Measuring Prescribing
(Last updated 11/06/2008)

Learning Objectives

On completion of this package you will be able to:

• Identify who in the NHS is interested in measuring prescribing
• Outline how you could measure prescribing, explaining when you would use the different units of measurement and patient denominators
• Recognise why measuring prescribing is important
• Discuss why both cost and quality of prescribing should be measured

The package is divided into the following sections:

Who?
How?
Why?

Who?

There are many different people who are interested in measuring prescribing at both a local and national level.

Make a list of the people/bodies within the NHS that you think will have an interest and then follow this link to check your answer.

The number of General Medical Practitioners (GPs) and nurse prescribers is growing and the range of professionals who can prescribe is increasing in light of the Crown Report. To find out more information on who can prescribe follow this link

In order to understand fully who might be interested in measuring prescribing you need to have some understanding of the NHS Primary Care structure (see diagram).

Primary Care, as its name suggests is the first care a patient would usually receive i.e. care given by GPs etc.

Secondary Care refers to the treatment of patients within hospitals.

Individual prescribers need to look at what they have prescribed to benchmark their own performance. They can use this information to improve their prescribing and therefore provide a better service for their patients.

GP Prescribing Leads and Primary Care Pharmacists within practices and Primary Care Trusts (PCT) also wish to measure prescribing. They use the information to compare either prescribers within a practice or practices within a PCT. Formularies can be developed and monitored. PCT executives and their Boards need assurance about the quality of prescribing and how much they are spending.

Strategic health authorities examine prescribing habits for public health and performance management purposes.

Area Prescribing Committees (APC) are interface groups set up to develop effective dialogue between clinicians and managers in primary and secondary care. Most former health authorities set up these committees of GPs, Trusts and themselves in response to a Department of Health Circular (Executive Letter - EL(94)72) in 1994. Their 2 key objectives are the better management of new drug entry into the NHS and ensuring the appropriateness of hospital led prescribing. Further information on APCs can be found in 'Area Prescribing Committees - maintaining effectiveness in the modern NHS' on the NPC website - www.npc.co.uk

At national level there are several bodies interested in prescribing trends. The following are acronyms of some of these bodies. What do the acronyms stand for and what is their interest / role? Jot down your ideas and then follow this link to check your answers.

N.I.C.E.
N.P.C.
P.S.U.
P.P.D.
D.H.
Healthcare Commission

Discuss with colleagues or your tutor/lecturer what you think are the roles of a primary care pharmacist? Further information on this subject can be found in ‘Competencies for pharmacists working in primary care‘ and ‘GP Prescribing Support’ on the National Prescribing Centre (NPC) website – www.npc.co.uk

These are some of the national bodies who are interested in prescribing trends:

N.P.C. - National Prescribing Centre
The NPC promotes high quality, cost-effective prescribing to relevant professionals and senior managers working in the NHS through a programme of activities.
www.npc.co.uk

P.S.U. - Prescribing Support Unit
This is a service of the NHS Health and Social Care Information Centre, a special health authority. The Prescribing Support Unit (PSU) manages three clinical and prescribing databases, provides information services based on those databases, and services based on access to information at the Prescription Pricing Division. It is committed to the dissemination of information through regular reports and standard tables. The PSU will also, whenever able, respond to individual requests for information and will provide reports within the terms of the Freedom of Information Act. Information available from its databases will soon be described within the authority's publication scheme. See www.ic.nhs.uk/foi

P.P.D. - Prescription Pricing Division
This is a division within the NHS Business Services Authority which processes all NHS prescriptions dispensed in England. The organisation calculates and makes payments due to pharmacists and appliance contractors and also produces information for NHS professionals regarding prescribing volumes, trends and costs. Furthermore, the Prescription Pricing Division manages a range of patient services including the NHS Low Income Scheme, Prescription Pre-payment Certificates and the European Health Insurance Card and produces the Drug Tariff containing the reimbursement prices of a range of prescribable items and remuneration rules.

Follow this link for further information

D.H. - Department of Health
The Government sets policies on health related matters and the Department of Health is responsible to government ministers for ensuring that these are carried out. The Department of Health are also responsible for the National Service Frameworks (NSFs). More information can be obtained from the Department of Health’s website – www.dh.gov.uk

Healthcare Commission
Commission for Healthcare Audit and Inspection (C.H.A.I.) is the legal name for the Healthcare Commission and was launched on the 1st April 2004 succeeding the Commission for Health Improvement. This organisation exists to promote improvement in the quality of healthcare in England and Wales. In England only, this includes regulation of the independent healthcare sector.

The Healthcare Commission have also taken over the private and voluntary healthcare functions of the National Care Standards Commission and covers the elements of the Audit Commission’s work relating to efficiency, effectiveness and economy of healthcare.
www.healthcarecommission.org.uk

How?

This section provides the opportunity to learn more about how prescribing can be measured. It covers:

• The different systems and reports that are available
• The use of different patient denominators
• The different units of measurement that can be used

The Prescription Pricing Division provides prescribing data to a variety of stakeholders.

Follow this link for Measuring Prescribing - Who?

Prescribing Information data provide GPs, Nurse Prescribers and Supplementary Prescribers with reliable and regular information on their NHS prescribing habits and costs. Prescribing Information data are available in electronic format.

Follow the links below to find out more information about Prescribing Information. You may wish to make a note about the differences between the different forms of Prescribing Information and discuss their advantages and disadvantages with your colleagues or tutor.

• Prescribing Information
• ePACT.net
  

There are several Prescribing Information reports, including the Prescribing Analysis Reports and the Practice Prescribing Report.

The Prescribing Analysis Report contains an analysis of the prescribing which has taken place during the reporting period. A quarterly and monthly report is produced at Practice level with details of each individual practice prescriber. The report shows the total level of prescribing, a breakdown of prescribing in the 6 highest cost BNF Therapeutic Groups, the top 20 leading cost drugs in the practice and the top 40 BNF Sections by cost in the practice. The practice prescribing is also compared with the previous year, with the PCT and nationally.

PACT is available electronically (ePACT.net). This system allows users real time on-line access via NHSnet to the five years prescribing data held on the Prescription Pricing Division NHS Prescribing Database.

To compare one GP practice or Primary Care Trust to another, the size of the practice or PCT has to be taken into account. Practices with more patients on their lists will need to prescribe more (GP list size is the number of patients registered with the GP). Prescribing rate can be expressed as the number of prescriptions per patient (or per number of patients) on the practice list. However comparative data can be analysed using a variety of patient denominators such as:

• Patient
• Prescribing Unit
• ASTRO-PU (Age Sex Temporary Resident Originated Prescribing Unit)
• STAR-PU (Specific Therapeutic group Age-sex Related Prescribing Units)

NB we have given an explanation of these patient denominators after the following question:

Why might you want to analyse the prescribing data using different patient denominators? Discuss the reasons with your colleagues or tutor and then follow this link to check your answer

Other reports and 'on-line' systems the Prescription Pricing Division provides are:

• The Prescribing Toolkit
• PCT Prescribing Report
• Electronic Prescribing and Financial Information for Practices (ePFIP)
• Prescribing Monitoring Documents (PMD)
• Itemised Prescribing Payment Report (IPP)
  

Prescription Cost Analysis (PCA) reports are provided to the Department of Health by the Prescription Pricing Division. PCA data cover all prescriptions dispensed in the community in England. The report covers prescriptions dispensed by community pharmacists, appliance contractors, dispensing doctors and items personally administered by doctors. GPs, nurses and other supplementary prescribers in England write the vast majority of prescriptions included in PCA data, prescribing by dentists and hospital doctors is included provided that the prescriptions were dispensed in the community. As PCA data includes prescriptions dispensed in England, those prescriptions written in Scotland, Wales, Northern Ireland or the Isle of Man but dispensed in England are included. Prescriptions written in England but dispensed outside England are not included. Items dispensed in hospitals or on private prescriptions are also not included.

'Prescription Cost Analysis: England' data are available on the Internet.

Follow this link for PCA data

Prescribing can be measured using a variety of different units. One way would be to use the number of prescription items. A prescription item refers to a single item prescribed on a prescription form. List as many of these different measures as you can. What do you think are the advantages and disadvantages of each? Follow this link to check your answer

Patient Denominators

The volume and cost of prescribing are influenced by the demography and morbidity of the population served. These should be taken into account when comparing data either between GP practices or PCTs.

Elderly patients have a greater need for medication than younger adult patients. The prescribing unit or PU was developed to take this need into account. To calculate the number of PUs, each patient on a GP's list aged 65 years and over is counted as 3 prescribing units, whilst each patient under 65 and temporary residents count as 1 prescribing unit.

Age Sex Temporary Resident Originated Prescribing Units or ASTRO-PUs - these were introduced in 1993 as a more sophisticated weighting system than PUs. Research has shown that overall prescribing rates are higher in the elderly and for females. Hence ASTRO-PUs weight individual practice populations for age in a greater number of bands (0-4, 5-14, 15-24, 25-34, 35-44, 45-54, 55-64, 65-74 and 75+), by sex (different weightings for male and female) and by temporary residents. In light of further research by the Prescribing Support Unit (PSU) the weightings of the age bands were adjusted in 1997. These new values became known as ASTRO(97)-PUs.

The original ASTRO-PU and ASTRO(97)-PU figures were based on cost, rather than the number of prescription items. They are used to compare the cost of prescribing between practices or PCTs. Item based ASTRO(97)-PUs are available by request to the PSU. The Prescription Pricing Division has included cost and item based ASTRO(97)-PUs on the ePACT.net system in order to give an appropriate choice of patient denominator.

Because cost based ASTRO-PUs were devised from the total of all drug costs, it is incorrect to use NIC per ASTRO-PU for making comparisons within a specific therapeutic group. Some groups of drugs are specifically for one sex or used for a distinct age band e.g. prostate cancer drugs - prescriptions will be for men and the majority will be over the age of 55. Specific therapeutic group age-sex related prescribing units or STAR-PUs have therefore been developed along the lines of ASTRO-PUs. STAR-PUs have also been revised and updated as STAR(97)-PUs and most recently STAR(01)- PUs

STAR-PUs have been developed for the 8 leading therapeutic groups; gastrointestinal, cardiovascular, respiratory, central nervous system, infection, endocrine, musculoskeletal and skin. These 8 therapeutic groups account for 85% of prescribing in England. Subsequently 2 more groups have been added by the PSU; 'all other groups' (this group includes all those BNF chapters not included in the 8 above) and 'Nurse Prescribing Formulary'.

As well as STAR-PUs for the therapeutic groups listed above, STAR-PUs have been developed for sub-groups of the above, e.g. central nervous system has values for: hypnotics, anxiolytics, antidepressant drugs, drugs used in nausea & vertigo, analgesics, treatment of acute migraine, antiepileptics, drugs used in Parkinsonism & related disorders, drugs for dementia, drugs used in Psychoses & releated disorders and drugs used in treatment of Obesity

 

Like ASTRO-PUs, item based STAR-PUs are only available by request from the PSU or on the Prescription Pricing Division's electronic information systems.

Follow this link to the Prescribing Support Unit (PSU) website to find out more information on ASTRO(97)-PUs and STAR(01)-PUs, www.ic.nhs.uk/psu

Units of Measurement

The volume of prescribing can be measured in many ways; some measures like the number of prescription items or the Net Ingredient Cost are easily obtained from Prescribing Information data. Others such as defined daily doses or average daily quantities require manipulation of the basic data.

Follow these links to find out some of the advantages and disadvantages of the various units of measurement.

Items
Quantity
Cost
Defined Daily Doses
Average Daily Quantities

Items - number of prescription items. A prescription item refers to a single item prescribed on a prescription form. For example there are 2 prescription items on the form below: atenolol and aspirin.

Items are:

• Easy to measure
• Of value in measuring the frequency of prescribing where treatments are given entirely as courses e.g. antibiotics

However:

• A GP issuing repeat prescriptions at monthly intervals would appear to prescribe twice as much as another GP issuing repeats every 2 months

Quantity - number of tablets, millilitres, grams etc

• Easy to measure

However:

• Using the quantity of tablets prescribed could be misleading, especially when different formulations with different dosing schedules are available, e.g.
  GP A prescribes Isosorbide Mononitrate 20mg tds
  GP B prescribes Isosorbide Mononitrate 60mg od.
  If you look at the quantity of tablets prescribed GP A will appear to prescribe 3 times as much as GP B in order for them to both give the patient one month's supply at the same dose.
  
  
• If you measure the amount of active ingredient, high potency drugs would appear to have lower usage than those of low potency, e.g.
  Patient A receives Atenolol 75mg daily
  Patient B receives Bisoprolol 10mg daily
  On a mg basis patient A is being prescribed 7.5 times more drug than patient B.

Cost - cost of drugs prescribed:

Net Ingredient Cost (NIC) is the basic price of a drug, i.e. the price listed in the Drug Tariff or if not in the Drug Tariff, the manufacturers price list. NIC is used in ePACT.net.

'Actual Cost' is calculated by deducting the National Average Discount from the basic price of the prescription items, then adding an allowance for the container. Actual cost is used in Prescribing Monitoring Documents (PMDs).

The cost of drugs that have been prescribed has to be measured. For further information follow this link for Measuring Prescribing - Why?

Is it possible to use NIC from Prescribing Information data to analyse the volume of prescribing? What are the potential problems? Use the following example to find the answer:

You are looking at the use of Angiotensin-converting enzyme inhibitors (ACE inhibitors) and Statins between two very similar practices A and B.
Practice A has chosen lisinopril 10mg daily, enalapril 10mg daily and ramipril 2.5mg daily as their formulary ACE inhibitors. Their formulary also recommends the use of simvastatin 20mg daily.
Practice B has chosen captopril 50mg daily, enalapril 10mg daily and ramipril 2.5mg daily as their formulary ACE inhibitors and atorvastatin 10mg daily.

Both Practive A and Practice B have given 10 patients a prescription for 28 days supply of each of the ACE inhibitors and statins.

Over the last month Practice A has spent £7.60 on lisinopril, £6.30 on enalapril, £9.00 on ramipril and £5.60 on simvastatin.

Practice B has spent £6.90 on captopril, £6.30 on enalapril, £9.00 on ramipril and £180.30 on atorvastatin.

Practice A has spent £5.60 on their chosen statin whilst Practice B has spent £180.30.

What conclusions can you draw about the use of ACE inhibitors and statins in these two practices using NIC as the measure?

By just looking at how much each practice has spent (NIC) it would appear that both practices are using a similar amount of ACE inhibitors but that Practice B is using thirty two times more of their chosen statin than Practice A. This is not true. NIC can be used to measure the volume of similarly priced groups of drugs at equivalent doses, but where there is a large price difference it is not an accurate measure of use.

The cost for 28 days treatment of the drugs are as follows (based on Drug Tariff June 2008):

• Lisinopril T. 10mg od £0.76
  
• Captopril T. 50mg od £0.69
  
• Enalapril T. 10mg od £0.63
  
• Ramipril C. 2.5mg od £0.90
  
• Simvastatin T. 20mg od £0.56
  
• Atorvastatin T. 10mg od £18.03

Defined Daily Doses - DDDs:

The World Health Organisation, in an attempt to overcome some of the problems in measuring the volume of prescribed drugs, developed and now maintains the ATC/DDD system as an international standard for drug utilisation studies. Drugs are classified according to the ATC system and DDDs are established for drugs which have been assigned an ATC code.

In the Anatomical Therapeutic Chemical (ATC) classification, drugs are divided into different groups according to the organ or body system on which they act and their chemical, pharmacological and therapeutic properties.

The basic definition of the DDD unit is:

The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults.

It must be stressed that the DDD is a unit of measurement; it is not a recommended dose and it may not be a dose that a patient could practically receive, for example simvastatin has a DDD of 15mg but the tablet strengths available are 10mg or 20mg.

The advantage of the DDD system is that the consumption of an individual drug can be expressed in DDDs and added to the number of DDDs of all the drugs within the same broad therapeutic class enabling trends in drug consumption to be assessed or comparisons between population groups to be made.

Follow this link for the website of the WHO Collaborating Centre for Drug Statistics Methodology www.whocc.no

There are particular groups of products where the concept of defined daily doses is inappropriate. Jot down for which groups you think it may not be possible to use a DDD.

Follow this link to check your answer

The following are groups where the concept of a DDD is inappropriate:

• Topical preparations e.g. skin creams and ointments. The majority of prescribing is by tube; patients use different quantities depending on the area of skin being covered and also the quantity applied to a particular area. It is therefore not possible to produce a meaningful 'daily dose'.
  
  
• Contraceptive pills and hormone replacement therapy (HRT) - different preparations are given for varying time periods, oral contraceptives may be taken for 21 days out of 28 or continuously. With HRT patients can use tablets, patches or a combination of both. Some patches are applied twice weekly, whilst others are used once weekly.
  
  
• Combination products, mixtures and compounds. Combination products contain more than one drug, it may be difficult to determine what the DDD should be, if you use the DDDs for the single drugs. For example co-amilofruse 5/40 is a combination of amiloride 5mg and furosemide 40mg. The DDD for amiloride is 10mg whilst the DDD for furosemide is 40mg. If a GP were to prescribe 28 x co-amilofruse 5/40 tablets the number of DDDs would vary depending on which single DDD was used.

 

 

 

The WHO does not calculate DDDs for combination products in this way. You can find out how to determine the DDD for a combination product on their website www.whocc.no

• As DDDs are defined as ….assumed average maintenance dose…. vaccines and other 'one-off' treatments should not be measured in DDDs.

Average Daily Quantities - ADQs

The WHO bases DDDs upon international prescribing habits and there are occasions when prescribing in England differs from that internationally. In order to reflect prescribing in England more accurately the Prescribing Support Unit (PSU) has convened an expert group to develop Average Daily Quantities or ADQs.

For example:
Oral metronidazole: DDD = 2g, ADQ = 1.2g

What do you think is the reason why these two values differ?

Follow this link to the Prescribing Support Unit website, www.ic.nhs.uk/psu, to find out more information on ADQs including ADQ values.

Why?

Primary Care Trusts (PCT) have local unified cash limited budgets, which include medicines expenditure. This means that cost effective prescribing has become a top priority within the NHS.

As prescribing costs are now within an overall cash limit this means that if for example a PCT overspends on its prescribing budget it will have to make savings in other parts of the budget. Likewise if a PCT were to underspend on its prescribing budget there would be more money available to spend on other areas.

Health Improvement and Modernisation Plans (HIMPs) address health improvement and the modernisation agenda. This includes tackling health inequalities, responding to Local Modernisation Review outputs, delivery of key NHS Plan priorities and tackling the wider determinates of health. Each PCT develops their own HIMP to meet local priorities. Prescribing issues may form an important part of many of these HIMPs e.g. use of statins to reduce coronary heart disease (CHD).

PCTs must fund drugs recommended in the Technology appraisals and clinical guidelines from NICE. They will also have to ensure that the targets in the National Service Frameworks (NSF) for the use of particular groups of drugs are met. Audit and monitoring of prescribing are essential to ensure that these national initiatives achieve their goals of improving the care patients receive.

PCTs fund the new General Medical Services (GMS) contract which came into force in April 2004. The contract contains a quality and outcomes framework designed to improve services being delivered by general practice. It targets key areas: clinical, organisational, patient experience and additional services. Additional funding is available based on achieving quality standards and some of the clinical indicators relate to prescribing appropriate medication.

For the last ten years there has been an increase each year in both the amount spent on drugs in primary care and also in the number of prescription items that have been dispensed. The graph below shows that for the financial year (2007/08) 730 million prescriptions were dispensed by pharmacists and appliance contractors at a cost of just above £8 billion.

enlarge

The average cost per prescription for 2007/08 is £11.13 compared to £9.45 in 1997/1998.

enlarge

The recent decrease in costs is due to Department of Health policies to control drug prices.
From 1st April 2005 the Department of Health reduced the Drug Tariff price of drugs which are readily available by introducing Category M. The prices of drugs in Category M are reviewed quarterly and price changes are introduced when appropriate.
Another mechanism to help maintain the downwards pressure on the drugs bill is the PPRS (Pharmaceutical Price Regulation Scheme). This is a voluntary, non-statutory scheme which indirectly controls the prices of branded licensed medicines to the NHS in the UK by regulating the profits that companies can make on these sales.
These policies aim to slow down the growth in cost of prescribing that would otherwise be seen from the increase in volume of prescriptions and the introduction of new more expensive products.

Prescribing needs to be measured to ensure that the cost of prescribing remains within the allocated budget. The quality of prescribing also needs to be measured. By quality we mean that the patient receives the most appropriate drug for the condition, given at the correct dose and for the correct length of time. There is often dispute over what to prescribe and how to interpret the evidence for a given treatment, hence the role of NICE in providing evidence-based clinical guidelines.

Clinical governance has been defined as: 'A framework through which NHS organisations are accountable for continually improving the quality of their services and safeguarding high standards of care by creating an environment in which excellence in clinical care will flourish'. The aim of clinical governance is to improve patient care, through a framework of accountability, support and continuing professional development. Prescribing is one area that PCTs are likely to have focused on as part of clinical governance.

Measuring quality is more difficult than measuring cost. Prescribing data from the Prescription Pricing Division tells you how many prescription items were dispensed, the quantity and the net ingredient cost (NIC). Information about why a drug was prescribed or for whom it was prescribed is not collected. This information can currently only be obtained by auditing patient records. The increasing use of electronic patient records and the introduction of the electronic transfer of prescriptions (ETP) will enable this type of information to be more easily captured.

A range of prescribing indicators has been developed based on Prescribing Information data. Indicators are agreed by a range of stakeholders to be a valid method to measure or monitor prescribing. Indicators are often used within the performance management process or locally in prescribing incentive schemes.

Original prescribing indicators were based on the Audit Commission Report (A Prescription for Improvement - Towards More Rational Prescribing in General Practice, 1994) and further indicators were developed by the Prescribing Indicators Group in 1997.The Prescribing Indicators Group also developed criteria that can be used to assess the validity of prescribing indicators, or to assist in the development of local indicators. For more information on Prescribing Indicators click here.

Examples of some of the indicators which are useful measures of quality include:

• items per STAR-PU for antibiotics
• ADQ per benzodiazepine STAR-PU for benzodiazepines
• ADQ per NSAID STAR-PU for NSAIDs

Examples of some of the indicators which are useful measures of cost include:

• generic prescribing rate (%)
• potential generic savings as a percentage of total drug expenditure
• NIC per ADQ for ulcer healing drugs
• overall prescribing costs per ASTRO-PU (excluding high cost and specialist drugs)

From 2003, The Healthcare Commission (then known as CHAI) assessed primary care trusts’ performance against a limited number of key targets and a larger number and range of indicators, including four that related to prescribing:

• prescribing of antibacterial drugs
• prescribing rates for drugs acting on benzodiazepine receptors
• generic prescribing
• prescribing of atypical antipsychotics

These four indicators are no longer used by the Healthcare Commission to assess performance but PCTs may still continue to monitor these areas.

Generic prescribing is the prescribing of a drug by its generic name rather than by a specific proprietary brand. For example if a prescriber writes a prescription for Amoxil 250mg caps, the pharmacist must dispense the proprietary brand Amoxil. If however the prescriber writes the prescription for amoxicillin 250mg caps then the pharmacist may dispense any manufacturer’s amoxicillin 250mg caps (since amoxicillin is in Part VIII of the Drug Tariff the pharmacist will be reimbursed the Drug Tariff price). There are several manufacturers who make amoxicillin 250mg capsules. The basic price of 21 amoxicillin 250mg caps is £0.85 (Drug Tariff June 2008) whilst the price of 21 Amoxil caps is £3.59 (Chemist & Druggist June 2008).

Discuss with colleagues or your tutor the issues around generic prescribing. Should all prescribing be generic? What percentage of prescriptions should be written generically? What are the pitfalls of using a set percentage for a generic prescribing rate?

There is no doubt that there are many drugs that can and should be prescribed generically and these drugs are generally cheaper than their proprietary equivalent.

The generic prescribing rate in England for 2007/08 was 83%. This figure does not tell you what was prescribed generically. It is possible to increase your generic prescribing rate by prescribing products generically that have no generic equivalent or by prescribing products where generic prescribing is not appropriate e.g. theophylline and certain modified release preparations. It is for these reasons that prescribers are not aiming for a 100% generic prescribing rate.

Occasionally the generic cost is more than the proprietary cost and as the idea of generic prescribing is to give the patient the same effective treatment but at a lower cost there would be little point in prescribing these products generically.

Generics are of the same quality as the equivalent proprietary and there is an advantage to prescribing generically which is not cost saving i.e. the indication of the drug class is often apparent from the generic name:·

• captopril, enalapril, fosinopril, lisinopril, ramipril are all angiotensin-converting enzyme inhibitors
  
• atenolol, bisoprolol, celiprolol, labetalol, metoprolol, oxprenolol, propranolol are all beta-blockers