Dosages

and
Drug Reactions
BY P.MWANZAWA
FEB 2015
1

SUB TOPICS
I.

Drug dosages & dosing schedules

II.

Adaptation of doses in special groups

- Diseases like renal, cardiac, hepatic, thyroid;
-- Age i.e the elderly & the young
- In pregnancy

I.

Adverse drug reactions (ADRs) allergies,

drug interactions

II.

Drug Use - prolonged use ; drug withdrawal ;

Self-medication ; Drug dependency ; Addiction ;
drug abuse ; Poisoning ; Overdose ; Antidotes
2

DRUG DOSING
Therapeutic window, Minimum effective
concentration (MEC) & minimum toxic
concentration (MTC)
Loading dose, maintenance doses,
individualizing dosage
Kinds of drug dosages
Therapeutic drug monitoring
Calculation of doses
3

MEC ,MTC
Minimum effective concentration (MEC)
its the lowest drug concentration that can
cause therapeutic effects.
Minimum toxic concentration (MTC) its
the lowest drug concentration a which toxic
effects begin to appear.
Therapeutic window / index is the range
between MEC & MTC.
4

DOSING SCHEDULES
How to dose a drug will depend on desirable
& achievable drug effects; therapeutic index,
drug half life etc. The following are
considered in designing a dosage regimen: Target Level is a set desired steady state
concentration in the plasma which is within
the therapeutic window / range. The dose
adjusted to achieve this target level. This
mode is applied for drug with a small
therapeutic index or whose effects are
difficult to measure.
5

 Loading dose ( LD) is a high dose given at onset

of therapy to achieve target concentration rapidly.
Its oftenly used when quick onset of action is
required e.g. in emergency or life threatening
conditions. The main disadvantage is abrupt
toxicity for sensitive patients.
Maintenance dose is calculated and its frequency
is determined so as to maintain a steady sate of
concentration with the therapeutic range. This is
based on target level, clearance, bioavailability
and drug T. e.g. if T is too small, continuous
IV infusions may be necessary, if T=6-8hrs TID
and if T>24hrs, OD.

Dosing Schedules contd

Individualizing dosage some patients may
have variations in absorption rate & extend,
distribution, elimination and bioavailability.
For drugs with a low therapeutic index,
these factors may cause in-efficacy or
toxicity. The dose should thus be precisely
adjusted while measuring the necessry
components.
7

When individualizing dosages consider: Pharmacokinetics

i.e. ADME, first pass effect, renal or
hepatic disease.
Pharmacodynamics
like potency, efficacy.
Patient factors like
age, inherited factors, other diseases
8

Kinds of Drug Dosages

Fixed dose therapeutic effect is
achieved well below toxic dose (have
large TI). Same drug dose is given to
all patients. most common drugs)
Eg ibuprofen, paracetamol, amoxicillin
Variable dose with fine adjustments
based on a vital easy to measure
variable function e.g. BP, blood sugar.
Adjust dose to achieve adequate value.
9

Kinds of Drug Dosages contd

Maximum tolerated dose increase
dose till S/Es appear then slightly
reduce dose e.g. in anticancer drugs. Is
used when ideal therapeutic dose cant
be used coz of S/Es
Minimum tolerated dose is used
when the therapeutic dose may cause
S/Es on long term use. Only
incomplete relief is achieved. Eg
steroids in asthma, arthritis.

10

WHY prolong drug action?

11

How can you prolong drug

action?

12

Fixed-dose drug combinations

Two or more drugs are put together
in a single formulation.
What are the aims of fixed dose
combinations:-

13

 Pediatric fixed dose combinations are not

common .WHY?

14

Precautions in fixed-dose drug

combinations use
They cant be used when the dose of
one of the drugs needs to be adjusted
independently.
They cant be used if the drugs need
different administration intervals.
Only use if a patient needs all the drug
components in the combination
15

Therapeutic drug monitoring (TDM)

Aim:
To achieve target drug concentrations measure plasma drug conc. at set time to
ensure its between MEC & MTC and
adjust the maintenance dose accordingly.
To achieve therapeutic effect eg measure
BP, blood sugar to see if its within normal
range and adjuste maintenance dose
accordingly.
16

Factors to consider in TDM

Time of blood sampling should be just
before the next dose when the
concentration is minimum. This can also
reveal any inadequate elimination.
Its too expensive and time consuming.
WHICH DRUGS NEED TDM?

17

ADVERSE DRUG
REACTIONS
(ADRs)
18

To Cover

Definitions
Introduction
Classification of
ADRs
ADRs predisposing
factors
Mechanisms of
ADRs
Ways to minimise
ADRs

Drug interactions
Allergies definition,
types, manifestation,
treatment.
Diagnosis

19

Differentiate the following terms

Adverse drug reactions (ADRs)

Side effects

20

Definitions
Toxicity

Secondary effects

21

Introduction
ADRs cause illnesses needing urgent
treatment to prevent death.
Distinguishing between natural
progression of the disease and an ADR
is always challenging so good recording
is necessary to predict ADRs
Pharmacovigilance is the principle of
collecting data on ADRs done either
during clinical trials or normal community
drug use. ( An important role for
pharmacy personnel)
22

Classification of ADRs
Type A (Augmented) reactions occur in all who
receive a high dose as are dose related e.g.
hypoglycemia, hypotension. Are easily controlled.
Type B ( Bizarre) reactions occur only in some
people as are not part of normal pharmacological
effects nor dose related. Patient interactions with drug
due to inherited abnormalities e.g. drug allergies.
Type C (Chronic) reactions due to long term
exposure e.g. analgesic nephropathy.
Type D (Delayed) effects manifests long after drug
use and may be due to short or long term drug use.
E.g. teratogenic
Type E (Ending of use) reactions due to abruptly
23
stopping long term therapy e.g. steroids

ADRs Predisposing Factors

Predisposing factors can be
1. Patient related e.g. age (old or paeds),
pharmacogenetics, allergy, disease, habits,
pregnant, gender (Female higher risk)
2. Drug related e.g. drug with small TI,
cytotoxic drugs, excipients in the
formulation.
3. Prescriber related e.g. high dose, long
term use, abrupt withdrawal, polypharmacy
(multiple drug therapy)
24

Ways to minimise ADRs

Ensure dose used is always within the
therapeutic window.
Adjust dose for sensitive patients eg
with renal/hepatic failure,
Keep good patient history eg of
allergies, hypersensitivity.
Patient education on ADRs & S/Es
25

Conclusion
When a suspected ADR has occurred, its
helpful to determine if its definitively,
probably or possibly due to the drug.
Issues to assess include Patient history
including other drugs taken eg OTCs,
herbals & Time of occurrence or previous
such effects.
Delayed ADRs are hard to discover &
confirm.
Re-challenge can confirm but its dangerous.
Though ADRs are inevitable, its the
pharmacy personnels role to minimize them26

DRUG
INTERACTIONS
27

INTRODUCTION
It may be desired or undesired, beneficial
of harmful. It may result in antagonism or
synergism.
drug-drug interactions two drugs taken
concomitantly interact. E.g. naloxone as
morphine antidote (beneficial).
Interaction can occur at different stages,
outside the body, pharmacokinetically
(ADME) or pharmacodynamically (at
receptors or body systems)
28

Kinds of drug interactions

Pharmacokinetic interaction affects drug
concentration e.g. enzyme inhibition /
induction.
Pharmacodynamic interaction at target site
1.Antagonism: the drugs have opposite
effects e.g morphine & naloxone
2. Synergism: is of two kinds namely:-summation/additive effect (drugs have the
same action).
-potentiation effect (one drug increases the
action of the other).
29

Drug interactions mainly occurs in:

Drugs with a small TI eg warfarin.
Drugs that are enzyme inducers or
inhibitors.
Drugs that are used long-term.
Drugs with the same S/Es.
Severely ill patients cant distinguish S/Es
signs and the existing disease.
Patients with impaired liver & kidney
functions.
In the elderly & neonates/infants
30

Site & explain examples of

Drug-drug interactions
Drug-food interactions
Drug-receptor interactions
Drug-enzyme interactions

31

ALLERGIES

32

ALLERGIES
Definition:- an allergy is stimulation of an
immune response that is harmful. It oftenly
stimulates the inflammatory process.
Chief target organs for allergies are skin,
respiratory tract, blood & blood vessels.
Cross-allergy means that a patient reacts to
all drugs in that chemical group eg
penicillins
33

Types of allergic reactions (4)

Immediate / anaphylactic type antibodies are
produced that stimulate production of substances
like histamine, prostaglandins, leukotrienes. Allergy
develops in minutes & lasts 1-2hrs. e.g. asthma
Antibody dependent cytotoxic type drug
combines with body proteins making them to be
treated as foreign e.g. penicillin induced
haemoilytic anaemia.
Immune complex mediated type antigen/
antibody complexes form, blood vessels damage &
stimulate inflammatory process.
Lymphocyte mediated type antigen-specific
receptors develop on T-lymphocytes. Subsequent
drug administraion causes local reaction eg
contact dermatitis,

34

Allergies manifestation & treatment.

Urticarial rashes & angiodema - are a result of
histamine and other chemicals released from mast
cells in the skin and mucous membranes.
Urticarial rashes are bumpy, red and itchy. They
come and go within a few hours, moving from one
place on the body to another.
Angioedema is swelling especially around eyes,
lips, face, usually not red or itchy, but tends to sting
and burn, numbness feeling. If sweeling is
severe, it affects a persons ability to breathe, can
be life-threatening.
Use anti-histamine, adrenaline, steroid

Non-urticarial rashes weeping exudative rashes

Use adrenal steroids if severe.

35

Allergies manifestation & treatment.

Anaphylactic shock occurs suddenly, within minutes
of drug use. Its fatal.
There is severe BP fall, bronchoconstriction,
angioedema, fluid loss.
Use adrenaline 500mg IM / IV (raises BP, vasodilates)

Pulmonary reactions like Asthma by NSAIDs eg

aspirin; pneumonitis etc
Blood disorders eg aplastic anaemia, haemolysis. By
chloramphenical, allopurinol
Use adrenal steroid.
Fever
Nephropathy
Use adrenal steroids if severe.
Hepatitis & jaundice
36

Allergy Diagnosis
Re-challenge is the best confirmatory test
but is not clinically justfied.
Patch skin test
Skin prick test
Antibodies detection.
NB: Drug allergy once occurred may not be
permanent, but its best for the patient to
avoid that drug.
37

SUMMARY cyt.P450 inducers &

inhibitors

INDUCERS
Rifampicin
Carbamazepine
Phenobarbitone
Nevirapine
Tobacco, smoke
Phenytoin

INHIBITORS
Ciprofloxacin
PIs e.g. ritonavir
Cimetidine
Ketoconazole
Isoniazid
Erythromycin

38