herbal medicines- not required to go through safety trials
Herbal Medicines- Licensing Issues

Herbal Medicines can be: 1.Unlicensed- no specific standards of safety or quality - dont require product information- dose, ADRs etc - internet
2. Registered Traditional Herbal Medicine Companies must supply evidence about the safety and use of the product. Manufacturers must meet certain safety & quality standards. Registered products must be accompanied by information about the product and its safe usage.
Herbal practitioners manufacture herbal medicines on site therefore not industrially produced. ie unprocessed herbs classed as ingredients not products Anything manufactured elsewhere should be covered by THR or MA.
3. Licensed- hold product license just like any other medicine. Required to demonstrate safety, quality, efficacy and accompanied by product information sheet
Herbal Medicines
Top selling herbal products: 1. 2. 3. 4. 5. 6. Ginkgo biloba St. Johns Wort Ginseng Garlic Echinacea Saw palmetto
Not much is known about how they act, what the side effects are, or drug interactions
Top selling herbal ingredients

1.
Ginkgo biloba Used for memory/ concentration problems Dizziness, tinnitus, headaches Stroke Relax blood vessels- evidence? Reduce blood viscosity- anti-platelet? Anti-oxidant Trials show inconsistent results
http://www.cochrane.org/reviews/en/ab003120.html
St Johns Wort (Hypericum) Anti-depressant shown to be as effective as some conventional antidepressants in mild to moderate depression Pure hyperforin has anti-depressant actions. Inhibits NA & 5-HT reuptake- similar to other antidepressants.
5-HT
SSRI SJW
5-HT 5-HT-R
5-HT 5-HT 5-HT 5-HT
Hyperforin increases protein & activity of CYP2C9 and CYP3A4 enzymes (see later). Wide number of drugs metabolised by CYP3A4. interactions with a number of drugs incl: oral contraceptives, warfarin, cyclosporin, digoxin, anticonvulsants, theophylline, ( plasma concentrations ) Decreased therapeutic effect e.g. kidney transplant rejection in patient taking cyclosporin.
Also: increase in P-glycoprotein drug transporter. Decrease in drug levels (eg digoxin) through increased efflux.
Also interaction with other anti-depressants: similar mechanism of action. Increase 5-HT (serotonin) levels in brain serotonin syndrome: neuromuscular hyperactivity eg tremor autonomic hyperactivity - sweating, fever, tachycardia & rapid breathing altered mental status - agitation, excitement & confusion
Self-Prescribing. SSRIs should be withdrawn gradually over a period of at least 4 weeks. Involves a gradual dose reduction. Rapid withdrawal may prescipitate a reaction eg depression, sensory and balance problems. e.g. Report of woman taking SJW for 10 days then took 20mg paroxetine. Complained of nausea, weakness, fatigue and became incoherent.
Side Effects: Hypericin causes photosensitivity- skin irritation.
Refs:
http://www.cochrane.org/reviews/en/ab000448.html Wurglics & Schubert-Zsilavecz 2006 Clin Pharmacokinet vol 45 p 449-468 List of drug interactions can be found at: http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/ safetymessages/sjwfsh.pdf
Hypericalm- granted Traditional Herbal Medicines License
Induction/Inhibition of metabolising enzymes

Activity of CYP1A2 CYP2C9 CYP2C19 CYP3A4 Grapefruit juice Seville orange juice Grapefruit juice Inhibited by Echinacea Cranberry juice Siberian ginseng Induced by Wu-chu-yu-tang SJW Ginkgo biloba SJW Garlic Echinacea root SJW
P-glycoprotein
3. Ginseng Short term: stamina, concentration, healing, stress Long term: well-being in debilitated/ degenerative conditions- old age ADRs: high doses may cause insomnia, nervous excitement, hypertension, euphoria, nausea, diarrhoea, oedema, skin eruptions Conventional doses: oestrogenic effects Interactions include: - Oestrogenic activity may oppose tamoxifen
4. Garlic - anti-hypertensive, antithrombotic, antimicrobial, cancer preventing, lipid-lowering - Some evidence to support these - Caution and ADRs: odour, indigestion, contact dermatitis, asthma, anti-platelet drugs (theory?) 5. Echinacea - now a Benylin product - Treatment of colds- no evidence - Immunostimulant
6. Saw palmetto -benign prostatic hyperplasia -Evidence that it improves urinary flow - may interact with diuretics or drugs used for incontinence Also claim to prevent hair loss
With all herbal medicinesWhat is the evidence? What is known about effective dose? What is the quality of the product like? Is it safe?
Reports of toxicity
Ephedra (Ma huang- ephedrine)
Used for: weight loss, coughs, bronchitis, nasal congestion Supplements containing ephedra & caffeine cause increased systolic BP and effects on heart rhythm Banned in US Feb 2008: Danish Medicines Authority issued warning about Therma Power slimming drug after a 36 yr old man died. Contains ephedrine and caffeine.
Reports of toxicity
Chinese herbs: reports of: - renal failure and renal cancer (Aristolochia for the treatment of eczema)
Women given Aristolochia for slimming. 100 developed kidney failure. Some developed renal cancer. In China, 12 out of 17 patients who took Aristolochia (Mu Tong) died of renal failure.
Traditional Chinese Medicines MHRA-some TCM pose a health risk due to poor quality Risk of heavy metal toxicity: High levels of mercury &/or lead found in some TCM as well as traditional Indian medicines. Ingredients unknown: Qianbai Biyan Pian- traditionally contains Senecioliver damage
Ingredients unknown: TCM slimming drugs found to contain prescription only medicines eg sibutramine, nitrosofenfluramine (1 case- patient required liver transplant) Corticosteroids in skin creams Illegal Ingredients: Nu Bao- contains human placenta, donkey skin, deer antler- potential sources of infection
Excite for Women and Ultimates for Men From Malaysia- to increase libido Found to contain sildenafil
OSAS Body Lotion Sold in Asian and African beauty shops Found to contain corticosteriods and an antifungal
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Reports of toxicity from Herbal Medicines

Hepatotoxicity comfrey, coltsfoot, Scullcap black cohosh increased use for menopausal symptoms Reports of liver toxicity Hypersensitivity- allergic reactions Chamomile, feverfew Uteroactivity- avoid in pregnancy blue cohosh, burdock, hawthorn, nettle, raspberry, vervain, motherwort
Problems with Herbal Medicines

Limited safety data Self-medication Cessation of medication without advice Exposure to toxic ingredients naturally present e.g. heavy metals, microbes, high levels of pesticides Quality may not have been assessed by a licensing authority (ingredients found to differ with label) Herb-drug interactions: toxicity or reduced efficacy
Herbal medicines can be a source of new drugs: Traditional Chinese Medicine- qinghao Used to treat bone steaming and heat vexation but also malaria From Artemisia annua. Contains artemisinin (qinghaosu).
Artemether with lumefantrine licensed for malaria in UK.
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Reference sources
Stockley Drug Interactions Text books:
Herbal medicines, Barnes et al. (tables at the end!) MHRA Website
Cochrane Reviews
Summary
Herbal Medicines may not be licensed and checked for safety Confusion may arise due to public perception of safety Potential for interactions with conventional medicines serious clinical consequences possible
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Abbreviations OTC- over the counter POM- prescription only medicine a.c.b.d.o.d.o.m.o.n.p.c.p.r.n. q.d.s.q.q.h.statt.d.st.i.d.before food (ante cibum) twice daily (bis die) every day (omni die) every morning (omni mane) every night (omni nocte) after food (post cibum) when required (pro re nata) to be taken 4 times daily (quarter die sumendus) every 4 hours (quarta quaque hora) immediately to be taken 3 times daily (ter die sumundus) 3 times daily (ter in die)
Easy way to remember what drugs are: Anything ending in: lol likely to be a beta-blocker pril likely to be an ACE inhibitor sartan likely to be an angiotensin (AII) receptor antagonist pine likely to be a calcium channel blocker statin likely to be a statin prazole likely to be a proton pump inhibitor one likely to be a steroid coxib likely to be a COX-2 inhibitor ol (rather than lol) likely to be a beta2 agonist ine could be an anti-histamine or an anti-depressant cillin likely to be a penicillin antibiotic mycin likely to be an antibiotic There are exceptions to these rules, but this is a good starting point.
Below is a list of drug families, examples of drugs (with Brand names in brackets) and common uses. Respiratory Disease Drug family 2-adrenoceptor agonists examples eg salbutamol (Ventolin) salmeterol (Serevent) Use asthma. COPD
Corticosteroids
Xanthines Muscarinic Antagonists Sodium Cromoglicate Leukotriene Receptor Antagonists
eg asthma Beclometasone (AeroBec) Some effect in COPD Budesonide (Pulmicort, Preventative Symbicort) eg theophylline (Nuelin) asthma (Slo-Phyllin) (Uniphyllin Continus) eg ipratropium (Atrovent) asthma COPD (Cromogen Easi-Breathe) (Intal) eg montelukast (Singulair) zafirlukast (Accolate) asthma
asthma prevention
Upper GIT Drug family Antacids Histamine H2 antagonists Proton pump inhibitors Prostaglandin analogues Dopamine D2 receptor antagonists H1- Histamine receptor antagonist Anti-muscarinic receptor agents Lower GIT Drug Family Opioids Laxatives Senna extracts Tricyclic antidepressants * * cross reference with CNS Examples Loperamide (Imodium) codeine Lactulose macrogels amitriptyline Use Anti GIT motility used in diarrhoea constipation constipation IBS Examples Sodium bicarbonate Magnesium hydroxide Ranitidine (Zantac) Cimetidine (Tagamet) Omeprazole (Losec) Lansoprazole (Zoton) Esomeprazole (Nexium) Misoprostol (Cytotec) Domperidone (Motilium) Promethazine (Phenergan) hyoscine Use Acid reflux Excess acid Peptic ulcer Acid reflux Acid reflux Peptic ulcer Acid reflux Peptic ulcer Acid reflux Bloating Anti-emetic Motion sickness (CNS effects) Motion sickness (CNS effects)
Cardiovascular Drug Family Beta-blockers Examples Propranolol (Inderal) atenolol (Tenormin) bisoprolol (Cardicor) Lisinopril (Carace) Ramipril (Tritace) captopril (Capoten) Simvastatin (Zocor) Pravastatin (Lipostat) Atorvastatin (Lipitor) Furosemide bendroflumethiazide Nifedipine (Adalat) Nimodipine (Nimotop) Amlodipine (Istin) Verapamil (Cordilox) Diltiazem (Tildiem) Losartan (Cozaar) Candesartan (Amias) Glyceryl trinitrate Isosorbide dinitrate (Angitak) Use Hypertension Heart failure Angina Myocardial Infarction Hypertension Angina? Myocardial Infarction Heart Failure Hypercholesterolaemia Possible use in: Hypertension? Angina? MI? stroke? Hypertension Heart failure hypertension Angina
ACE Inhibitors
statins
diuretics Ca
2+
channel blockers
Angiotensin II receptor antagonists nitrates Warfarin Anti-platelet
Hypertension Heart failure Angina Heart failure Atrial fibrillation Thromboembolic prophylaxis Myocardial Infarction Stroke Atrial fibrillation
Aspirin Clopridogrel (Plavix)
Obesity Drug Orlistat Sibutramine Rimonabant Examples Orlistat (Xenical) Sibutramine (Reductil) Rimonabant (Accomplia) Use Obesity Obesity Obesity
Diabetes Drug Family Insulin Examples NovoRapid Actrapid Humalog Insulatard Chlorpropamide Glibenclamide Tolbutamide Metformin (Glucophage) Nateglinide (Starlix) Repaglinide (Prandin) Pioglitazone (Competact) Rosiglitazone (Avandamet) Use Type I Diabetes
Sulphonylureas
Type II Diabetes
Biguanides Meglitinides Glitazones
Type II Diabetes Type II Diabetes Type II Diabetes
Nutrition-specific Adverse Drug Reactions Reduced appetite: digoxin, fluoxetine (SSRI) Weight gain: corticosteroids, oral contraceptives, Tricyclic anti-depressants Taste disturbance: terbinafine (anti-fungal), allopurinol (gout), metronidazole (anti-bacterial), metformin (anti-diabetic) Dry mouth: antihistamines, Tricyclic anti-depressants Nausea & Vomiting: Many, particularly chemotherapy, SSRIs Dyslipidaemia: -blockers, thiazide diuretics Hyperglycaemia: corticosteroids, thiazide diuretics Malabsorption from the duodenum: colestyramine, liquid paraffin Altered gastric mobility: Opioids (constipating)
Drug-Nutrient Interactions Folic acid Anti-convulsants (epilepsy) such as phenytoin reduce plasma levels of folic acid. Vitamin D Long-term use of Phenytoin can reduce plasma concs of vit D Vitamin A Oral contraceptives can increase levels of vit. A Iron Chronic use of antacids can reduce uptake of iron Tetracyclines (antibiotics) bind to iron, calcium, aluminium ions- reduce uptake Fat-soluble vitamins Eg orlistat (obesity)- may impair absorption of fat soluble vitamins Vitamin C Aspirin reduces absorption of vit C by 1/3 Vit B6 Reduces concentration of leva dopa in brain (Parkinsons) Vit K Antagonises effect of warfarin

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School of Life Sciences

Clinical Pharmacology & Medical Pharmacology Module Handbook

Convenor: Dr Roberts email: richard.roberts@nottingham.ac.uk

Clinical Pharmacology/ Medical Pharmacology Modules

Dr. Richard Roberts- Module Convenor

Cytoplasm Steroid hormone receptor

Steroid response element

Contraction of smooth muscle

Relaxation of smooth muscle

Get different responses depending on proportion of receptor subtypes present

Therefore can create selective drugs- selective effects

Adrenoceptors- role in fight or flight

Drugs can be agonists ie activate a receptor eg b2-adrenoceptor agonist acting on airways

Alteration of Neurotransmitter Function

eg SSRI, St Johns Wort, Sibutramine, Bupropion

eg calcium channel blockers

Inhibitors Inhibitors or activators R Enzymes

The Physiology and Pharmacology of Drug Abuse.

Famous Drug abusers

Addictive behaviours; eating, sex, exercise, Everton FC.

Nerves communicate by releasing neurotransmitters that are recognised by receptors

Brain Reward Pathways

Dopamine release in the nucleus accumbens is a common response to drugs of abuse

Does taking drugs recreationally do you any harm?

Ecstasy (MDMA (3,4 methylenedioxymethamphetamine);

Cannabis: (active agent THC) mimics effects of small endogenous

How common is the use of abused drugs?

Pharmacological approaches to treatment of drug abuse

Acomplia (rimonabant, SR141716A)

Antibiotics, antifungals, & antivirals

Inhibiting these processes will prevent bacteria growing and dividing

Tetrapeptide Side-chain Peptide crosslinks

Flucloxacillin- b-lactamase resistant penicillin.

Chloramphenicol prevents chain elongation

Tetracyclines prevent tRNA binding 50S subunit

Aminoglycosides: misreading of message

Griseofulvin Fungistatic Interferes with division/ growth Given orally

HIV replication in host cell

Innervation of the airways

Role of Sensory Nerves in Local Control: Potential Role in Exercise-Induced Asthma

eg COPD, asthma- cannot expel all air quickly

FEV1 = 32% of Normal FEV1:FVC= 0.42

Peak Flow Meter

Phases of an Asthmatic Attack

Chemokines eg ILs Chemotaxins

Late Phase Leukocytes eg T cells neutrophils basophils

Two main categories: 1 Relief of symptoms bronchodilators

Prevents late phase caused by release of cytokines.

Adenylyl cyclase cAMP Relaxation of airway tone

Long Acting -adrenoceptor agonist (LABA)

Regulation of cAMP by PDEs

Adenylyl cyclase cAMP ATP Phosphodiesterase (PDE) 5 AMP

Muscarinic M-receptor antagonists

Preventative; do not reverse an attack

Corticosteroids: Act at intracellular glucocorticoid receptor. Inhaled:

Oral: Prednisolone eg acute asthma attack OR IV Hydrocortisone eg life-threatening acute asthma

Cytoplasm Steroid hormone receptor

Steroid response element

AnnexinA1: inhibits synthesis of PGs and LTs: Corticosteroid Membrane

PLA2 Arachidonic acid

Bronchoconstriction Early Phase

Late Phase Leukocytes

CysteinylLeukotriene receptor antagonists e.g. montelukast, zafirlukast