handouts 2014

School of Life Sciences

2013 – 2014

ClinicalPharmacology

&Medical

PharmacologyModule

Handbook

Convenor: Dr Robertsemail: [email protected]

06/01/2014

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Clinical Pharmacology/Medical Pharmacology Modules

Dr. Richard Roberts- Module Convenor

Aim of the Module:

To provide background information aboutcommon drugs that may come across inclinical situation

-Mechanism of action

-Use

-Side effects

What is pharmacology?

Study of drugs:

The effect of the drug on the body-pharmacodynamics.

The effect of the body on the drug-pharmacokinetics.

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Receptors

•Neurotransmitters and some hormones cannot crossthe plasma membrane.

•Receptors: proteins in plasma membrane which bindthese compounds.

•Binding causes activation of the receptoractivates intracellular signalling cascadesresponse in the cell.

Membrane

contraction

eg noradrenaline released from sympathetic nerve endings acting onvascular smooth muscle cells.

a adrenoceptor

•Some receptors are intracellular eg nuclearreceptors

•Steroids act at nuclear receptors to alter genetranscription.

•Can cross plasma membrane.

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Steroid responseelement

Target Gene

Steroid hormone

Steroid hormone receptor

Dimer formation

Nuclear membrane

Cytoplasm

ExtracellularMedium

Intracellular receptors

Receptor Nomenclature

Receptors are combined into families based on the agoniststhat activate them and function.

eg adrenoceptor family

Activated by noradrenaline and adrenaline

adrenoceptors b-adrenoceptors

1 a2 b1 b2 b3

Contraction ofsmooth muscle

Relaxation ofsmooth muscle

Get different responses depending on proportion of receptor subtypespresent

Different subtypes useful for therapy.

Can generate compounds selective for 1 subtype overthe other.

eg Noradrenaline & adrenaline- act at a & b-adrenoceptors

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 thereforepreventing the agonist from having an effect.

eg b1-adrenoceptor antagonist acting on the heart

Membrane

contraction

eg noradrenaline released from sympathetic nerve endings acting onvascular smooth muscle cells.

a adrenoceptor

Antagonist binds to receptor, preventing agonist from binding.

x

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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 candisplace the antagonist and the response recovers.

contraction contraction

Non-competitive anatagonist

Binds to the receptor in such a way that the agonistcannot displace it, no matter how much agonist ispresent.

R

NT

Alteration of Neurotransmitter Function

Agonist

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R

NT

Antagonist

eg b-blockers

R

NT

egLoperamide,Domperidone

Pre-synapticreceptor

Agonist orantagonist

Increaseor

decrease

R

NT

NTNT

NTNT

Reuptakeinhibitor

eg SSRI, St John’sWort, Sibutramine,Bupropion

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R

NT

NT Metabolism

Synthesis

Pre-cursor

Hormone

eg MAOIs

eg ACEis

R

NT

Enzymes

Inhibitors

eg PDE inhibitors

Inhibitorsor

activators

eg calciumchannelblockers

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 thesereceptors.

•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)

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The Physiology and Pharmacology ofDrug 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 DrJekyll & Mr Hyde in six days and nights on a cocaine binge. "That an invalid inmy 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 almostincredible," 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 (NobelPrize 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 Ihadn'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 beforeevery 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.

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Definitions

Addiction; the compulsion to take a drug irrespective of any associatedadverse consequences.

Dependence; the need for continuing exposure to a drug (to avoidphysical and/or psychological disturbances associated with abstinence

(withdrawal syndromes)). Many abused drugs not associated withwithdrawal symptoms; many therapeutic drugs are!

Tolerance; the need to increase drug dose to maintain the sameeffect.

All compulsive drug taking now considered to have an element ofdrug-seeking behaviour.

Abused drugs have very different structures; can they have a common mechanismin promoting reward?

Nerves communicate by releasing neurotransmitters that arerecognised by receptors

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Brain Reward Pathways

•Many essential behaviours are pleasurable (rewarding).

•Activity in some neuronal pathways in the brain are associated withreward. For example; rats will self-administer some drugs and these drugs

activate reward pathways.

•Much attention on the meso-limbic dopamine pathway (cell bodies inventral 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 commonresponse to drugs of abuse

Drugs of abuse enhance release of dopamine from VTAneurones. GABA inhibits neuronal activity.

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Functional Magnetic Resonance Imaging(FMRI) for measurement of human brain activity

•Can be used to measure regional blood flow in the brainby BOLD technique.

•Increases in neuronal activity increase oxygenrequirement, accompanied by changes in local blood flow.

•Changes ratio of haemoglobin to oxyhaemoglobin (havedifferent characteristics in magnetic field).

•Can, therefore, detect which areas of the brain areactivated by different drugs.

•Administration of opiates, amphetamine and cocaine tohumans enhances blood flow in dopamine-rich areas suchas the nucleus accumbens and the VTA.

Does taking drugs “recreationally” do you any harm?

Short-term effects appear soon after a single dose and disappear in a fewhours. After an injection, the user reports feeling a surge of euphoria ("rush")

accompanied by a warm flushing of the skin, a dry mouth, and heavyextremities. Following this initial euphoria, the user goes "on the nod," an

alternately wakeful and drowsy state. Mental functioning becomes cloudeddue 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 andvalves, abscesses, cellulitis, and liver disease. Pulmonary complications,

including various types of pneumonia, may result from the poor health conditionof 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 and72 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 heroinwithdrawal is considered less dangerous than alcohol or barbiturate withdrawal.

Heroin

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The powdered, hydrochloride salt form of cocaine can be snorted or dissolved inwater 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 canbe heated and its vapours smoked. “Crack" refers to the crackling sound when it

is heated.

Cocaine blocks the re-uptake of monoamine neurotransmitters in theperipheral and central nervous systems.

Physical effects include constricted blood vessels, dilated pupils, andincreased temperature, heart rate, and blood pressure. The duration of

cocaine's immediate euphoric effects, which include hyperstimulation, reducedfatigue, and mental alertness, depends on the route of administration. The

faster the absorption, the more intense the high. On the other hand, the fasterthe 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

Some tolerance, but sensitisation possible. Binges, during which the drug istaken repeatedly and at increasingly high doses, may lead to a state ofincreasing irritability, restlessness, and paranoia; can result in full-blownparanoid psychosis. Cardiovascular complications, arrhythmias, heart

attack, stroke.

Appetite reduction leading to malnourishment.

Cocaine cont.

releases monoamine neurotransmitters (5HT, noradrenaline, dopamine). Acts asboth a stimulant and psychedelic, producing an energizing effect, as well as

distortions in time and perception and enhanced enjoyment from tactileexperiences.

In high doses, MDMA can interfere with temperature regulation. On rare butunpredictable occasions, this can lead to severe hyperthermia, resulting in liver,

kidney, and cardiovascular system failure, and death. ( Leah Betts died fromdrinking 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, asevidenced by continued use despite knowledge of physical or psychological

harm, withdrawal effects, tolerance and almost 60 percent of people who useMDMA report withdrawal symptoms, including fatigue, loss of appetite,

depressed feelings, and trouble concentrating.

Ecstasy (MDMA (3,4

methylenedioxymethamphetamine);

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

lipid messengers (e.g. anandamide) , inhibits wide range ofneurotransmitter release in the brain and periphery.

Mild euphoric effect in moderate doses; dysphoria in high dosesparticularly naïve users. Context dependent.

Very low acute toxicity but some concerns about precipitationof schizophrenia in chronic heavy users.

Stimulates appetite through actions on feeding centres in thethe hypothalamus and possibly gut.

CNS depressant (excitatory effects due to disinhibition). Large dosesirritate stomach (nausea, dyspepsia). Inhibits anti-diuretic hormone causingdehydration (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.Wernicke’s encephalopathy (psychosis)); myopathies (most seriously primarycaridomyopathy); hepatotoxicities (cirrhosis most common), haematological

disorders.

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 formdelirium tremens. Confusion, delusions, tactile and visual hallucinations,

convulsions, cardiovascular collapse (15-50% mortality)

Alcoholics often obese (high calorific intake) but malnourished, particularlyvitamin deficient.

Alcohol

Drug abuse costs society up to £18.8bn a year - or more than £300per person - in England and Wales including the costs of crime, socialsecurity and bringing drugs offenders to justice, as well as the bill tothe 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 healthservice and criminal justice costs.

Self-reported drug use (ever in lifetime) in 17-18 year old USstudents, 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),

How common is the use of abused drugs?

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Pharmacological approaches to treatment ofdrug abuse

(Not effective without psycho-social support).

Substitution e.g. methadone treatment for opiate abuse.

Long-acting synthetic opiate agonist administered orally forsustained period at dose sufficient to prevent opiatewithdrawal, blocks effects of illicit opiate use, and decreasesopiate craving. Patients stabilised on adequate, sustaineddosages of methadone can hold jobs, avoid crime andviolence of the street culture, reduces exposure to HIV bystopping injecting.

Nicotine replacement

•Nicotine-containing gum and sub-lingual tabletsprovide slow buccal absorption avoiding bolusobtained by smoking, reduces withdrawalsyndrome.

•Clinical trials evidence mixed: little use inreducing cigarette consumption, cravingsignificantly reduced but one year quit ratesunaffected (around 20%).

•Nicotine patch results similar: little effect on quitrates irrespective of nicotine dose or patientpopulation.

•Nicotine nasal sprays also available.

Antagonist treatments

Naltrexone therapy for opiate addiction

Long-acting synthetic opiate antagonist; all the effects of self-administered opiates, including euphoria, are completelyblocked. Few side effects, taken orally either daily or threetimes a week for a sustained period of time. Individuals mustbe medically de-toxified and opiate-free for several daysbefore naltrexone can be taken to prevent precipitating opiateabstinence syndrome. Best used in outpatient settings aftermedical 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 thehabit of opiate addiction.

Naltrexone itself has no subjective effects or potential forabuse. Patient non-compliance is major problem.

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Nicotine Antagonists

•Mecamylamine: nicotinic acetylcholine receptor antagonist.Blocks rewarding actions of nicotine and (apparently) cue-induced craving.

•Interestingly, mecamylamine also reduces craving andanxiety associated with handling paraphernalia in cocaineaddicts.

•Since smoking is more common amongst cocaine users andnicotine enhances cue-induced cocaine craving, some arguethat the link supports “gateway theory”.

Peripheral “antagonists”

•General approach to produce circulating antibodies thatbind drugs of abuse in the bloodstream. Extension of this isto use enzymes or engineered antibodies that bind to andmetabolise drugs. Can be overcome by increasing dose ofdrug.

•Cocaine fragments bound to a protein carrier have beenused 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 inalcohol-dependant patients (666mg tds). Reduces alcoholconsumption in alcohol-preferring rats!

•Reduces neuronal excitability that occurs during alcoholwithdrawal.

•Naltrexone in addition to role in opioid dependence alsoreduces alcohol craving by interfering with positivereinforcement and possibly alcohol-conditioned cues.

•Possibly acts by blocking endogenous opioid disinhibitionof GABA neurones in VTA thereby reducing firing ofdopamine releasing neurones.

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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 inalcohol craving but differences between individual SSRIsindicates complex mode of action.

•Contraindicated in seizure-prone patients.

Acomplia (rimonabant, SR141716A)

•Cannabinoid receptor antagonist; blocks the effects ofnatural cannabinoids (endocannabinoids) such asanandamide 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 endocannabinoideffects (e.g. ability to forget, anxiolysis, anti-cancer etc).

“Curing” addiction

Ibogaine, an hallucinogenic alkaloid found in the root barkof the African shrub Tabernanthe iboga.

•Claimed to be a complete “cure” for heroin, cocaine,alcohol etc, addiction.

•Has a complex pharmacology; reduces reward inexperimental animals but also somewhat neurotoxic.

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Antibiotics, antifungals,& antivirals

Learning Objectives:

To understand the mechanisms of action ofcommonly-used antibiotics, anti-fungals and anti-virals.

Precursormolecules& ATP

Aminoacids &

nucleotides

Peptidoglycan

Proteins

RNA

DNA

Cell Wall Cell membrane

Inhibiting these processes will prevent bacteriagrowing 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.Penicillins2.Cephalosporins and cephamycins3.Carbapenems and monobactams

Interfere with synthesis of peptidoglycan whichmakes up bacterial cell wall- not present in humans

Inhibits formation of cross-linking between peptidechains.

Peptide crosslinks

TetrapeptideSide-chain

b-lactams

-

--

Peptidoglycan Formation

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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, IMor IV

-septicaemia, pneumonia, menigitis, UTI.

- Can cause hypersensitivity reactions.

Resistance

Penicillins and cephalosporins contain beta-lactamring.

Beta-lactamases produced by bacteria break this ring.

NC

O

R1

SH

ON

COOH

CH3

CH3

Penicillin

b-lactamase

Carbapenems and monobactams developed to deal withb-lactamase producing bacteria

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Flucloxacillin- b-lactamase resistant penicillin.

Tetracyclines

Antibiotics affecting Bacterial Protein Synthesis

-Protein synthesis occurs in ribosomes-Tetracyclines compete with tRNA (translational RNA)prevent binding to ribosome, prevents proteinsynthesis.-Selective for bacterial ribosome.

-Bacteriostatic

-Wide spectrum of activity-eg tetracycline, minocycline, doxycycline

-Resistance due to induction of proteins promotingefflux of drugs from bacterium.

Chloramphenicol

-Prevents peptide chain elongation

-Reserved for serious infections due to toxicity

-Resistance through production of chloramphenicolacetyltransferase

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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

tRNAV

30S subunit

50S subunit

TetracyclinespreventtRNA bindingChloramphenicol

prevents chainelongation

Peptide chain

Aminoglycosides:misreading ofmessage

Macrolides

eg erythromycin, clarithromycin

-Prevent peptide chain extension.

-Used in penicillin-sensitive patients.

-Given orally

-Side effects- GIT disturbances

-eg H. pylorri, Legionnaire’s disease, diptheria

-Resistance due to an alteration of the binding site onthe 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 inprotein coat

DNA Viruses- eg smallpox, herpes virusesDNA translated into mRNA by host

RNA viruses- eg influenza, measles, mumps,rubellaRNA acts as mRNA

Retroviruses- DNA copy made of RNA by reversetransciptase. DNA then integrated intohost cell DNA

Transcription

ProteinsReversetranscriptase

HIV replication in host cell

Anti-HIV Drugs (anti-retroviral drugs)

-Reverse transcriptase inhibitors.

-Prevents copying of viral RNA into DNA. Henceprevents replication.

-Nucleoside Reverse Transcriptase Inhibitors

-eg zidovudine (azidothymidine, AZT)

-Analogues of nucleosides. eg AZT analogue ofthymidine.

-Competes with host nucleosides for reversetranscriptase- causes chain termination.

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Reverse

TranscriptaseRNA DNA

ACGTCCTGC

AZT

ACGTCCTGCT

AZ

Morenucleosidescan’t attach

Associated with a number of unwanted side effects-can effect DNA replication in host.

Therapeutic response of zidovudine wanes with timedue to mutation of the virus and hence resistance.

Non-Nucleoside Reverse TranscriptaseInhibitors

Bind to reverse transcriptase near catalytic site anddenature it.

eg Nevirapine & Efavirenz

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Protease Inhibitors

HIV mRNA- transcribed into 2 polyproteins

These are converted into structural proteins by avirus-specific protease.

Protease inhibitors prevent this

eg saquinavir (SQV)nelfinavir (NFV)indinavir (IDV)

Can cause GIT disturbances and metabolicabnormalities (eg insulin resistance).

Combination Therapy

Changed prognosis of HIV.

Highly Active Antiretroviral Therapy (HAART).

2 Reverse transcriptase inhibitors with one or moreprotease inhibitor.

HIV replication is inhibited. Patient survival isprolonged.

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, genitalinfections) 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 newtargets to be identified and hence new drugs.

-Antiviral drugs inhibit replication, but do noteradicate.

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RESPIRATORYRESPIRATORYPHARMACOLOGYPHARMACOLOGY

Dr. Richard RobertsDr. Richard Roberts

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Objectives

• Understand the pathophysiology ofasthma and COPD

• Be familiar with the pharmacologicaltargets of the drugs used

• Be familiar with current treatmentrecommendations

• Have a knowledge of the adverseeffects of the drugs used

Lung Structure

3

Trachea

Main Bronchi

Bronchi

Bronchioles

Increasedsurfacearea

2

Alveoli

4

5

Structure

Alveoli

Epithelial cells

cilia

Smooth musclecells

Mucous secretinggloblet cells

LUMEN

Mucous traps particles and cilia help to move these particles out of lungNB cystic fibrosis- thick mucous

6

Epithelial Cells

3

Innervation of the airways

7

Pathways involved:

Sympathetic: circulating adrenaline- act on β2-adrenoceptors on bronchial smooth

muscle to cause relaxation- - inhibition of mediator release from mast cells

• β2-adrenoceptors also on mucous glands to inhibitsecretion

• Increased clearance of mucous.

• b adrenoceptors: Subtypes• b1 adrenoceptors eg sino atrial node and

ventricles in heart- rate andforce of contraction

• b2 adrenoceptors eg airway smooth muscle-relaxation

• b3 adrenoceptors eg skeletal muscle, adiposetissue

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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 increasedmucous secretion

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4

Muscarinic Receptors

• Subtypes:

• M1 CNS, salivary glands, gastric glands

• M2 Heart- rate of contraction, GI smoothmuscle 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 releaseof mediators and activates sensory nerves:

Annals of Allergy, Asthma & Immunology Volume 110, Issue 5 2013 311 - 315

Thanai Pongdee , James T. Li

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Sensory Nerves

Other local controleg 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 etal. (2010) Cell Calcium 48, 202-208TRPM8 mechanism of autonomic nerve response to cold in respiratory airway . Xing etal. (2008). Molecular Pain

Sensory nerves: up-regulated by inflammation-are sensory nerves hypersensitive in asthmatics?

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Normal

Obstructive

FEV1 (4.0L)

FEV1 (1.3L)

FVC(5.0L)

FVC(3.1L)

FEV1:FVC= 0.42FEV1 = 32% of Normal

Normal v Obstructiveeg COPD, asthma- cannot expel all airquickly

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

Way of patients keeping an eye ontheir lung function

Small, hand held device.

Measures flow of air out of lungs.

PEF- rises rapidly during forcedexpiration, then drops.

Constriction of airways reduces peakflow.

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Peak Flow Meter

15

Asthma

• Affects 5-10% of population

• Reversible increases in airway resistance, involvingbroncho-constriction and inflammation

• Decreases in FEV1 and the FEV1:FVC ratio

• Value of < 70% suggests increased airwayresistance. If it is asthma this should be reversed bya 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)

Allergen

histamine

PGD2

LT C4

LTD4

Bronchoconstriction

MastCell

Chemokines eg ILsChemotaxins

Leukocytes

Phases of an Asthmatic Attack

Early Phase

Late Phase

eg T cellsneutrophilsbasophils

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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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Two main categories:

1 Relief of symptoms – bronchodilators

Block early phase of asthma attack caused bybronchoconstriction.

2 Prevention of attack - anti-inflammatoryagents

Prevents late phase caused by release of cytokines.

ASTHMA THERAPY

Reverse bronchospasm Rapid relief

2-adrenoceptor agonists eg. Salbutamol (ventolin)

Agents of 1st choice

Increase FEV1

Act on 2-adrenoceptors bronchodilation

Given by inhalation

Longer acting agents (e.g. salmeterol) given forlong term prevention.

BRONCHODILATORS

cAMP

Salbutamol

Gs

Adenylylcyclase

ATP

Relaxation of airway tone

8

β-adrenoceptors also on mast cells

Increase in cAMP prevents release of eg histamine

Also effects on mucous secretion

2-adrenoceptor agonists

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 ofcells

Slowly released over time to activate receptor

Long Acting β-adrenoceptor agonist(LABA)

2 Adrenoceptor agonists

Tremor, palpitations, hypokalaemia (high dosese.g. nebulisers)

Adverse effects

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Regulation of cAMP by PDEs

cAMP

Salbutamol

Gs

Adenylylcyclase

ATP

Phosphodiesterase (PDE) 5’ AMP

PDE Isoform Metabolises

PDE1 cAMP & cGMP

PDE2 cAMP & cGMP

PDE3 cAMP

PDE4 cAMP

PDE5 cGMP

PDE6 cGMP

PDE7 cAMP

PDE8 cAMP

PDE9 cGMP

PDE10 cAMP & CGMP

PDE11 cAMP & cGMP

•Roflumilast (PDE4) inhibitor (Daxas)

•COPD

•Reduces inflammation

•Potential for enhancing β-AR effects

Phosphodiesterase Inhibitors

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Block parasympathetic bronchoconstriction

e.g. ipratropium (non-selective antagonist)

Given by inhalation- no systemic side effects

Also inhibits mucous secretion

Tiotropium- long-acting

Muscarinic M-receptor antagonists

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cAMP

Bronchodilation

Adrenaline

Ca2+

Contraction

ACh

Gq

Non-selective therefore block muscarinic receptorsaround the body:

•Dry mouth (salivation)•Nausea/ headache (CNS)•Atrial fibrillation & tachycardia & palpitation (cardiac)•Constipation (GI)•Urinary retension•Blurred vision (accommodation)

Side Effects

11

eg theophylline (doxofylline, enprofylline)

Bronchodilators, but not as good as b-adrenoceptoragonists (2nd line use)

Oral (or i.v. aminophylline in emergency)

Historically- phosphodiesterase inhibitors- increasecAMP, but not at clinically relevant concentrations

Adenosine receptor antagonist?

Anti-inflammatory effects

Xanthines

Mix of theophylline and ethylenediamine (2:1 ratio)

Improves solubility

Monitor plasma levels- toxicity

Aminophylline

Side effects:

Tremor, palpitations, nausea

CNS stimulation (sleep disturbance, “overactivity”)

Drug interactions:

inhibition of metabolism increases risk of toxicityeg cimetidine

induction of metabolism reduces plasma levelseg smoking (NB smoking cessation will lead toincrease in plasma levels!)

12

Preventative; do not reverse an attack

Corticosteroids:

Act at intracellular glucocorticoid receptor.

Inhaled: BeclometasoneBudesonideCiclesonideFluticasoneMometasone

ANTI-INFLAMMATORY AGENTS

Oral:

Prednisolone eg acute asthma attack

OR IV

Hydrocortisone eg life-threatening acute asthma

ANTI-INFLAMMATORY AGENTS

Steroid responseelement

Target Gene

Steroid hormone

Steroid hormone receptor

Dimer formation

Nuclear membrane

Cytoplasm

ExtracellularMedium

Intracelular receptors

13

Leads to altered gene transcription:

•results in decreased cytokine and chemokineproduction eg TNFα, IL-1β, IL-2, IL-3, IL-6

•Upregulation of anti-inflammatory genes egannexin A1 (also known as lipocortin).

•Annexin A1 appears to act through formyl peptidereceptors (FPR)

oInhibits release of histamine from mast cells

oInhibits cPLA2- PGs

Mechanism

38

AnnexinA1: inhibits synthesis of PGs and LTs:

Membrane

PLA2

Arachidonic acid

Leukotrienes Prostaglandins

Side effects of corticosteroids:throat infections (inhalation) and adrenal suppression (oral)

Annexin A1-

Corticosteroid

Side effects

Corticosteroids

• Throat infections or oral candidiasis with inhaled

• Osteoporosis (diet/risk factors, bisphosphonatesfor prevention)

• Adrenal suppression in children

– Use lowest effective dose of steroid and notexceed max.

– Monitor height

• Indigestion (oral)

• Chicken pox severe (avoid contact)- immuneresponse

• Withdrawal effect (reduce oral steroids graduallyif >3 weeks)

14

•COPD is a chronic inflammation

•BUT, steroids largely ineffective at reducing inflammation inCOPD

•Suggests: steroid resistance

•May be due to alteration of glucocorticoid receptor.

Steroid Resistance

CysteinylLeukotriene receptor antagonistse.g. montelukast, zafirlukast

Allergen

histamine

PGD2

LT C4

LTD4

BronchoconstrictionMastCell

ChemokinesChemotaxins

Leukocytes

Early Phase

Late Phase

Block LT receptors – block inflammatory actions ofcysteinylleukotrienes (cystLTs)

Leukotrienes also cause bronchoconstriction,therefore this also blocked

Leukotriene synthesis inhibitors-block synthesis ofleukotrienes and LTB4.

eg zileuton, ZD-2138, Bay X 1005, and MK-0591(not licensed)

CysteinylLeukotriene receptor antagonistse.g. montelukast, zafirlukast

15

Side effects

• Headache, rash

• Nausea, jaundice or other signs of liver toxicity

• Mood disorders/ suicidal thoughts reported withmontelukast

Severe, allergic asthma that cannot be controlledby steroids.

Monoclonal antibody against free IgE

Prevents IgE from binding to immune cells thuspreventing allergen-induced mediator release

s.c. injection every 2-4 weeks

Omalizumab (Xolair)

Sodium cromoglicate

Preventative (both early + late)

May be of benefit in exercise-induced asthma

Inhalation

Uncertain action: mast cell stabiliser?

Cromones

16

46

Treatment of Asthma

Initially identify and avoid the triggers for an asthmatic attack-Dust, animals, smoke, cold air etc

Lifestyle changes- weight reduction. Breast feeding of babiesmay prevent development of asthma

47

British Thoracic Society Guidelines for the managementof asthma in adults

Step 2 Add regular inhaled Steroid.

Step 3 Step 2 plus trial of:long acting b2 adrenoceptor agonistTheophyllineLeukotriene receptor antagonist

Step 4 As above, but consider increasing concentration ofsteroid or adding 4th drug eg leukotriene receptor antagonist

Step 5. Add oral steroid to existing therapy

Step 1 Occasional bronchodilator (eg short acting b2

adrenoceptor agonist).If this is required frequently (> twice/week)- move up to step2:

48

If inhaled therapy isn’t working, may need to check thepatient is using the inhaler properly!

17

49

Acute severe asthma

Treatment• Oxygen• Nebulised 2 adrenoceptor agonist• Oral prednisolone or i.v. hydrocortisone

Life-threatening:+ Nebulised Ipratropium

s.c. 2 adrenoceptor agonisti.v. aminophylline

~ 15% of Asthmatics

• NSAIDs - inhibit COXMore AA Leukotriene production

• β adrenoceptor antagonists- especially non-selective e.g. propranolol- ‘selective’ e.g. atenolol also contraindicated inasthma/COPD

except extreme circumstances (specialist only)

• Drug allergy e.g. penicillins, cephalosporins,dipyridamole, tramadol, excipients (tartrazine)

Bronchoconstriction as anadverse drug reaction

Non-steroidal Anti-Inflammatory Drugs (NSAIDs)May provoke asthma in a number of sensitive patientsIncreased production of leukotrienes

Membrane

PLA2

Arachidonic acid


Lipoxygenase Cyclo-oxygenase

NSAIDS

X

Increased inflammation/ spasm

18

52

• 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 ofdeath worldwide.

• 5% of deaths in UK

Chronic obstructive pulmonary disease(COPD)

53

http://www.nhs.uk/Conditions/Chronic-obstructive-pulmonary-disease/Pages/Lynnsstory.aspx

54

COPD

“Airflow limitation that is not fully reversible”

FEV, % predictedMild 80% ‘Smokers’ cough’ - little/no breathlessness

Moderate 50-79% Breathless on moderate exertion

Severe 30-49% Breathless at rest/mild exertionUsually with wheeze and cough

Very severe <30%

Prognosis depends on severity.Generally poor with progressive deterioration.

(NICE 2010)

19

55

•Destruction of parenchyma- emphysema

•Remodelling and thickening of airways- small airways disease

•Mucus hypersecretion- chronic bronchitis

56

COPD- aim of treatmentImprove 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 itsown.

Mild COPD may be helped by short-acting b2 adrenoceptoragonist

More severe- a regular inhaled antimuscarinic blockershould be added (eg ipratropium)

57

BTS Guidelines for treatment of COPD

Mild bronchodilator drugs (b2-adrenoceptoragonist or anti-muscarinic)

Moderate bronchodilator drugs (poss. in combination)plus trial of corticosteroids

Severe regular bronchodilators, a trial of steroidsconsider nebuliser at home.

Long-term oxygen therapy (24-28%, 15 hours/day) isonly treatment known to improve outlook in severeCOPD

20

58

3) Corticosteroids - relatively ineffective in most patients onown.

BUT some evidence that combinations of steroids withb2-AR agonists beneficial.

eg carbocysteineErdosteineMecysteine

Antioxidants“Break up” thick mucous

Used in COPD

Mucolytics

60

Contents of cigarrette smoke:Particulate matter and tar- effects on lungsTar- solid material inhaled. Forms sticky brown residue.Oxidative stressBenzenebenzo(a)pyrene- DNA damageArsenicAcrolein- mitochondrial damageCyanideCOHeavy metals eg Cadmium

Smoking

21

• About 120,000 people die becauseof smoking in the UK each year.

• Smoking causes one-third of allcancer deaths.

• Half of long-term smokers will dieprematurely as a result ofsmoking.

61

Smoking

62

Time

Decline in lung function with smoking

63

Cystic fibrosis

• Inherited disorder of ion transport in epithelialcells

• Respiratory, hepatobiliary, gastrointestinal andreproductive tracts and pancreas affected

• Defect in chloride transporter (CFTR) leading toreduced Na+ and H2O transport

– Thicker secretions with obstruction and destruction ofexocrine glandular ducts

– Recurrent infections

22

64

CF- disease characteristics

• Pancreatic exocrine insufficiency– Reduced or absent secretions

• PERT- pancreatin. Inactivated by gastric acidtherefore given with food.

• Patients living longer- developing othercomplications:– Diabetes (20%)

– Liver Disease

– Osteoporosis

65

Management of CFAim: 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 dyingneutrophils in the airway which contributes to increasedmucus viscosity.

66

Further Reading

•Disease Management- Randall & Neil

•Pharmacology- Rang et al.

•BNF

•National Institute for Clinical Excellence (NICE) Website

•British Thoracic Society Website

1

Cardiovascular DrugsAnd 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 notknown but may be multifactorial

• 2o hypertension:Caused by disease: eg renal disease, Cushing’s

syndrome, hyperthyroidism

Or pregnancy

Or drugs

2

• Stage 1 hypertension

bp measurement >140/90 mmHg.

Patient given ambulatory blood pressure monitoring(ABPM) or home blood pressure monitoring (HBPM) inthe daytime over 1 week.

Hypertension if average ABPM or HBPM bp >135/85mmHg.

• Stage 2 hypertension

bp measurement >160/100 mmHg & ABPM average orHBPM average bp is >150/95 mmHg.

• Severe hypertension

bp measurement >180 mmHg or diastolic bp >110mmHg.

Who to Treat?

•Stage 1 hypertensive if evidence of organ damageor 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.

3

Treatment of Newly Diagnosed Hypertension (NICE 2011)

Ca2+ channel blocker

ACEI + Ca2+ channel blocker

ACEI + Ca2+ channel blocker + thiazide

ACEI (or AT1 antag)

Add further diuretic, alpha-blocker, or beta blocker

< 55 yrs > 55 yrs or black pt

STEP 1

STEP 2

STEP 3

STEP 4

ACE Inhibitors

Angiotensinogen AI AII

StimulatesAldosterone

secretion

Vasoconstriction

Renin ACE

ACE: Angiotensin converting enzyme- found mainly in lungs

Renin- proteolyticenzyme from kidneys

Plasma protein

ACEIs

e.g. captopril, enalapril, lisinopril, perindopril,ramipril

• Inhibition of ACE angiotensin II, whichleads to:– Reductions in arterial and venous vasoconstriction

– Reduced aldosterone production leads to reductionsin salt and water retention

– Also potentiate bradykinin – cough

• May increase potassium – interaction with saltsubstitutes

4

AT1 receptor antagonists

e.g. candesartan, irbesartan, losartan,valsartan

• Block the action of angiotensin II at theAT1 receptor.

• Have similar consequences as ACEIs butdo not give rise to a cough.

Calcium channel blockers

• e.g. diltiazem, verapamil & DHPs (felodipine,nifedipine)

• Verapamil- heart rate cardiac output

• Dihydropyridines inhibit VOC on VSM,vasodilatation and a reduction in BP.

RCalciumchannelblocker

Smoothmuscle cell

Contraction

Diuretics

• Thiazides (e.g. bendroflumethiazide)

• Inhibit Na+/Cl- reabsorption in distalconvoluted tubule

• Reduction in circulating volume- reduceworkload of heart

• Hypokalaemia (decrease K+)

• Vasodilatation

5

Na+ Cl-

Thiazides

Na+

LoopDiuretics

K+

Loop ofHenle

DCT

Aldosterone

Na+

-

-

+

Cl-

Beta-Blockers

e.g. atenolol, propranolol

• Block action of Noradrenaline (andadrenaline) on heart.

• 1 ARs in sino-atrial node- blockersdecrease rate of contraction

• 1 ARs in ventricles muscle and atria-blockers 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.

6

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 andAtherosclerosis

• Hypercholesterolaemia: elevatedplasma cholesterol, leads to:

• Atherosclerosis: focal lesions (plaques)on the inner surface of an artery.

7

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 havehypercholesterolaemia (TC>6.5mM)

• Especially important is high LDL-C componentor low HDL-C

Management

Modify risk factors– Stop smoking

– Treat HT/DM

– Exercise

Low cholesterol diet

– but only 25-30% of cholesterol comes fromdiet

8

The Statins

HMG-CoA Reductase Inhibitors• Hydroxymethylglutaryl coenzyme A reductase which

catalyses:Hydroxymethylglutaryl

HMG-CoA reductaseMevalonate

Cholesterol (ultimately)• HMG-CoA reductase is the 1st committed step in

cholesterol synthesis

Statins

Cholesterol synthesis greater at night therefore statins takenat night

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

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 ofatherosclerosis

• Treatment for 2 years with 40 mg rosuvastatin perday caused a reduction in size of atheroma in 75% ofpatients (ASTEROID study, 2006)

9

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 ofcholesterol?

• Statin + aspirin + b-blocker + ACEi : independently andadditively reduce risk in secondary prevention. Total of75% reduction in risk.

Adverse Effects of statins

• Cautions: use with care in liver disease, monitor liverfunction

• May cause rhabdomyolysis –– Risk : 1 in 1,000 to 10,000.

– Cerivastatin withdrawn Aug 2001 because of reportsof fatal rhabdomyolysis.

– No evidence of muscle pain in Heart Protection Studyactually being due to simvastatin.

OTC Statins• What are the implications?

• 10mg simvastatin withoutcholesterol test withoutprescription

• For pts at high risk– All males over 55

– Males 45-55 and females over55 with

• Family history of IHD

• Smokers

• Overweight

• S Asians Indian sub-continent) ethnicity

• But treatment might not bedocumented with GP

10

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

Fibrateseg Bezafibrate, clofibrate, gemofibrozil

• Activate: PPAR-a, alters lipoprotein metabolism throughgene transcription (increase lipoprotein lipase)

• Promote breakdown in VLDL (with small reductions inLDL-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 buthigh absorption

• Vytorin- combination of simvastatin &ezetimibe

11

OthersSterols/Stanols• Present in Benecol margarine

• Prevents absorption of cholesterol

• Reduces LDL cholesterol by 10-15%

• Helpful add on to dietary restrictions and statintherapy

ISCHAEMIC HEARTDISEASE

IHD

• IHD: angina or MI

• Can lead to CHF.

• IHD associated with atherosclerosis withinthe coronary artery - impaired blood flowor thromboembolic occlusion.

• Coronary blood flow does not matchdemand, leading to ischaemia, whichprovokes the symptoms.

12

Risk Factors

• Male gender

• Family history

• Smoking*

• Diabetes mellitus*

• Hypercholesterolaemia*

• Hypertension*

• Sedentary lifestyle*

• Obesity *

• Lifestyle– Stop smoking

– Exercise

– Diet

– Weight

• Coronary Artery Bypass Grafting

• Percutaneous transluminal coronaryangioplasty & stenting (open up CA)

Angina pectorisManagement

Pharmacological ManagementNitrates

eg GTN

• Via release of NO

• Venodilatation, leading to a decrease in preloadand a reduction in cardiac work

• Coronary vasodilatation

SmoothMuscle

Cell

NO cGMP PKG dilation

PDE5 Viagra

Guanylatecyclase

13

b-blockers

• First choice drugs for prevention

• HR & force cardiac work andpreventing symptoms.

• Slowing HR increases diastolic period, as willthe time for coronary blood flow.

Calcium channel blockers

• Vasodilatation and improve coronary bloodflow, so preventing symptoms.

• Verapamil- effects on HR so reducingcardiac work.

ACEIs

• vasodilatation

• HOPE trial indicated that ramipril reducedmortality in patients with IHD

• reduction in MI & stroke

14

Potassium channel activators

• Nicorandil: combined NO donor andactivator of ATP-sensitive K-channels.

• The target is the ATP-sensitive K+-channel (KATP):

K

Hyperpolarization

Increased K+pumped out of cell

SmoothMuscle

Cell

Antiplatelet drugs

• Low dose Aspirin (75mg)

• Used to prevent MI in patients who havepreviously had an MI

• Prevents clot formation

• Reduces incidence of stroke

• Inhibits cyclo-oxygenase (irreversible):

Arachidonic Acid in membrane

Free AA

PLA2

Cyclo-oxygenase

Endoperoxides

ThromboxaneProstaglandinsPGI2

X

Aspirin

Endothelium Platelets

15

Favours PGI2 production over TXA2 because

AA PGI2

COX

AA TXA2

COX

-

Endothelialcell

Platelets


AA PGI2

COX

AA TXA2

COX

-

X

XAspirin

Endothelialcell


AA PGI2

COX

AA TXA2

COX

-

X

NucleusmRNA Endothelium

16

Favours PGI2 production overTXA2 because

• Platelets have no nuclei - can’t produceany more cyclo-oxygenase (COX) - nomore TXA2 - until new plateletssynthesised (7 days)

• Endothelial cells have nuclei - can producemore 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 plateletsleading to increased inhibition of plateletaggregation by adenosine

• Abciximab- antibody targettingglycoprotein receptor on platelets

17

Drug Choice

• Low dose aspirin and/or clopidogrel.

• Reduce BP to a target of < 140/85 mmHg (anti-hypertensive drug)

• Reduce Hypercholesterolaemia (statin).

• For symptomatic relief or occasional treatment, aGTN spray or sublingual tablets.

Drug Choice - prevention

• In terms of continuous, preventativetreatment:

• 1st choice: b-blockers. Oral long-actingnitrates might be added.

• 2nd choice: if a b-blocker is ineffective orcontra-indicated, then verapamil (ordiltiazem) would be used

Myocardial Infarction

• MI: thromoembolism or rupture of plaque

18

Thromboembolism leading to MI

INFARCTION

Thrombusformation

Immediate Treatment:Thrombolysis

• Dissolves the clot, with reperfusion, salvages the cardiacmuscle

• Fibrinolytics convert plasminogen to plasmin- degradesfibrin

• If indicated, the earlier the better – damage is irreversible6h post MI. Only really effective in 1st 12h.

Discharge

• Aspirin and/or clopidogrel

b-blocker (or Ca-channel blocker if b-blocker contraindicated)

• ACEI

• Statin

• All lower risk –additive

19

Chronic/ Congestive HeartFailure (CHF)

Heart Failure

Failure of the heart as a pump to meetthe circulatory needs

Heart Failure

• May be due to failure of the heartmuscle 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 ordamage of heart muscle

20

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

CO

AII

aldosterone

Na+/waterretension

Circulatingvolume

oedemalungs

Work loadOn heart

Can’tcope

SympatheticNS

Renalbloodflow

HF

21

CHF

Left-sided Failure

• Most common

• Associated with pulmonary oedema

Right-sided failure

Both sides

Signs & Symptoms

• Fatigue, listless

• Poor exercise tolerance (determinesgrade)

• Cold peripheries

• Low blood pressure?

• Reduced urine flow

• Weight loss

• Breathlessness- pulmonary oedema

Diagnosis

• Symptoms

• Echocardiogram: Ejection fraction <45%

• Chest X-ray – cardiomegaly (enlargedheart), pulmonary oedema

22

Prognosis

• Poor

• Median survival in mild/moderatefailure of 5 years

Goals of treatment

• Identify / treat any cause (valvulardisease; IHD)

• Reduce cardiac workload

• Increase cardiac output

• Counteract maladaptation

• Relieve symptoms

• Prolong quality life – reducehospitalization

Pre-load &After load

CO

AII

aldosterone

Na+/waterretension

Circulatingvolume

oedemalungs

Work loadOn heart

Can’tcope

SympatheticNS

Renalbloodflow

HF

ACEIsSpironolactone

Diuretics

bblockers

23

Pharmacological Management:ACEIs

See earlier• Reduce arterial (after load) and venous (pre-

load) 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 don’t cause the cough

• Dual blockade with ACEIs?

Diuretics

• Mainstay

• Prevent water retention

• Thiazides (bendroflumethiazide)– usedin mild failure or in elderly

• Loop diuretics (furosemide) esppulmonary oedema

24

Spironolactone

• Spironolactone – aldosterone receptorantagonist

• Now being used as an effective agentwhich 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 rateand O2 consumption

• Antiarrhythmic activity reduces suddendeath

• Symptoms may get worse at 1st.

Digoxin• +ve inotrope by inhibiting Na+/K+ ATPase, Na+

accumulates in myocytes, promotes Ca2+ entryleading to increased contractility.

• Impairs atrioventricular conduction and increasesvagal activity (via CNS). Leads to-

• Heart block and bradycardia- beneficial in heartfailure with atrial fibrillation as it controls ventricularrate.

• Digoxin reserved for failure with atrial fibrillation

• Reduces rate at which contraction passes from atriato ventricles. Allows time for ventricles to fill withblood.

25

A-V node

Atrial Fibrillation (AF)

• Atrial fibrillation – Commonconsequence of CHF. Impaired ejectionof blood dilation of left atriumimpaired rhythm of contraction of atria

• AF: stasis of blood, leading to thrombiwhich may dislodge and move tocerebral circulation – need forprophylaxis, warfarin or aspirin.

WarfarinWarfarin: 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

26

• Factors are glycopoteins with glutamic acidresidues at N-terminal end of peptide chain

•Glutamic acids converted to carboxyglutamic acidsafter synthesis of the chain- dependent on vit K

•Warfarin blocks Vitamin K reductase, needed forVit K to act as a cofactor: vit K needs to be inreduced form

New factor

Post-translational modification

Vit K-dependent

Carboxylation of glutamicAcid residues

Warfarin inhibition

Vit K-dependentX

X

WARFARIN

27

Warfarin

• Also used to prevent thrombosis

– in patients with replaced heart valves

– atrial fibrillation

– Pulmonary Embolism

– DVT

– Several days to act- existing clotting factorsneed to be used up.

Warfarin- specific advicevitamin K antagonist

If increase amount of vit K in diet, then reduceeffectiveness of warfarin (large amount of greenveg, green tea).

Avocado & soya bean products may also reduceeffects

Cranberry products/juice should be avoided (CSMwarning)- possible increase in metabolism

1

Diabetes Mellitus

Dr Richard Roberts

Diabetes Mellitus

TYPE 1 Insulin dependent (IDDM)insulin production impaired

TYPE 2 Non-insulin dependent (NIDDM)body not as sensitive to insulin

Gestational DMConsequences of XS GHXS cortisolRare 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 andhyperlipidaemia

• Cardiovascular disease, nephropathy, neuropathy,retinopathy, infections, arthropathy (stiffness)

2

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 withouthypoglycaemia

– Reduce co-morbidities\complications

Trials (Diabetes Control & complications(Type I) & (UK Prospective DiabeticStudy (Type II) found:

– Improving glycaemic control prevented ordelayed complications of DM

– But in type I this is often at expense ofincreased incidence of hypoglycaemia

3

Managing Type 2 Diabetes

Blood GlucoseLoweringTherapy

ManagingCardiovascular

Risk

Managing long-term

complications

Nephropathy Retinopathy Neuropathy

Dietary Advice

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\ObeseType 2

• Recent onset type 2 - Dietary change may beenough

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

4

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 increaseutilisation

– 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 (KATP-channels), causing depolarisation

•Increase insulin secretion from b-cells

•Short acting: tolbutamide, gliclazide

•Long acting (glibenclamide, chlorpropamide) avoidedin elderly due to hypoglycaemic effects

Insulin

K+

KATP channel

Ca 2+

Glucose

Glut-2

ATP

Sulphonylureas

X

Meglitinides

Islet b cell

5

• Meglitinide analogues (nateglinide, repaglinide)– Act on b-cells to close KATP-channels- release insulin

– Shorter acting- given at mealtimes to stimulate insulinrelease

– Nateglinide only licensed for use with metformin

– Repaglinide licensed for monotherapy for patients notoverweight or metformin contraindicated or nottolerated

Glucosidase inhibitor (acarbose)-Inhibition of alpha-glucosidases in small intestine

- reduces production of glucose in GI tract

-Problem of flatulence and osmotic diarrhoea- maydecrease in time

-Used alone or in combination with sulphonylurea ormetformin

Glitazones (thiazolidinediones) e.g. pioglitazone

enhance glucose utilisation by tissues, reducing insulinresistance

- PPAR- agonists- gene expression- insulin-like effects.Slow effect- takes 1-2 months for max. effect.

- hepatic glucose output; glucose transporters in skeletalmuscle- increased glucose utilisation; promotion of fatty aciduptake into adipose cells

- Not first line due to risk of liver toxicity (troglitazonewithdrawn), monitoring

- ‘add on’ to sulphonylurea OR preferably metformin

- NICE recommend for patients unable to take sulphonylureawith metformin combination or failure of this combination

6

Cardiovascular safety:

• Rosiglitazone and pioglitazone should not beused in patients with heart failure. Increased riskof heart failure when combined with insulin.

• Rosiglitazone not recommended for use inpatients with ischaemic heart disease- increasedrisk, particularly with insulin.

• MHRA warning increased risk with rosiglitazonecompared to pioglitazone (July 2010).

PPARg

Adipose tissue, skel muscle, liver

GLUT-4

Protein

Glucose

Glitazones

Fatty acidTransporterprotein

FAs

Newer treatments:

Glucagon-Like Peptide Receptor Agonist

Exenatide -GLP-1 Receptor Agonist

-stimulates insulin release from b cells in aglucose-dependent mechanism.

-Lower risk of hypoglycaemia

Used in combination with metformin or a sulphonylurea.

S.C. Injection

Reports of acute pancreatitis.

7

Insulin

K+

KATP channel

Ca 2+

GLP-1 agonistX

Islet b cell

GLP1-R

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 aglitazone.

Lifestyle changes

1st Line- Metformin

2nd Line- Add sulphonylurea

3rd Line- Add insulinOR a-glucosidase inhibitorOR DPP4 inhibitorOR TZD

IDF Guidelines for Treatment of Diabetes

8

• 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 formore 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 unlesscomplexed with protamine (isophane) and/orzinc to reduce absorption.

• Short acting– soluble insulin

– 6-8 hr effect

– Peak response 2-5 hr

– Given 15-30 min before meals

9

•Intermediate-isophane insulin and insulin zincsuspension

•Long-actingcrystalline insulin zinc suspensionNew product- insulin glargine- humaninsulin analogue given once a day

• Biphasic-Combination of short & long-acting insulin

•Insulin pumpscontinuous subcutaneous infusion,expensive, reserved for poorly controlleddiabetes

Insulin regimens• Regimens adapted to suit individual. Insulin

requirements may alter eg depending on level ofexercise

eg

• Short-acting mixed with intermediate twice a daybefore meals

• Short-acting mixed with intermediate beforebreakfast; short acting before evening meal;intermediate at bedtime

• Short-acting 3 times a day before each meal;intermediate at bedtime

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

Treatment of diabetes may result in hypoglycaemia:

10

HypoglycaemiaHypoglycaemia unawareness - risk factors:

• Alcohol- may mask effects

• Sleep- NB hypoglycaemia common at night

• Exercise- may require reduction of insulin dose beforeexercise

Treatment of hypoglycaemia

• Oral CHO (drink, food)

• i.m. glucagon

• i.v. glucose

Ketoacidosis

In the absence of insulin- increasedbreakdown 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

Blood GlucoseLoweringTherapy

ManagingCardiovascular

Risk

Managing long-term

complications

Nephropathy Retinopathy Neuropathy

Dietary Advice

11

Management of cardiovascular riskfactors

• Statin

• Low dose aspirin

• BP control reduces risk of cardiovascular disease

• ACEi (benefit in nephropathy)

• Increased risk of new-onset diabetes with thiazideand β-blocker combination- use with caution

b-blockers (atenolol) can mask hypoglycaemicsymptoms

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

12

Treatment of neuropathy Diabetic neuropathy- common secondary

complication Reduced sensory (& motor) neurones Loss of sensation- ulceration

Painful neuropathy:

Optimal diabetic control to prevent neuropathy1st step: paracetamol/aspirin- mild to moderate pain

2nd step: low doseTricyclic antidepressants (shown to beof use in some patients)

3rd step: anticonvulsants eg phenytoin, carbamazepine-shooting 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

13

References

• BNF

• Disease Management, Randall and Neil

• Stockley’s Drug Interactions

06/01/2014

1

PHARMACOLOGY OF THE GASTROINTESTINAL TRACT

Dr Richard Roberts

First Part

• Acid secretion, GORD, Peptic Ulcers

• Treatment options

• Warning symptoms

• COX-2 inhibitors

• Case study

Oesophagus

Liver Abdominal aorta

StomachGallbladder Spleen

PancreasDuodenum

Colon Small intestine

Rectum

Ileum

Appendix

UpperRespiratoryTract

Overview of the GI Tract

06/01/2014

2

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

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3

Gastric Secretion

•Hydrochloric Acid (HCl)

•Mucus

•Bicarbonate ions (trapped in mucosa)

Others:

•Intrinsic Factor (uptake of vit B12)

•Pepsinogen (protease)

Protectmucosa

Control of Acid Secretion.

• Parietal cells release gastric acid followingstimulation of:

– Histamine receptors (H2)

– Muscarinic receptors (acetylcholine)

– Gastrin receptors (secreted by mucosa)

• Contain a proton pump which exchangesintracellular H+ for extracellular K+- acidsecretion

ECF-likeM

M1

VagusNerve

ACh

ACh

Histamine

H2

Gastrin

GR

PP

H+ K+

PGs PGR

Inhibits

GR

ParietalCell

Enterochromaffin-like cell

06/01/2014

4

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 reliefHigh doses POM.

Histamine H2 receptors : coupled via adenylyl cyclase toincrease 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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5

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 toachlorhydria. Increase risk of Campylobacterinfection (food poisoning).

Prostaglandin Analogues:

eg Misoprostol

Inhibits release of acid& stimulates mucus & bicarbonate secretion

ECF-likeM

M

VagusNerve

ACh

ACh

Histamine

H2

GR

PP

H+

PGR

Inhibits

GR

ParietalCell

K+

PPI

H2 receptorantagonist

Misoprostol

06/01/2014

6

Neutralising AcidAntacids :- anti-acid; widely available (OTC) and act to raise pH.Provide relief

Sodium bicarbonate : simplestHCO3

- + H+ CO2 + H20

Magnesium hydroxide and Aluminium hydroxide also used:

Al(OH)3 + 3HCl AlCl3 + 3H2OMg(OH)2 + 2HCl 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 complexese.g. hydrotalcite (Altacite), magnesium carbonate

Alginates :

•Antacids may be combined with Alginateseg Gaviscon Double Action

• Mucopolysaccharides. The alginic acid combineswith saliva to form a viscous foam.

06/01/2014

7

Dyspepsia (“indigestion”)

Symptoms:

Heart burnAcidityNauseaAcid reflux

Symptoms can often be confused with cardiacproblems- need to rule these out.

Also need to rule out carcinoma

•GORD: gastro-oesphageal reflux disease, leading tooesophagitis

Dyspepsia can occur as a result of:

• 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 byhiatus hernia

Can lead to tightening of oesophagus- difficulty swallowing

06/01/2014

8

Hiatus hernias

Management of GORD

Lifestyle: Weight reduction, reduce fatty foods, stopsmoking, avoid tight clothes

Pharmacotherapy:Initially antacids or antacids + alginates

Sometimes H2 antagonists- but not as effective as:

Proton pump Inhibitors- most effective agents. Removesymptoms & 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 painHunger pain- relieved by eatingNight pain- relieved by milk or food or antacidsnausea

80-95% ulcers due to Helicobacter pylori infection

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9

Early 1980s Robert Warren & Barry Marshall found H. pyloriin cultures from peptic ulcer sufferers. Not believed bacteriacould live in stomach.

1984 Barry Marshall drank culture of H. pylori. Developedgastritis- cured by antibiotics.

H. Pylori & Peptic Ulcers

Treatment:

•Decrease acid (antacid)

•Decrease acid production (H2 antagonist or PPI)

•Kill H. pylori (antibiotics)

•Remove NSAIDs

Treatment of Peptic Ulceration: H. Pylori Infection

“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

Infection identified by serology (antibodies to H. pylori) orurea breath test

06/01/2014

10

Treatment of peptic ulcers (cont.)

If eradication failure:

PPI + Bismuth Chelate + tetracycline + metronidazole

Bismuth chelate- kills H. pylori, coats the ulcer, & absorbspepsin.

prostaglandin secretion acid secretion & neutralisesacid by increasing bicarbonate secretion

ECF-likeM

M

VagusNerve

ACh

ACh

Histamine

H2

GR

PP

H+

PGs PGR

Inhibits

GR

ParietalCell

K+

PPI

H2 receptorantagonist

Bismuthchelate

NSAID-Induced Ulcers

Oral NSAIDS commonly associated with pepticdamage/ulceration (includes low dose aspirin).

Ibuprofen low incidence of GI side effects.

Paracetamol not ulcerogenic

06/01/2014

11

Prostanoid pathway:

Arachidonic acid (membrane)

AA (free)


COX-1 - gastric?COX-2 - inflammationCOX-2 selective inhibitors (celecoxib) may have lessGI-side effects, but only reserved for certain patientgroups.

COX

Inhibits H+ secretion

NSAIDs

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 & increasedbody temperature.

eg aspirin, ibuprofen, naproxen, diclofenac

Inhibit cyclooxygenase and therefore production ofprostaglandins.

Non-selective inhibit COX-1 & COX-2

COX-2 responsible for production of prostaglandinmediators of inflammation.

06/01/2014

12

COX-2 inhibitors

• Anti-inflammatory drugs with lower GI side effectse.g. celecoxib

BUT:

• COX-2 inhibitors are associated with small increasedrisk of CV effects (MI or stroke)

• Rofecoxib (Merck) voluntarily withdrawn 2004(lawsuits)

Other Problems:

• Valdecoxib (Pfizer) withdrawn 2005 due to seriousskin reactions

• Lumiracoxib (Novartis) withdrawn Nov 2007 due tohepatotoxicity

CSM guidance:

- COX-2 inhibitors should be used inpreferance to standard NSAIDs only inpatients with high risk of GI problems ANDafter 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 incardiovascular risk with ibuprofen and diclofenac at highestdoses used on a daily basis

MHRA guidance (October 2006):

NSAIDS and COX-2 inhibitors should be used at lowestpossible dose and shortest duration

06/01/2014

13

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-lineibuprofen<diclofenac<naproxen

•Use lowest effective dose

•Give in combination with PPI or misoprostol

•Encourage patients to report warning symptoms

Warning symptoms for Upper GIproblems

• Unexplained weight loss

• Dysphagia

• Anaemia

• Vomiting

• Upper abdominal pain

• Evidence of GI blood loss

• Patient on long-term/high dose NSAIDs and takingGaviscon OTC

Case study• Mr DU 67 year old smoker (>20 per day)Medical history:

– Hypertension– Osteoarthritis– COPDComplains of stomach pains & heart burn

Medication includes:• Celecoxib (osteoarthritis)• Low dose aspirin (anti-platelet)

AlsoH.Pylori negative

First step? Check medication-

06/01/2014

14

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-2inhibitors shouldn’t 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

06/01/2014

15

Physiology of vomiting

Highly co-ordinated physiological response:

1. Discomfort, dry mouth, salivary inhibition.2. Yawning – sympathetic distress3. Reappearance of saliva4. Pyloris closes5. Tone of stomach increases6. Deep breath7. Contraction of abdominal muscles to force food out8. 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 tothe 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 preventsnausea & vomiting

06/01/2014

16

Chemotherapy-Induced Nausea & Vomiting

Some chemotherapy agents stimulate release of 5-HTfrom enterochromaffin cells.

Acts at vagal afferents.

Feeds into CTZ & vomiting centre.

CTZ

VomitingCentre

Nucleusof the

Solitary Tract

VisceralAfferents

StimulifromGIT

Drugs,toxins

5-HT3

antagonists

Dopamine & 5-HT3

antagonists

Muscarinicantagonists

H1

antagonists

Anti-emeticsH1- Histamine receptor antagonistse.g. promethazine.

– Effective in motion sickness. Also have anti-muscarinicactions. Produce drowsiness.

Anti-muscarinic agentse.g. hyoscine, prochlorperazine

– Effective in motion sickness.– Also reduce gastric motility (see later).– Anti-muscarinic side effects (eg dry mouth).– Produce drowsiness.

06/01/2014

17

Anti-emetics 2Dopamine antagonistse.g. domperidone, metoclopramide.

– Act in CTZ but has unwanted CNS effects. Effective againstanticancer drug-induced emesis.

– Also stimulates gastric emptying reduce nausea

5-hydroxytryptamine antagonistse.g. ondansetron

– blocks 5-HT at 5-HT3-receptors in gut and CNS - particularlyeffective against anti-cancer drugs. Act in CTZ.

Cannabinoid receptor agonistnabilone licensed for chemotherapy- action unclear

Newer Agents:

Neurokinin Receptor Antagonists

• NK1 Receptor activated by Substance P

• NK1 receptor antagonists suppressnausea & vomiting.

• eg Aprepitant

used in chemotherapy-induced N&V incombination with 5-HT receptorantagonist.

• Steroids eg dexamethasone also haveanti-emetic action.

• Used in chemotherapy-induced N&V

• Mechanism unknown.

06/01/2014

18

Standard Prescription for chemotherapyN&V:

• 5-HT3 receptor antagonist

• + steroid

• + NK1 receptor antagonist

LOWER GI PHARMACOLOGY

Constipation

’Persistent, difficult, infrequent or seemingly incompletedefecation’

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

06/01/2014

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Diverticular disease

Diverticulitis- occurs when these become inflammed/infected or strangulated (cuts off blood supply)

Diverticula- small sacs/ pouches that can form in the wall ofthe large intestine

May cause abdominal pain or altered bowel habits

Pain results from muscle spasms

Occurs in ~ 80% of elderly

Caused by long-term constipation- straining

Weak area of gut.Pouches formFood can get stuck

Infection

Management of constipation

• Determine the causee.g diet, lifestyle, medication, underlyingcondition eg. intestinal obstruction

• Best approach is diet with NSPs and fluid

• Could add bulking agents eg ispaghula husks

• Laxatives

06/01/2014

20

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- stimulatesperistalsis.

Laxatives- Osmotic

• 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 over well-

established, cheaper products

• Magnesium sulphate & magnesium hydroxide- Remain in lumen & retain water

Work by increasing water in faecal matter

Stimulant laxatives

For use when required rather than regular use. Usually taken at night toproduce effect next morning.

Senna extractsEnter the colon & metabolised to anthracene derivatives. Stimulate GIT

activity by irritation.

DantronAlso a GIT irritant. Limited for terminal care only due to potential

carcinogenicity

BisacodylUsually taken as suppository.Rapid effect (1-2 hours)Stimulate rectal mucosa- causes peristaltic action

06/01/2014

21

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 GImotility (used when others have failed).

M

ACh

D2Inhibits

X

Dopamine

06/01/2014

22

M

ACh

D2Inhibits

X

Dopamine

Domperidone

X

X

5-HT4

Prucalopride

Stimulates

5-HT (Serotonin)

5-hydroxytryptamine

Tryptophan

5-hydroxytryptophan

5-hydroxytryptamine (5-HT)

5-HT Receptors- Numerous subtypes

5-HT3

5-HT2

5-HT4

5-HT5

5-HT6

5-HT7

5-HT1 1F1A

5A

2A

5B

2C

to

to

&

06/01/2014

23

Prucalopride

•selective serotonin 5-HT4-receptor agonist

•chronic constipation in women

NICE guidancePrucalopride for constipation in women (December2010)treatment of chronic constipation in women for whomtreatment with different laxatives has failed

Prucalopride should be prescribed only by cliniciansexperienced 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 inGORD

– Increases gastric emptying and increasesduodenal peristalsis

– Can prevent bloating.

central side effects (metoclopramide only):

•drowsiness, restlessness, insomnia,fatigue.

•10-20% can experience Parkinson’ssyptoms

•Domperidone- doesn’t cross BBB (NB butcan act in CTZ)

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24

• Gastroparesis- delayed gastric emptying

• Symptoms- nausea, vomiting, bloating, pain.

• Due to post-viral syndrome, diabetes mellitus,post surgery or unknown.

• Dopamine receptor antagonists beneficial byincreasing gastric emptying and anti-emeticeffects.

Diarrhoea

Common, debilitating and can be life threatening (5million deaths world wide due to dehydration).

Causes:

Often bacterial or viral infection.

Rotaviruses cause damage to small bowel villi

Adhesive enterotoxigenic bacteria : adhere to brushborder and increase Cl- and Na+ secretion followed bywater.

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 muscosae.g.Campylobacter

Adhesive enterotoxigenic bacteria: adhere tobrush border, increase cAMP leading to Cl- andNa+ secretion followed by water:

06/01/2014

25

Diarrhoea can also be caused by drugs:

• antibiotics can alter gut flora leading to superinfectione.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 allowinginfection

• Metformin (type 2 diabetes)

Treatment of diarrhoea

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 co-transporter on epithelial cells (H2O follows)

• Young & old are particularly at risk of dehydration.

• Also patients on concurrent diuretic treatment

Many GIT infections are viral- can only treat symptomsAntibiotics may be of use in eg ingestion of contaminated food

Water

Water Absorption

Na+

Glucose

Na+

Symporter

H2O2

Osmosis

06/01/2014

26

Drugs that Reduce GIT Motility

Neurotransmitters & Receptors:

• Acetylcholine (ACh) stimulates muscarinic or nicotinicreceptors on cholinergic neurons

– Muscarinic ACh receptors involved in the contraction ofsmooth muscle of the GIT (and the control of vomiting)

• Enkephalins via opioid receptors involved in GI motility

Treatment of diarrhoea

Opiateseg loperamide

gut motility. Reduce motility of lower GITallowing reabsorption of water and reducing waterstools

Allows bowel control and normal daily activities

Symptomatic relief

M

Ca2+

ACh

mOpioidreceptor

XX

Loperamide

Inhibits

06/01/2014

27

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 analgesiceffect of opioids.

Antimotility agentsOpioids (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

• Rarely employed as primary therapy for diarrhoea due toeffects 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 doses-CNS effects

Anti-muscarinic agents act directly at muscarinic receptorseg atropine, buscopan (hyoscine)

Anticholinergics and opioids ADR

– All patients prescribed long-term opioidsshould 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 psychologicalassociation- stress or depression

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Treatment of IBS

-Treat symptoms as appropriateeg constipation- NSPs to diet or laxative

Diarrhoea- opioid as required

-For bloating/ pain:-Anti-spasmodic agents such as anti-muscarinics eg buscopaneg 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 Antidepressantseg 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

http://jpet.aspetjournals.org/content/344/1/196.full.pdf+html

Pharmacologic Properties, Metabolism, and Disposition of Linaclotide, a Novel Therapeutic Peptide Approved for the Treatment ofIrritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipations

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Lubiprostone

Cl- channel activator

Increases intestinal fluid secretion

Constipation

Inflammatory Bowel Disease

Ulcerative Colitis-•mucosal inflammation in the colon.

•Cause unknown- possible role of colonic bacteria.

•Causes bloody diarrhoea. Severe attack ispotentially life-threatening.

Less nutritional consequences than:

Crohn’s Disease•Transmural inflammation. Can effect anywherein GIT (mouth to anus)•Cause unknown•Pain, diarrhoea, weight loss due to impairedabsorption and increased losses.•Fatigue•Micronutrient deficiencies.•Protein-energy malnutrition in 20-80% ofpatients.•Strictures can cause GI obstruction.•70-80% of patients require surgery at somepoint.•Exacerbations and remission.

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Treatment of inflammatory bowel disease

5-aminosalicylates

• All these compounds are broken down to 5-aminosalicylic acid (5-ASA).

• 5-ASA inhibits leukotriene & prostanoid synthesis,scavenge free radicals, & decrease neutrophilchemotaxis

• eg Sulfasalazine- metabolised to 5-ASA.Mesalazine- pH changes yield 5-ASA

Questionable use in Crohn’s but some effect in Ulcerative collitis

Drugs used are intended to reduce the inflammatory response

Treatment of IBD (cont)

Corticosteroids

e.g oral prednisolone

– anti-inflammatory, immunosuppressive actions.

– eg budesonide - poorly absorbed so far lesssystemic side effects.

– Used to induce remission, particularly in moresevere disease

– Enemas used for more distal or rectalinflammation e.g. Predfoam

Treatment of IBD…..

Immunosuppressants

e.g. Azathioprine and methotrexate- Inhibit purine synthesisand 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 Crohn’s

- Neutralises inflammatory cytokine TNF-a, implicated inCrohn’s

– 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 requireclose monitoring

• Drugs that alter gastric motility can be used to treatconstipation and diarrhoea.

• Nausea & vomiting are controlled by the CNS- CNS-acting drugs

Summary

• Irritable Bowel Syndrome- treatment of symptoms

• Ulcerative Collitis & Crohn’s- treatment withimmunosupressants.

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/ReleasedGuidance/

• British Society for Gastroenterology Guidelines:www.bsg.org.uk/pdf_word_docs/ibd.pdf

• National association for Colitis and Crohn’s diseasewww.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 & Crohn’s- treatment withimmunosupressants.

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

Parkinson’s, Huntingdon’s, Alzheimer’s, Motor Neurondiseases

Disordered thought and perception

Schizophrenia

Mood disorders

Depression, Bipolar disease, Anxiety

Neurodegenerative diseases of movement

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Parkinson’s Disease;

•Progressive disease of movement (mainly in elderly)

•Symptoms; tremor at rest (“pill rolling”), muscle rigidity,suppression of voluntary movement (hypokinesia) comprisinginertia in motor system.

•Patients walk with shuffling gate, finding starting, stopping,changing direction difficult.

•Cause not known; might follow cerebral ischemia, viralencephalitis or other brain damage. Can be drug-induced;reserpine (depletes dopamine), anti-psychotic drugs (blockdopamine receptors). Rarely genetic link (2 gene mutations;synuclein & parkin). Neurotoxin MPTP, contaminant in designerdrug, causes destruction of nigro-striatal dopaminergic neuronesand Parkinsonian symptoms.

Organisation of extrapyramidal motor system

Dopamine-inhibitory; ACh (acetylcholine) excitatory;GABA (gamma amino butyric acid) inhibitory

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In Parkinson’s disease there is a progressive degeneration ofdopaminergic neurones in the substantia nigra. Symptoms notevident 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 orblock excitatory effect of acetylcholine (on muscarinic receptors).

•Most effective drug is levodopa (L-DOPA), brain permeabledopamine precursor. Co-administered with carbidopa (inhibitsDOPA-decarboxylase peripherally) and sometimes entacapone(inhibits catechol-o-methyl transferase) to prevent breakdown.

•Levodopa’s efficacy usually wanes after about 2 years. Sideeffects are involuntary movements and unpredictable “on-off”behaviour

• Other useful drugs include bromocriptine (DA agonist),amantadine (DA releaser) & benztropine (muscarinicantagonist).

Attempts to cure Parkinson’s disease include foetal stem celltransplantation, sub-thalamic lesions & deep brain stimulation.

DBS leaves electrodes in place in the brain to deliver continuousstimulation. The electrodes are powered by a programmablestimulator (like a pacemaker), which is implanted in the chestwall. Some positive effects on tremor reported.

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Huntington’s 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 rangeof regulatory proteins causing excitotoxicity and neuronalapoptosis.

•75% reduction in GABA content in striatum; produceshyperactivity of dopaminergic

transmission (converse of PD).

•Drugs that alleviate the symptoms include

neuroleptics (e.g. chlorpromazine) and

the GABA receptor agonist baclofen.

Alzheimer’s disease (AD)

•Age-related dementia distinct from ischemia-related conditions.

•Can involve 75% loss of (particularly cholinergic) neurones inforebrain causing memory loss and language difficulties.

•Characteristic amyloid plaques and neurofibrillary tangles.

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•Amyloid plaques consist of excessive (neurotoxic) amounts ofAβ fragment of amyloid precursor protein (APP) a normal cellmembrane constituent.

•Neurofibrillary tangles are aggregates of highly phosphorylatedform of Tau (another normal neuronal protein); role inneurotoxicity not clear.

•Most AD of unknown cause (sporadic). Familial AD (rare) dueto mutations in genes for APP and unrelated presenilin; bothcause increased Aβ formation.

Treatment

•Anticholinesterases (preserve released ACh) e.g. tacrine are ofsome limited benefit.

•Anti-inflammatory drugs might retard neurodegeneration (someevidence that long term NSAID consumption associated withlowered risk of developing AD; not proven).

Motor neurone disease (MND);

•Also known as amyotrophic lateral sclerosis (ALS), affectsmovement due to progressive degeneration of the motor nervesconnecting the spinal cord to the skeletal muscles. Only 10%cases have a genetic component.

•Sufferers eventually lose allcontrol over voluntary movements,even processes like swallowing andeye movements, although it doesnot affect mental ability (StephenHawking !).

•No effective drug therapy althoughmodest success in slowingprogression claimed for riluzole;inhibits release and action ofglutamate.

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Nutrition and neurodegenerative disease;

•Alzheimer’s disease is often accompanied and worsened bymalnutrition.

•Weight loss can be progressive; loss of 4% body wt. in 1 y (aboutone third of patients) or severe loss of > 5 kg in 6 months (about10%).

•Disease severity a risk factor.

•Nutritional interventions indicated for severe groups.

•Up to 80% Parkinson’s patients suffer constipation.

•Related to reduced water intake (don’t feel thirst) throughout life.

•Complication in some with PD is oropharyngeal dysphagia, asymptom complex recognized by difficulty in transfer of a foodbolus from mouth to oesophagus.•Dysphagia is also major problem in motor neuron disease.•Gastrostomy feeding tubes are being inserted more frequently inMND patients but not associated with increased survival times.•Median survival from tube insertion 146 days; 1 month mortalityafter gastrostomy was 25%.•Body mass index should be used with caution for the evaluationof the nutritional status of patients with MND.•Experimental evidence that dietary restriction is neuroprotectivein PD and AD models.

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Schizophrenia; a disease of disordered thought & perception

Criteria for schizophrenia (DSM IV); 2 or more of eachpresent 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 bizarreor hallucinations consist of voice running a commentary onpatient’s behaviour or thoughts, or 2 or more voices conversingwith 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 identicaltwins only 50%.

Pathology; cause unknown but dopamine hypothesis partly basedon similar symptoms following some drugs that increase dopaminelevels or stimulate dopamine receptors (e.g. amphetamine, cocaine,apomorphine).

•Suggested hyperactivity in the mesolimbic system, dopaminergictract originating in the ventral tegmental area and projecting tonucleus accumbens, ventral striatum, amygdala, hippocampus andother parts of the limbic system (involved in emotion and memory).

• Supported by PET studies showing reduced mesolimbic bloodflow in schizophrenics.

Human dopaminergic pathways

movementcognition

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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 dopaminergicactivity in mesolimbic and mesocortical pathways.

•Major side effect; extra-pyramidal symptoms, Parkinsonian-like, due to blockade of D2 receptors in nigro-striatal pathway.

•As D2 receptors become supersensitive, Parkinsonian symptomsreduce. After months/years 20% patients develop tardivedyskinesia; repetitive, involuntary stereotyped movementsresembling Huntington’s chorea.

•“Atypical” antipsychotics; e.g. clozapine, olanzapine,risperidone. Fewer side effects, poor correlation between D2

antagonism and efficacy.

•Antagonists at D4 receptors; located in frontal cortex, medullaand 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.

clozapine

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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 ofbetween 4.5 and 7 kg in the 3 months following commencementof olanzapine.

•Good take up with free fruit and vegetable programmes.

•But, consumption fell to pre-intervention levels 12 months afterthe intervention stopped.

•No differences at any time in blood micronutrients, body massindex, physical activity or risk of heart disease compared withcontrols.

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 thefollowing nine symptoms are present during the same two-weekperiod. At least one of the five symptoms must be either adepressed 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; inabilityto enjoy usual hobbies or activities (anhedonia)

•Fatigue or loss of energy

•Feelings of worthlessness; excessive and/or inappropriateguilt

•Difficulty concentrating or thinking clearly

•Morbid or suicidal thoughts or actions

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Raphe nuclei

Locus coeruleus

Noradrenaline and serotonin (5HT) pathways in the brain.

Synthesis of catecholamines

Metabolism via monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)

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Synthesis of 5HT

Metabolisedby MAO

Reuptake and metabolism of noradrenaline

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Monoamine theory of depression:

•Reserpine (old anti-hypertensive drug) depletes nerves ofmonoamines and caused depressive symptoms.

•1st generation antidepressant drugs (ADs; tricyclics e.g.imipramine) block monoamine reuptake (increase synapticlevels).

•Suggested (1965) that depression due to deficiency of brain MA.

Problems

•Increased synaptic [MA] happens immediately but benefit fromADs takes weeks to appear.

•Some drugs that increase MA availability (e.g. cocaine) are notantidepressant.

Neurotrophic hypothesis

•Stress causes over-activity of hypothalamic-pituitary-adrenal(HPA) axis.

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•Increased hormones (glucocorticoid, ACTH, CRH) cause atrophyof stress-vulnerable neurones (e.g. hippocampus) and reduction inneurogenesis.

•Imaging studies demonstrate “shrinkage” of some brain areas indepressives.

•ADs increase the expression of protective neurotrophic factorssuch as brain-derived neurotrophic factor (BDNF) reversingstress-induced damage.

Treatment;

Despite problems with monoamine theory, most effective ADs dointeract with monoamine neurotransmission.

Antidepressant drugs:

•Tricyclics e.g. imipramine

Inhibit NA & 5HT re-uptake. Delayed effects, inhibit variety ofreceptors, dangerous in overdose (cardiac dysrhythmias), many druginteractions.

•Monoamine oxidase inhibitors (MAOI)

e.g. phenelzine

Reduce intracellular MA metabolism. Delayed efficacy; majorproblem of “cheese effect” (preserve dietary tyramine, asympathomimetic). Can cause fatal cerebral hypertension. Must notbe 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 moreeffective or rapid in action than older drugs. Side effects includenausea, anorexia, insomnia, reduced libido, ejaculation failure.

Other MA uptake inhibitors

Inhibit uptake by noradrenaline selective (e.g. reboxetine) or non-selective (e.g. venlafaxine). No more effective but less side effectsand safer in overdose that TCAs.

Electro-convulsive treatment

Patients anaesthetised and muscle relaxant given. Mechanismunknown but can be life saving in refractory depression. Someshort 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; PattyDuke, 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 & cardiacdysrhythmias) and has narrow therapeutic window (plasma levelsmonitored and kept between 0.5 and 1.0 mmol/L).

•Given prophylactically, both phases reduced. Takes 3-4 weeks towork. Mechanism not clear.

•Neuroleptics used to manage acute mania.

•Some patients prefer to avoid treatment, preferring possibly creativemanic phase at expense of depression.

Anxiety

•Normal fear response to threat comprises

various components; defensive behaviour, autonomic reflexes,arousal, alertness, corticosteroid release, negative emotions. Inanxiety states, these occur in an anticipatory manner, independent ofimminent 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); panicdisorder (marked somatic symptoms); phobias; post-traumaticstress disorder (anxiety triggered by insistent memory of paststressful 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 actingdrugs (e.g. flurazepam) preferred as anxiolytics.

•Benzodiazepines obliterate memories of events experienced undertheir 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 controlphysical symptoms of anxiety (palpitations, sweating etc). No effecton emotional component.

•Alcohol; short term effectiveness, side effects all too familiar.

•Anxiety commonly co-exists with depression. Can treat acutelywith benzodiazepine prior to ADs taking effect.

•Some disorders with anxiety component treated with other drugs;

e.g. GAD and obsessive compulsive disorder treated with SSRIsor 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 moreat risk of CVD than non-depressed.

•Depressed patients do not value modest weight loss; one studyreported that one third of patients thought that 10% loss in bodyweight required for benefit and were prepared to risk death toachieve 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 andbulimia nervosa. A third type, binge-eating disorder, has beensuggested but has not yet been approved as a formal psychiatricdiagnosis.

•Eating disorders frequently co-occur with other psychiatricdisorders such as depression, substance abuse, and anxiety.

•Females are much more likely than males to develop an eatingdisorder. 5 to 15 % of people with anorexia or bulimia and about35% with binge-eating disorder are male.

•Syndromes are complex and treatments require psycho-social aswell as medical intervention.

•SSRIs can contribute to treatment regime.

11

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 obesityDiscuss the treatment options for

patients with obesity

22

How do we assess obesity?

Body Mass Index

Risk ofco-morbidity

<18.5 underweight18.5-24.9 healthy average> 25 overweight25-29.9 pre-obese increased30-34.9 grade I moderate35-39.9 grade II severe40 and above grade III very severe

(WHO)

BMI= weight (kg)/height2 (m2)

Foresight model: by 2050 60% men, 40% women

Prevalence of obesity, adults aged 16-64, 1986/87 - 2004, England

0

5

10

15

20

25

30

1986/87 1991/92 1994 1996 1998 2000 2002 2004

Year

%B

MIo

ver

30

Men

Women

www.heartstats.org

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

33

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 ofcancer- even within healthy range of BMI

Adult weight gain due to increase in fat

http://www.dietandcancerreport.org/

WCRF Report 2007- Systematic Review

Risk Risk

Convincing

Probable

Exposure Cancer Exposure Cancer

Body fatness OesophagusPancreasColorectalBreast (postmen)EndometriumKidney

Abdominal Fat Colorectal

Body fat Breast(premen)

Body fatness Gall bladder

Abdominal Fat PancreasBreast (postmen)Endometrium

Adult weightgain

Breast (postmen)

Waist Circumference

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

MEN WOMEN

Waist circumference 94-102cm >102cm 80-88cm >88cm

Odds ratio for 1 ormore risk factors

2.2 4.6 1.6 2.6

Apples or pears- waist:hip ratioApples- greater risk of complications

44

Weight Loss Target:

An achievable target should be set-5-10% of original weightMax 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 suspendedOct. 23rd 2008.

Dexfenfluramine, fenfluramine and phentermineassociated with valvular heart disease andpulmonary hypertension.No longer recommended.

55

Orlistat

– Tetrahydrolipostatin.Synthesised derivative of lipostatin, (a metaolicproduct of Streptomyces toxytricini)

- Inhibits Gastric and Pancreatic lipase

- minimal absorption

- Needs to be taken before each main meal

- ~ 30% inhibition of lipases at normaltherapeutic 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 tomonitor 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 thanplacebo.

With calorie-reduced diet.

BUT – Controlled trials are not always mirrored inClinical Practice.

66

Prescribing guidelines

To be combined with reduced calorie diet.

BMI > 30 kg/m2 orBMI > 28 kg/m2 if other risk factors eg type 2diabetes, hypercholesterolaemia, hypertension

Should only be continued after 12 weeks if weightloss exceeds 5%

Dose

120 mg taken immediately before, during or 1 hr aftereach 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 betried before Orlisat

http://www.rpsgb.org/pdfs/otcorlistatguid.pdf

77

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 marketingauthorisation Oct. 23rd 2008.

-Review found that benefits do not outweigh therisks.

•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)

88

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 20–40% weight lossmaintained over at least 15 years.

99

Laparoscopic adjustable gastric banding(LAGB)results in 15–30% weight loss.

From O’Brien et al.Obes Surgery vol 16pp1032-1040

•Surgery can lead to major, sustained weight loss.

•Not possible with drugs

•Increases satiety and reduces appetite

•Therefore patients don’t want to eat as much.

1010

Bariatric Surgery reduces mortality and morbidity inmorbidly 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 Healthservice of co-morbidities

Control of Appetite and Future Treatments

1111

Ghrelin

PYY

Pancreas

Insulin

Leptin

Vagus

ARC NPY/AgRP

POMC/CART

CCK

Adiposetissue GIT

Brain

Leptin (Greek: thin)

•Peptide hormone secreted from adipose tissue

•Mutations causing absence of leptin leads to severeobesity

•Many obese people have increased levels of leptin-Leptin resistance?

Ghrelin

•Produced from GIT.

•Secreted on anticipation of food

•Hunger at certain times of day- Ghrelin

1212

Ghrelin

Leptin

Insulin

B L D

Cummings et al., 2001

•Ghrelin levels peak before meal.

•Stimulates hunger in humans.

•Ghrelin antagonists/ synthesis inhibitors indevelopment for treatment of obesity.

•NPY orexigenic therefore blocking receptors-decrease 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

NPY as a Drug Target

1313

Appetite linked to reward processes in the brain.

eg opioid receptors (endorphins)Cannabinoid receptorsDopamine

Reinforcement of motivation to find and consumefoods of high incentive/energy content?

Reward Centres also involved

Dopamine & Reward

•Feeding is associated with dopamine release in thedorsal striatum.

•Degree of pleasure correlates with the amount ofdopamine 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 fordepression.

•Weight gain after smoking cessation less in patientstaking bupropion.

1414

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 receptorsubtypes.

5-HT1B, 5-HT2c, 5-HT6 all cause weight loss in rodents.

Serotonergic compounds alter expression ofneurotransmitters in hypothalamus:

POMC mRNA

NPY mRNA -

POMCCART

NPYAgRP

Food Intake

+ -

ARC

5-HT

5-HT1B5-HT2c

1515

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

Contains:

Fucus- kelpBoldoDandelion rootButternut

“A natural way to help speed up weight loss”

1

Drug Metabolism


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 withadverse drug reactions and other risk factorsinvolved

• Understand the mechanisms of drug interactions

Involves:

AbsorptionDistribution

MetabolismExcretion

Contribute to:Interindividual variation in response to drug

Pharmacology- the study of what a drug does to thebody & what the body does to a drug

Pharmacodynamics- what the drug does to the body

Pharmacokinetics- what the body does to the drug

ADME

2

Absorption ADME

“The passage of a drug from its site of administrationinto the plasma”

Absorption is important for all routes ofadministration 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.)

...

. .

.. .

.

Circulation

1st passmetabolism

Oral Dose Drug is takenby mouth &swallowed

Tablet dissolves

Enters smallintestine-absorbed

Bioavailability:Proportion ofdrug thatreachessystemiccirculation

3

Rate of travel to small intestine- altered by:

• gut motility- some disorders decrease gut motility- Presence of food decreases gut motility

GIT Absorption dependent upon:

• Particle size- dependent on tablet formulation

eg. Capsules may be designed to stay intact forseveral hours to delay absorptionOr formulations designed to give gradual release overtime

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

4

• 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 alsoprotect gut mucosa from aspirin.

Food can Affect Drug Absorption

SINGLE ORAL DOSE – Availability over timeTime to peak plasma concentration determined by dissolution oftablet & rate of absorption

TimePla

sm

aconcentr

ation

Therapeuticlevel

Toxic level

Excretion

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 sitesof action, binding, and elimination

Rate and extent of distribution depends on:• relative arterial blood perfusion rate of different

organs• permeability characteristics of barrierseg Blood-brain barrier prevents some drugs reachingbrain• binding in blood (eg albumin) or tissues (eg fat)

5

METABOLISM AND EXCRETION ADME

Like any compound taken into the body, drugs areexcreted.

Most drugs are excreted in urine.Some through lungs (eg gaseous anaesthetics)

Lipophilic drugs require metabolism to polarmetabolites in order to be excreted.

General Features of Drug Metabolism

• Enzymes arose either to handle endogenouscompounds or eliminate toxic compounds

• Enzymes non-selective

• Enzymes exist in isozymic forms

• A single substrate may be metabolised thoughseveral 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 substituentgroup. Increased water solubility.

eg GlucuronidationSulphationGlycine conjugationAcetylation

6

Prodrugs

Some drugs require metabolism to form active drug

e.g. acetylsalicylic acid (aspirin) metabolised to salicylicacid

Codeine morphine

Toxic Metabolites

Metabolism can also produce active, but toxicmetabolites

eg paracetamol- see later

COOH

OCOCH3Aspirin

COOH

OH

COOH

O- glucuronide

SalicylicAcid

Phase 1

Phase 2

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 tocycloguanil (active form). Genetic polymorphism-poor metabolisers- less of active form.

Also codeine morphine

CYP2D6.

Poor metabolisers- no pain relief

7

Alterations in drug metabolism is important site ofdrug-drug interactions.

Also, environmental factors can alter drugmetabolism eg nutrients

Alcohol and cigarette smoke can alter drugmetabolism

Drug-Drug Interactions

InductionInduction of drug metabolismeg phenytoin, ethanolDecrease plasma levels of drugs

eg Chronic heavy drinking reduces phenytoinconcs

Warfarin

Continuous heavy drinking stimulates hepaticenzymes leading to increased metabolism.

Inhibition

Inhibition of drug metabolismeg. erythromycin, cimetidine, fluconazoleIncreased plasma levels of drugs-toxic

8

Antibiotics & Antifungals with AlcoholMetronidazole & ketoconazole- flushing & gastric pain

Inhibition of alcohol dehydrogenase?

“Disulfiram-like reaction”

Most other antibiotics fine.

Smoked or barbacued food-Contain polycyclic aromatic hydrocarbons.Potent inducers of CYP1A1 & CYP1A2.Regular consumption of these foods can reduceplasma concentrations of drugs.

Brassicas- brussels sprouts, cabbage etcregular consumption decreases plasma levelsof some drugs by 50%

Broccoli every day induces CYP 450 enzyme activity.

Decrease plasma levels of drugs

Drug Metabolism

Grapefruit juice- phytochemicals increasebioavailability of certain drugs- inhibition ofCYP450 enzymes. Transient effect.

• Interactions with:– Simvastatin: Avoid concomitant use

– Dihydropyridine calcium channel blockers(nifedipine, nicardipine)

Effects of Nutrients on Drug Metabolism

9

Grapefruit and pills mix warningBy James Gallagher Health and science reporter,BBC NewsNov 2012

Cytochrome P450 induction

St John’s Wort (herbal medicine)

Stimulates CYP450 enzymeseg oral contraceptives

Increased metabolism and reducedlevels of drug

Effects of Herbal Medicines on Drug Metabolism

Effects of Vitamins on Drug Metabolism:

Folic Acid: Increases hepatic metabolism ofphenytoin.

NB As a result, phenytoin also decreases plasmalevels of folic acid

Vit B6: required for conversion of levodopa todopamine in brain.

However, if vit B6 levels are high (< 10mg od), getconversion to dopamine outside of brain.

10

Drug-Drug Interactions- Excretion

Competition for renal excretion e.g methotrexatewith NSAIDs

Consequence- increase methotrexate levels- toxic

Metabolism of paracetamol

Paracetamol is non-toxic at normal dosesOverdose- hepatotoxicity & death

Normal doses

GlucoronidationSulphation

Excretion

Toxic doses

NAPBQI

Saturated Oxidation

Glutathioneconjugate

Removal of toxiccompound

GSH becomesdepleted

NAPBQI

Cell damage

Death

Paracetamol Toxicity

•Serious liver damage at 150mg/kg (~10g for70kg)

•5g or more can cause liver damage in somepatients eg existing liver damage, gluthioninedepleted.

•Standard dose: 1g, 4 x per day.

•4th most common cause of death due to selfpoisoning in UK

•Treatment with acetylcysteine or methionineincrease GSH levels and reduces mortality

11

Plasma concentrations- relationshipto elimination

Plasma concentration of a drug determined by rateof absorption and rate of elimination.

Determines how often a drug needs to be given tomaintain plasma levels within therapeutic dose BUTbelow toxic dose

Single IV Injection

T im e

Injection

Injection- rapid rise inplasma concentration.

Gradual decline inconcentration due toelimination

Single Oral dose:

Pla

sm

aconcentr

ation

Time

Dose

Absorption Elimination

12

REPEATED ORAL DOSES

Pla

sm

aconcentr

ation

Dose every 12 hoursGradual increase in plasma conc. Until steady stateie absorption = excretion

Dosing rate depends on rate ofabsorption & elimination

Repeated oral doses

• drugs with long half lives (i.e. long time to beexcreted) 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 hepaticimpairment or drug interactions result in reduceddose or dosage interval

IV INFUSION

Aim- to produce steady plasma concentration. Rate In = Rateout

May need to give bolus dose to start off with beforecontinuous infusion

Infusion

13

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 adrug is effective at the concentration used, or istoxic.

Adverse Drug Reactions (ADRs)

ADRs or side effects?

Side effect - secondary effect of a medicine, oftenpredictable

sometimes desirable (e.g. sedation withantihistamines in OTC sleep medicine)

sometimes undesirable (e.g. sedation withantihistamines used in allergy relief)

ADR - side effect which is always undesirable

14

Time

Pla

sm

aconcentr

ation

Therapeuticlevel

Toxic level

TherapeuticIndex

Therapeutic Index- ratio of toxic dose: effective doseie benefit: risk ratioOTC medicine- high benefit: low risk of ADR/toxicity

However, anti-cancer/HIV treatment may be able to put up withnarrower therapeutic index (more risk of ADR)

Examples of ADRs:

• NSAIDS – ulcers

• Antibiotics (severe diarrhoea due to Clostridiumdifficile)

• 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

15


Nausea & Vomiting: Many, particularlychemotherapy, SSRIs

Dyslipidaemia: -blockers, thiazide diuretics

Hyperglycaemia: corticosteroids, thiazidediuretics

Malabsorption from the duodenum:

colestyramine, liquid paraffin

consider supplementing fat-soluble vitamins

No. of factors that may predispose a patient to an ADR:

• Polypharmacydrug interactions e.g cytochrome P450inducers or inhibitors

•Drugs with narrow therapeutic indexwarfarin, lithium, digoxin, theophylline

• Extremes of ageMildly impaired renal function in most elderlypatients

• Concurrent disease•Altered pharmacokinetics

e.g. renal, hepatic disease

Polypharmacy-Drug Interactions

• i.e. interactions of the effect of two or moredrugs on the body

• May result in an ADR but may be beneficial(e.g. atenolol + thiazide combine to reduceb.p. further)

• Can alter uptake/metabolism or oppose orenhance action of drug

16

Drug Interactions

Pharmacodynamic interactions

Similar pharmacological targets

– eg. b-adrenoceptor agonists for asthma & b-adrenoceptor 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 (sedativeantihistamines, BDZ)- increased sedativeeffect

• Disturbances of the equilibrium of fluid andelectrolyteseg K+ sparing diuretics, ACEIs and K+

- hyperkalaemia

• Anticoagulants garlic (anti-coagulantproperties)

• Theophylline caffeine (same action)

17

Specific Information for Dieticians

Some of the components of enteral and parenteralfeeds may interfere with drugs. The next two slidescontain general points for use of enteral andparenteral feeds with drugs.

General points:

• Never put drugs into feed.

If nasogastric tube is to be used for drugadministration:

• Always stop feed and wash tube with waterbefore and after drug admin.

• If possible, separate feed and drug by 2 hours

• Consider drug-nutrient interactions

• Consider other routes of administration.

Drugs & Enteral 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 highprotein feeds

Drugs & Parenteral Feeds

18

Further reading

• British National Formulary!

• Pharmacology, Rang, Dale, Ritter & Moore

• Disease Management, Randall and Neil

• Stockley’s Drug Interactions

1

Herbal Medicines

Dr Richard Roberts

Objectives

Herbal Medicines• Licensing issues and health claims

• Herbal preparations and common uses

• Toxicity of herbal preparations and druginteractions

•UK study: people > 50 use 2.26 prescription drugs5.91 herbal & nutritional supplements2.66 herbal supplements

2

Licensing issues

• Most herbal medicines not controlled under theMedicines Act

• No sale restrictions

• Product Licence not required therefore rigorous clinicaltrials 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 claimse.g. cannot claim to cure, treat or prevent adisease

• However, can have health claims e.g. ‘for ahealthy nervous system’

Public perception-herbal medicines are safer thanconventional medicines because they are natural.

40% of people think herbal medicines are safebecause they are natural

However, conventional medicines need to gothrough rigorous trials to determine safety.

Herbal medicines- not required to go through safetytrials

3

Herbal Medicines can be:

1.Unlicensed- no specific standards of safety orquality

- don’t require product information- dose,ADRs etc

- internet

Herbal Medicines- Licensing Issues

2. Registered Traditional Herbal MedicineCompanies must supply evidence about thesafety and use of the product.

•Manufacturers must meet certain safety & qualitystandards.

• Registered products must be accompanied byinformation about the product and its safeusage.

Herbal practitioners

•manufacture herbal medicines on site thereforenot industrially produced.

ie unprocessed herbs classed as ingredients notproducts

•Anything manufactured elsewhere should becovered by THR or MA.

4

3. Licensed- hold product license just like any othermedicine.

Required to demonstrate safety, quality,efficacy and accompanied by product

information sheet

1. Ginkgo biloba

2. St. John’s Wort

3. Ginseng

4. Garlic

5. Echinacea

6. Saw palmetto

Not much is known about how they act, what theside effects are, or drug interactions

Herbal Medicines

Top selling herbal products:

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

5

St John’s Wort (Hypericum)•Anti-depressant

•shown to be as effective as some conventionalantidepressants in mild to moderate depression

•Pure hyperforin has anti-depressant actions.

•Inhibits NA & 5-HT reuptake- similar to other anti-depressants.

5-HT-R

5-HT

5-HT

SSRI

SJW

5-HT

5-HT

5-HT

5-HT

•Hyperforin increases protein & activity of CYP2C9and 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 takingcyclosporin.

6

Also:increase in P-glycoprotein drug transporter. Decreasein 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 ofat least 4 weeks. Involves a gradual dose reduction.

Rapid withdrawal may prescipitate a reaction egdepression, sensory and balance problems.

e.g. Report of woman taking SJW for 10 days thentook 20mg paroxetine.Complained of nausea, weakness, fatigue andbecame incoherent.

7

Side Effects:

Hypericin causes photosensitivity- skin irritation.

Refs:http://www.cochrane.org/reviews/en/ab000448.html

Wurglics & Schubert-Zsilavecz 2006 Clin Pharmacokinet vol 45 p449-468

List of drug interactions can be found at:http://medicines.mhra.gov.uk/ourwork/monitorsafequalmed/safetymessages/sjwfsh.pdf

Hypericalm- granted Traditional Herbal MedicinesLicense

Activity of Inhibited by Induced by

CYP1A2 Echinacea Wu-chu-yu-tang

CYP2C9 Cranberry juice SJWSiberian ginseng

CYP2C19 Ginkgo biloba

CYP3A4 Grapefruit juice SJWSeville orange juice Garlic

Echinacea root

P-glycoprotein Grapefruit juice SJW

Induction/Inhibition of metabolising enzymes

8

3. Ginseng• Short term: stamina, concentration, healing, stress

• Long term: well-being in debilitated/ degenerativeconditions- 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, anti-

microbial, cancer preventing, lipid-lowering

- Some evidence to support these

- Caution and ADRs: odour, indigestion, contactdermatitis, 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

9

With all herbal medicines-What is the evidence?What is known about effective dose?What is the quality of the product like?Is it safe?

Reports of toxicityEphedra (Ma huang- ephedrine)

Used for: weight loss, coughs, bronchitis, nasalcongestion

• Supplements containing ephedra & caffeine causeincreased systolic BP and effects on heart rhythm

• Banned in US

Feb 2008: Danish Medicines Authority issuedwarning about Therma Power slimming drug after a36 yr old man died. Contains ephedrine andcaffeine.

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.

10

Traditional Chinese Medicines

MHRA-some TCM pose a health risk due to poorquality

Risk of heavy metal toxicity:

High levels of mercury &/or lead found in some TCMas well as traditional Indian medicines.

Ingredients unknown:Qianbai Biyan Pian- traditionally contains Senecio-

liver damage

Ingredients unknown:

TCM slimming drugs found to contain prescriptiononly medicineseg sibutramine, nitrosofenfluramine(1 case- patient required liver transplant)

Corticosteroids in skin creams

Illegal Ingredients:Nu Bao- contains human placenta, donkey skin, deerantler- 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 beautyshops

Found to contain corticosteriodsand an antifungal

11

Reports of toxicity from HerbalMedicines

Hepatotoxicity• comfrey, coltsfoot, Scullcap• black cohosh

– increased use for menopausal symptoms– Reports of liver toxicity

Hypersensitivity- allergic reactionsChamomile, 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 licensingauthority (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 formalaria in UK.

12

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 licensedand checked for safety

• Confusion may arise due to publicperception of safety

• Potential for interactions withconventional medicines

–serious clinical consequences possible

Abbreviations

OTC- over the counterPOM- prescription only medicine

a.c.- before food (ante cibum)b.d.- twice daily (bis die)o.d.- every day (omni die)o.m.- every morning (omni mane)o.n.- every night (omni nocte)p.c.- after food (post cibum)p.r.n. – when required (pro re nata)q.d.s.- to be taken 4 times daily (quarter die sumendus)q.q.h.- every 4 hours (quarta quaque hora)stat- immediatelyt.d.s- to be taken 3 times daily (ter die sumundus)t.i.d.- 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 inbrackets) and common uses.

Respiratory Disease

Drug family examples Use

2-adrenoceptor agonists eg salbutamol (Ventolin) asthma.salmeterol (Serevent) COPD

Corticosteroids eg asthmaBeclometasone (AeroBec) Some effect in COPDBudesonide (Pulmicort, Preventative

Symbicort)

Xanthines eg theophylline (Nuelin) asthma(Slo-Phyllin)

(Uniphyllin Continus)

Muscarinic eg ipratropium (Atrovent) asthmaAntagonists COPD

Sodium (Cromogen Easi-Breathe) asthmaCromoglicate (Intal)

Leukotriene eg montelukast (Singulair) asthmaReceptor zafirlukast (Accolate) preventionAntagonists

Upper GIT

Drug family Examples Use

Antacids Sodium bicarbonateMagnesium hydroxide

Acid refluxExcess acid

Histamine H2 antagonists Ranitidine (Zantac)Cimetidine (Tagamet)

Peptic ulcerAcid reflux

Proton pump inhibitors Omeprazole (Losec)Lansoprazole (Zoton)Esomeprazole (Nexium)

Acid refluxPeptic ulcer

Prostaglandin analogues Misoprostol (Cytotec) Acid refluxPeptic ulcer

Dopamine D2 receptorantagonists

Domperidone (Motilium) Acid refluxBloatingAnti-emetic

H1- Histamine receptorantagonist

Promethazine(Phenergan)

Motion sickness (CNSeffects)

Anti-muscarinic receptoragents

hyoscine Motion sickness (CNSeffects)

Lower GIT

Drug Family Examples Use

Opioids Loperamide (Imodium)codeine

Anti GIT motility used indiarrhoea

Laxatives Lactulosemacrogels

constipation

Senna extracts constipation

Tricyclic antidepressants*

amitriptyline IBS

* cross reference with CNS

Cardiovascular


Beta-blockers Propranolol (Inderal)atenolol (Tenormin)bisoprolol (Cardicor)

HypertensionHeart failureAnginaMyocardial Infarction

ACE Inhibitors Lisinopril (Carace)Ramipril (Tritace)captopril (Capoten)

HypertensionAngina?Myocardial InfarctionHeart Failure

statins Simvastatin (Zocor)Pravastatin (Lipostat)Atorvastatin (Lipitor)

HypercholesterolaemiaPossible use in:Hypertension? Angina?MI? stroke?

diuretics Furosemidebendroflumethiazide

HypertensionHeart failure

Ca 2+ channel blockers Nifedipine (Adalat)Nimodipine (Nimotop)Amlodipine (Istin)Verapamil (Cordilox)Diltiazem (Tildiem)

hypertensionAngina

Angiotensin II receptorantagonists

Losartan (Cozaar)Candesartan (Amias)

HypertensionHeart failure

nitrates Glyceryl trinitrateIsosorbide dinitrate(Angitak)

AnginaHeart failure

Warfarin Atrial fibrillationThromboembolicprophylaxis

Anti-platelet AspirinClopridogrel (Plavix)

Myocardial InfarctionStrokeAtrial fibrillation

Obesity

Drug Examples Use

Orlistat Orlistat (Xenical) Obesity

Sibutramine Sibutramine (Reductil) Obesity

Rimonabant Rimonabant (Accomplia) Obesity

Diabetes


Insulin NovoRapidActrapidHumalogInsulatard

Type I Diabetes

Sulphonylureas ChlorpropamideGlibenclamideTolbutamide

Type II Diabetes

Biguanides Metformin (Glucophage) Type II Diabetes

Meglitinides Nateglinide (Starlix)Repaglinide (Prandin)

Type II Diabetes

Glitazones Pioglitazone (Competact)Rosiglitazone (Avandamet)

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 acidAnti-convulsants (epilepsy) such as phenytoin reduce plasma levels of folic acid.

Vitamin DLong-term use of Phenytoin can reduce plasma concs of vit D

Vitamin AOral contraceptives can increase levels of vit. A

IronChronic use of antacids can reduce uptake of ironTetracyclines (antibiotics) bind to iron, calcium, aluminium ions- reduce uptake

Fat-soluble vitaminsEg orlistat (obesity)- may impair absorption of fat soluble vitamins

Vitamin CAspirin reduces absorption of vit C by 1/3

Vit B6Reduces concentration of leva dopa in brain (Parkinson’s)

Vit KAntagonises effect of warfarin

handouts 2014

Documents

agonist ispresent

concentration of agonist

compounds selective

b1adrenoceptor antagonist

noradrenaline adrenaline

receptor thereforepreventing

cross plasma membrane

crossthe plasma membrane