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Prescribing Exam
Farmacología Clínica | 5º Medicina | María Fernández Pérez
PAIN MEDICATION
Tissue damage releases substances that stimulate nociceptors (pain receptors) directly (histamine, serotonin and bradykinin) or
indirectly (prostaglandins increase the sensitivity of sensory nerve endings for the aforementioned substances).
analgesics can be divided into:
• Non-opioids • Opioids
o Paracetamol o Opiates
o NSAIDs o Tramadol
PAIN LADDER
MEDICATION INFORMATION
Paracetamol (500mg-1g, 4/day) Widely used and generally safe
If the effect is insufficient, a NSAID can be added:
1 - Ibuprofen (max. 2,4g in 4-6 doses/day)
- Diclofenac (50 mg, 3-4/day)
- Naproxen (250-500mg, 2-3/day)
Phase 1 can be replaced or added to a weak opioid:
2 - Codein (30-60mg/dose, max. 200mg/day) Can be skipped in cancer pain
- Tramadol (50-100mg, 3-4/day)
Stronger opioid should be considered: Always in combination with a phase 1 drug:
- Morphine retard (maximum dosage is determined by the side multiple pain mechanisms can be targeted,
effects) and a better therapeutic outcome is offered.
3 - Fentanyl patch (in patients in continuous opioid need and/or with Fentanyl patch’s disadvantage is the
dysphagia) considerable delay before a therapeutic
If insufficient or can’t bare the side effects, switch to a different strong effect is seen, and it accumulates on the
opioid: opioid rotation skin.
4 Parenteral administration should be considered if oral route isn’t enough

NON-OPIOIDS
1. PARACETAMOL / ACETAMINOPHEN
Analgesic + antipyretic activity, with no anti-inflammatory effect.
1.1. Side effects
The most important side effect is liver damage, which occurs at >150mg/kg, when the metabolic processing capacity is exceeded.
N-acetylcysteine is indicated if poisoning.
The most common paracetamol dose prescribed (1g, 3-4/day) has few side effects. If the patient is at risk (alcoholism, pre-existing
liver damage or malnutrition) the maximum dosage permitted is 2g/day.
RISK FACTOR PHYSIOPATHOLOGICAL EFFECT
Chronic use of alcohol may induce CYP2E1 enzymes to convert a greater proportion of paracetamol into
Alcoholism NAPQ1 (N-acetyl-P-benzoquinonimine), which causes liver damage. Under normal circumstances
NAPQ1 is detoxified by glutathione, but if NAPQ1 > glutathione = liver damage
Liver failure Increases the formation of hepatotoxic metabolites
Malnutrition There is less glutathione in the liver
2. Prostaglandin synthase inhibitors / NSAIDs
The mechanism of action of NSAIDs is based on the inhibition of prostaglandin synthesis by inhibiting COX. This leads to analgesic,
antipyretic and anti-inflammatory effects. Side effects are linked to this mechanism of action.
Classic NSAIDs include ibuprofen, naproxen and diclofenac. There’re also selective COX-2 inhibitors, e.g. celecoxib.
2.1. Physiopathology
COX is the central enzyme in prostaglandin synthesis. COX metabolizes arachidonic acid into prostaglandin H2, which turns into
prostaglandin, prostacyclin and thromboxane.
COX-1 COX-2
Produces prostaglandins which play a role in various It has more specific roles, such as: inflammation, ovulation, implantation,
homeostatic mechanisms, such as: autoregulating closure of ductus arteriosus, CNS functions (fever, pain perception and
renal perfusion, gastric protection or thrombocyte cognitive function) and autoregulation of renal perfusion.
function. They cause fewer gastrointestinal side effects, but more CV events.

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 2.2. Side effects
Most important ones are peptic ulcers (RF: previous ulcers, rheumatoid arthritis, heart failure and DM; PPIs or COX-2 are used as
prevention), renal failure (RF: heart failure, dehydration, sepsis and pre-existing kidney failure), thrombocytopathy and worsening
of heart failure.
2.2.1. Gastrointestinal side effects
By inhibiting the production of prostaglandins, the protective function of the gastric mucosa is reduced. There is a higher risk of
GI complications in patients over 60-70 yo and in those with previous history of ulcers. Other risk factors are: use of
corticoesteroids, SSRIs, oral anticoagulants (OAC) or acetyl salicylic acid (ASA), the presence of H. pylori or serious comorbidities,
such as DM or heart failure. In patients with ≥1 RF, a PPI like omeprazole or misoprostol should be prescribed.
When NSAIDs are prescribed, it is important to consider an increased risk of injury to the stomach lining:
• Preventive measures indicated in:
o History of stomach ulcers
o >70 yo
o Untreated H. pylori infection in the context of ulcer disease
• Preventive measures should be considered in:
o 60-70 yo o Heart failure or DM
o Using anticoagulants or aspirin o Using corticosteroids
o Severe debilitating arthritis o Using SSIRs
2.2.2. Renal side effects
The renal blood flow depends only to a small extent on prostaglandins. However,
reducing its circulating volume results in a decreased perfusion of the kidney, which
triggers an increase in prostaglandin production. They cause dilation of the afferent
arteriole, ensuring that renal blood flow remains constant even if the circulating
volume decreases. Administering NSAIDs inhibits this mechanism, decreasing renal
blood flow and fluid retention, or even acute renal failure.
Renal blood flow is more prostaglandin-dependent if there is low renal perfusion
pressure, which, in turn, depends on the pumping force of the heart, volume status
and blood pressure. The following conditions entail a higher risk of developing loss of renal function with the use of NSAIDs:
• Heart failure • Use of RAAS inhibitors
• Dehydration because of diarrhea, fever or diuretic use • Pre-existing renal failure (GFR<30)
• Sepsis
2.2.3. Cardiovascular side effects
NSAIDs can cause water and salt retention, which in turn can lead to peripheral edema. If heart failure, NSAIDs should be avoided,
because of the increased risk of cardiac asthma.
2.3. Interactions
• NSAIDs + coumarin-related anticoagulants, antiplatelet medications, steroids or SSRIs = increased risk of gastrointestinal
bleeding
• NSAIDs + RAAS inhibitors, diuretics or antihypertensives = increased risk of heart and renal failure by salt retention

OPIOIDS
1. OPIATES (μ-agonists)
Opioids bind to different receptors (μ, κ or δ), but opiates bind specially to μ and κ. These unions cause analgesia, supraspinal
analgesia, respiratory depression, euphoria, physical dependence, miosis, sedation, dysphoria and psychomimetic effects.
1.1. Medicinal properties
DRUG PHARMACOLOGICAL PROPERTIES
MORPHINE Morphine binds all three receptors, but its effects relate to the CNS μ-receptors
Low affinity for opioid receptors, so its effect is weak. About 10% of codeine is converted to morphine by
CODEINE CYP2D6 (although 10% of people lack this enzyme). It also has a strong constipating effect. Due to all of these,
it is not used.
Fentanyl selectively binds μ-receptors and has a higher analgesic effect than morphine. Due to the high degree
FENTANYL
of lipophilicity, it is suitable for transdermal administration (patches).
OXYCODONE There is a short acting variant, as well as a long one.
*NALOXONE* Competitive antagonist for the opiate receptors, counteracting the side effects of opiates
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Patients can derive greater benefit from one opioid than another, due to different affinities. However, whilst a higher affinity leads
to a greater painkilling effect, it also entails a larger risk of side effects. Thus, “opioid rotation”, making sure there is always
painkilling effects, as well as minimum tolerance as possible.
1.2. Side effects
Include constipation (prevented by standard laxatives), respiratory depression (COPD being a RF) and dependence (especially if
history of substance abuse). They could also cause delirium, sedation, miosis, nausea and vomiting, biliary colic and itching.
Naloxone is the antidote.
1.3. Interactions
• Anticholinergics, antidepressants and diuretics: constipation
• Benzodiazepines: respiratory depression
2. TRAMADOL
It is a relatively weak opioid agonist with some selectivity for μ-receptors, and an inhibitory effect on the reuptake of
norepinephrine and serotonin. CNS side effects affect specially to the elder. Its effect is weak and comparatively it has more side
effects, so it is better to use a low dose opiate or non-opioid rather than tramadol.

ANTICOAGULANTS
1. Physiopathology
a. Primary hemostasis: interaction between platelets and the damaged vessel wall
(adhesion), clumping of platelets to each other (aggregation, using IIb/IIIa-
receptors) and activation. of platelets, producing procoagulant factors (including
TXA2)
b. Secondary hemostasis (formation of a blood clot): it begins when the tissue
factor (thromboplastin), which is normally under the endothelium, meets blood.
Through binding and activation of coagulation factors, fibrinogen à fibrin.
Anticoagulants act on factor Xa and/or IIa, two essencial clotting
factors. Majority of clotting factors are produced in the liver, and
vitamin K is needed for factors II, VII,
IX and X.
c. Fibrinolysis (removal of blood clot):
when the normal structure of the
tissue has been restored,
plasminogen-activators convert
plasminogen à plasmin, which, in
turn, converts fibrin à soluble
degradable fibrin products.
2. Pathological thrombosis
Site of thrombotic event Clinical problem Relevant medications
Arterial thrombosis: caused by an Antiplatelet agents:
interruption in the endothelial layer. The - Aspirin
Myocardial infarction, stroke
resulting white thrombi consist mainly - Clopidogrel (Plavix)
of platelets with little fibrin. - Dipyridamole (Persantine)
Coumarin derivatives and vitamin K antagonists:
- Acenocoumarol (Sintrom)
Venous thrombosis: usually caused by
- Phenprocoumon (Marcoumar)
circulatory stasis, leading into a
Deep vein thrombosis (DVT), - Warfarin (Coumadin, Jantoven)
hypercoagulable state. The resulting red
pulmonary embolism (PTE) Heparins:
thrombi consist mainly of red blood cells
- Heparin IV
and fibrin.
- Low dose LMWH
- High dose LMWH
These can occur because of the following (triad of Virchow):
• Increased coagulability of the blood
• Slowed blood flow velocity
• Damage of the vascular wall
Blood thinners can be divided into anticoagulants and antiplatelets. Anticoagulants slow down the clotting process, whereas
antiplatelets prevent platelets from clumping together to form a clot.
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ANTIPLATELET AGENTS
There are multiple ways to interfere with platelet aggregation, effectively preventing the formation and growth of clots/thrombi.
Platelet adhesion to subendothelial structures leads to their activation, releasing serotonin, ADP and TXA2. The latter acts on
damaged endothelium, mediating vasoconstriction, and promoting platelet aggregation, so it becomes a target for this drugs.
1. Medicinal properties
Agent Mechanism of action
Irreversibly inhibits TXA2, targeting COX. This effect on the nucleus-free platelet lasts the lifetime
Acetylsalicylic acid (ASA)
of the cell (approx. 10 days)
Blocks adenosine diphosphate (ADP) receptors, irreversibly inhibiting the ADP-mediated activation
Clopidogrel
of the GP IIb/IIIa complex, which inhibits platelet aggregation. It also lasts 10 days.
Dipyridamole Reversibly inhibits platelet aggregation, so the duration lasts less than 1 day (t1/2 12h).
2. Indications
Platelet aggregation inhibitors are indicated for the secondary prevention of formation of arterial thrombosis.
Medication Indications
• Secondary prevention after TIA or non-disabling stroke, with no intracerebral hemorrhage
• Secondary prevention of myocardial infarction
ASA (Cardio 80mg/day; • Treatment of acute coronary syndrome
Neuro 30mg/day) • Prevention of cardiovascular morbidity in patients with stable angina pectoris
• Prevention of graft occlusion after aortic-coronary bypass
• Peripheral arterial disease
• Acute coronary syndrome/myocardial infarction
Clopidogrel (75mg/day) • After implantation of coronary stents in combination with ASA
• After TIA or stroke
Dipyridamole (200mg/12h) • Secondary prevention after TIA or non-disabling stroke in combination with ASA
3. Side effects and interactions
The main side effect is increased risk of bleeding, being more frequent with age. Also, corticosteroids, NSAIDs and SSRIs increase
even more this bleeding risk.
In most surgeries, ASA can be continued, but if a lot of blood loss is expected, a platelet transfusion is required.
4. Hemorrhage linked to antiplatelet use
It can be recommended to discontinue the ASA use at least 5 days prior to surgery.
Situation Guideline
• ASA/clopidogrel: 5 days before surgery
Stopping treatment in
• Dipyridamole: 1 day before surgery
non-acute situations
They can be continued the day after the surgery
Subacute situations Regarding non-elective surgery, it is preferred to wait 3 days before the procedure
Desmopressin (DDAVP) may be administered pre-op. Most surgical interventions can be carried out
with the patient on ASA, but DDAVP improves the platelet adhesion, so it shortens the bleeding time.
Acute situations ASA must be stopped in neurosurgery, head and neck surgery and liver/kidney biopsies.
If surgery cannot be delayed, a platelet transfusion should be given pre-op, at least 40 mins after ASA
or 12 hours after clopidogrel.

VITAMIN K-ANTAGONISTS / COUMARINS

Four major coagulation factors (factor II, VII, IX and X), as well as protein C and S, are dependent on vitamin K. If vitamin K is
inhibited, there is a decrease in fibrin formation.
1. Medicinal properties
Drug Pharmacological difference
Has a half-life of 8 hours and a maximum effect after 36-48 hours. It is co-administered with
Acenocoumarol (Sintrom)
heparin for one week to bridge this interval.
Phenprocoumarol (Marcoumar) Has a half-life of 160 hours and a maximum effect after 48-72 hours. It lasts for a few weeks.
2. Indications
Atrial fibrillation, PTE, DVT and in patients with mechanical valve protheses. TIA/stroke risk in AF can be calculated using CHA2DS-
VASc score: with a score of 2-6, vitamin K antagonists are indicated.

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3. Side effects
The main side effect is the risk of bleeding (1-2% patients/year), greatest in
patients who have poor therapy adherence, irregular alcohol intake and febrile
illness. The correct dosage is calculated based on the INR value.
If bleeding occurs, vitamin K should be administered. In case of severe
bleeding, prothrombin complex concentrate (PCC) can be administered.
4. Interactions
Factor Resultant effect
The enzymes that degrade coumarin derivatives function poorly, allowing the INR to rise
Febrile disease
or peak above the target range (2,5-3,5)
Low intake of vitamin K It can cause the INR to peak
Irregular alcohol intake It can enhance the effects of coumarin derivatives
NSAIDs, platelet inhibitors,
They increase the bleeding risk. ASA at analgesic doses (>300mg/day) is contraindicated.
corticosteroids
It potentiates the effects of coumarin derivatives, inhibiting the metabolism of
Cotrimoxazole
coumarins by CYP2C9
Anticonvulsants (carbamazepine, They decrease the effects of coumarin, as they are enzymes inducers. Users of these
phenytoin), rifampicin medications should get a higher dose to get the INR right.
5. Hemorrhage linked to anticoagulant use
Before undergoing an invasive procedure, coumarin derivatives must be stopped and replaced with LMWH.

HEPARINS
They are direct inhibitors of activated clotting factors (especially IIa (thrombin) and factor Xa) and can only be administered
parenterally.
Drug Mechanism of action
Activates antithrombin III, which neutralizes clotting factors. This inhibits the conversion of
Heparin
fibrinogen into fibrin.
LMWH has a 2-3x higher anti-factor Xa activity, but a weaker inhibition of IIa, therefore, its
Low molecular weight
activity can only be measured by an anti-factor Xa activity test.
heparin (LMWH):
LMWH has two major advantages: t1/2 is longer, so administration once/twice a day is enough;
• Nadroparin
and the anticoagulant activity is more predictable, so coagulation checks aren’t as frequent.
(Fraxiparine)
LMWH is eliminated by the kidney, so one should be aware in. those with renal failure, and
• Enoxaparin (Clexane)
dosage should be calculated depending on the renal function.
1. Indications
Used as prophylaxis (6-8 hours after a surgical procedure) and therapy of venous and arterial thromboembolic disorders, mainly
as an introduction to therapy with coumarin derivatives.
2. Side effects
The main side effect is bleeding. With LMWH this occurs specially in those with renal insufficiency.
Heparin Guideline
Unfractionated heparin: Non-acute situations: stop heparin
t1/2 1,5-2 hours, and Acute situations: if life threatening or intracranial hemorrhage, inhibit BEWARE OF
increases with dose heparin with 1mg protamine IV ANAPHYLAXIS
LMWH: t1/2 3-4 hours Acute situations: protamine IV, although it can only naturalize 50% of LMWH
A relatively uncommon complication is heparin-induced thrombocytopenia (HIT), and though it occurs in <1%, platelet levels
should be checked regularly for prevention.
3. Interactions
The anticoagulant effect may be enhanced by NSAIDs, salicylates, vitamin K-antagonists and corticosteroids (which have
ulcerogenic activity).

DIRECT ORAL ANTICOAGULANTS (DOACS)

They have a direct interaction with activated proteins in the coagulation cascade. Dabigatran binds directly and reversibly to factor
II (thrombin), whereas apixaban, endoxaban and rivaroxaban are direct selective inhibitors of factor Xa.
There is a 2–3-day delay on the effect, so heparin is commenced concurrently with DOACs, lasting around 7 days.
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1. Indications
Patients with non-convulsive atrial fibrillation, a CHA2DS2-VASc score >1, DVT or PTE. Also, one advantage of DOACs vs. coumarins
is that intracranial bleeding occurs less frequently.
2. Side effects
The main side effect is the risk of bleeding. Dabigatran is 80% renal excreted (the rest of DOACs are 30% renally cleared) and renal
function loss thus have a major impact on clearance and hence a higher risk of bleeding. To prevent all of this, a dose adjustment
is required, or maybe the DOAC should be switched to a coumarin.
3. Interactions
Dabigatran’s blood levels may be higher when prescribed with nephrotoxic drugs.
4. Bleeding while on DOACs
Bleeding can be stopped with idaruzicimab.

CARDIOVASCULAR AGENTS
Cardiovascular agents are divided into the following groups:
a. Diuretics c. Calcium channel blockers (CCBs)
a. Thiazide diuretics a. Dihydropyridines
b. Loop diuretics b. Other calcium antagonists (diltiazem, verapamil)
c. Potassium-sparing diuretics d. RAS-inhibitors
b. β-adrenergic receptor blockers a. ACE-inhibitors
a. Selective β-blockers b. Angiotensin II-antagonists or angiotensin receptor blockers (ARBs)
b. Non-selective β-blockers e. Cardiac glycosides
f. Nitrates
Most of these are used as anti-hypertensives. For the lowering of blood pressure, there are three mechanisms:
• Promoting arterial vasodilatation (à reduction of peripheral resistance): calcium antagonists, RAS-inhibitors
• Decreasing the preload by venous vasodilatation (nitrates, RAS-inhibitors) or absolute decrease of circulating volume
(diuretics)
• Reducing the contraction force of the heart or frequency of the heartbeat (β-blockers, diltiazem, verapamil)

DIURETICS
Diuretics increase the excretion of sodium chloride and water by reducing the reabsorption of these electrolytes in the kidney.
• Loop diuretics (bumetanide, furosemide): loop of Henle
o Inhibition of Na+/K+/2Cl- cotransporter
o Higher concentration of Na+ in the distal tubule and the first part of the collecting duct
activates the Na+/K+ counter transport with increased K+ excretion
• Thiazide diuretics (chlorothiazide, hydrochlorothiazide): distal tube
o Inhibition of Na+/Cl- cotransporter
o The presence of larger amounts of Na+ in the distal tubule and the beginning of the
collecting duct activates the compensating Na+/K+ exchange transport leading to more K+
excretion
• Potassium-sparing diuretics (spironolactone, amiloride, triamterene): cortical collecting duct
o Blocking of the aldosterone receptor thereby limiting Na+/K+ exchange (in/out)
o Inhibit cortical Na+ channels
o Weak diuretic effect
1. Medicinal properties
Diuretics Indication Kinetics
• Heart failure (edema, dyspnea by congestion) Furosemide effects last 6 hours. If renal
Loop diuretics
• Cirrhosis (edema, congestion) impairment, doses should be raised.
• Hypertension
Thiazide diuretics If renal disfunction, use loop diuretics
• Dyspnea and edema in mild heart failure
Amiloride, triamterene Preventing K+ depletion when using loop/thiazides diuretics
Potassium-sparing • Heart failure NYHA 3, due to its positive effect on adverse cardiac remodeling
diuretics Spironolactone • Avoiding K+ depletion
• Be aware of hyperkalemia
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2. Side effects
Side effect Medication Risk factors Clinical symptoms Management
Old age, fever, diarrhea Hypotension (falls Monitor hydration state,
Reduced effective Loop/thiazide
and vomiting increase the and dizziness) and rehydration and/or stopping the
circulating volume diuretics
risk of dehydration dehydration medication
Loop/thiazide Old age, reduced intake of Arrhythmias, muscle K supplementation, K-sparing
Hypokalemia
diuretics K through diet, diarrhea weakness diuretic, RAS-inhibitors
Check sodium levels 5-9 days after
Thiazide Old age, reduced intake of Nausea, confusion, start of treatment if patient >80, or
Hyponatremia
diuretics protein and salt falls >70+SSRIs or has ongoing
vomiting/diarrhea
Dizziness while
standing/getting up, Checking K+ levels, if patient >70 +
K-sparing Old age, DM, heart failure
Hyperkalemia falls, dehydration, RF: limit K intake, calcium
diuretics and renal failure
hypotension, renal gluconate, insulin, dialysis
failure
3. Interactions
Drug Side effect
Antihypertensives, opiates, benzodiazepines Tendency to fall
SSRIs (SIADH) Hyponatremia
NSAIDs, RAS-inhibitors Renal failure and/hiperkalemia
NSAIDs Reduced effect

b-ADRENERGIC RECEPTOR BLOCKERS

Receptor Location and effects
Myocardium’s pacemaker cells: tachycardia, increase in cardiac output by increasing heart rate and stroke
β1-receptor
volume, accelerated impulse conduction of the heart
Walls of certain blood vessels and airways: bronchodilatation, vasodilatation in striated muscle (reflex
β2-receptor
tachycardia)

Non-selective β-blockers (propranolol, labetalol, sotalol) Selective β-blockers (atenolol, bisoprolol, metoprolol)
Blockade of β1 and β2 receptors diminishes heart rate and oxygen
Selective β1-blockers, so bronchospasm is less
use by the heart. β2 blockade impairs smooth muscle relaxation in
frequent
the respiratory tract, causing bronchospasm and dyspnea
1. Indications
β-blockers lower the heart rate, blood pressure and cardiac contractility, so they are indicated for:
• Atrial fibrillation: rate control achieved by all β-blockers, sotalol also causes rhythm control)
• Angina pectoris, secondary prevention after acute myocardial infarction
• Hypertension
• Stable chronic heart failure with reduced systolic ventricular function
2. Side effects
The main side effects are hypotension (orthostatic hypotension in elders), bradycardia and increased tendency to fall. Sotalol can
also cause arrhythmias (QT prolongation and torsades de pointes), especially if the patient has hypokalemia and/or an impaired
renal function.
3. Interactions
Drug Side effect
Verapamil, diltiazem and other negative chronotropic drugs Bradycardia
Agents that lower potassium levels (loop, thiazides diuretics)
Arrhythmia (specially with
Agents that decrease renal function (NSAIDs)
sotalol use)
Agents that prolong QT (some antipsychotics)

CALCIUM CHANNEL BLOCKERS

1. Mechanism of action
They can be divided into:
a. Dihydropyridine compounds (nifedipine, amlodipine and barnidipine): block L-type calcium channels on smooth muscle cells,
reducing vascular tone, relaxation of coronary as well as peripheral blood vessels, explaining their use on hypertension.
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b. Other calcium channel blockers (verapamil and diltiazem): they are more cardiac specific, reducing heart rate and causing
bradycardia. If prescribed combined with a β-blocker, they can cause slow conduction and even heart block. They can be used
in hypertension as well as in atrial fibrillation.
2. Side effects
a. Dihydropyridine compounds: headaches, flushes, dizziness, reflex tachycardia, hypotension, falls and peripheral edema
b. Other calcium channel blockers: bradycardia negative inotropy

RAS-INHIBITORS
The renin-angiotensin system (RAS) controls the electrolyte balance and blood pressure
(BP). When BP decreases and Na+ levels in the blood drop, renin is secreted by the
juxtaglomerular cells in the kidney. This causes the cleavage of AT-I, which ACE turns
into AT-II. Angiotensin II has vasoconstrictive properties and induces the release of
aldosterone from the adrenal cortex, resulting in an increase in BP, sodium and water
retention, and an increased potassium excretion.
1. ACE inhibitors (captopril, enalapril, lisinopril)
1.1. Side effects
Inhibition of the formation of AT-II results in a lower BP in hypertension. It also helps
reduce the perfusion pressure in the glomerulus, being helpful in nephropathic
diabetes. They can also be used in heart failure and angina pectoris/acute coronary syndrome.
1.1. Side effects
The main side effects include hyperkalemia, renal failure, hypotension, tendency to fall (it can be reduced by taking the ACE-
inhibitor in the evening), tickling cough and angioedema of the pharynx area.
1.2. Interactions
Medication Side effect RF for adverse effects
Diuretics, NSAIDs Renal failure Dehydration, diarrhea, vomiting, fever, anorexia
Potassium-sparing diuretics Hyperkalemia DM, heart failure, renal failure
Diuretics Hypotension Old age, dehydration
Antihypertensives, opiates, BZDs Risk of falling Old age, dehydration
2. Angiotensin II (AT1)-antagonists (losartan, valsartan)
They affect the RAS system by selectively blocking the AT1 receptor, which inhibits the action of AT-II. They are only indicated as
an alternative to an ACE-inhibitor, if side effects are unbearable.

CARDIAC GLYCOSIDES (DIGOXIN)

It increases cardiac contractility and decreases heart rate by vagal stimulation. It is indicated in AF with rapid ventricular response
and heart failure. It binds specifically to the cardiac cells, where accumulation is key for its action.
One disadvantage is its narrow therapeutic index, being able to cause arrhythmias if surpassed.

NITRATES
Nitrates (nitroglycerin) have a direct vasodilatory effect on venous blood and coronary vessels, or even on arterioles at high doses.
Patients can develop tolerance, which can be prevented by intermittent dosing.
Nitrates are converted within the smooth muscle cells of the vessel wall into nitric oxide (NO). NO also inhibits platelet adhesion
and aggregation. Furthermore, it plays a role in the endocardial function and contractility of the myocardium.
They are indicated for angina pectoris and in pulmonary edema/cardiac asthma. The most important side effect is the nitrate
collapse, especially in patients using the fast-acting preparation (for acute chest pain), and ever worse if the patient is dehydrated.

ANTIDIABETICS

ORAL HYPOGLYCEMIC AGENTS

1. Metformin
It inhibits glucose production in the liver, inhibits glucose uptake by the ilium and increases peripheral insulin sensitivity. It does
not stimulate insulin production, so it cannot cause hypoglycemia.

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 1.1. Indications
Treatment of DM2 if there is adequate renal function (>30ml/min/1,73m2). With a GFR of. 30-
60ml/min/1,73m2 the maximum dosage is 1g/day, instead of 3g.
1.2. Kinetics
It is excreted by the kidneys, so it is contraindicated in renal or hepatic impairment, because
otherwise it would accumulate and cause lactic acidosis. It is also contraindicated in heart
failure and severe hypoxemia, as well as diagnostics procedures with iodinated contrast or
elective surgery under general anesthesia (metformin should be interrupted on the day of the
procedure and restarted 48 hours after).
1.3. Side effects
Especially at the start of the treatment, it can entail gastrointestinal symptoms, such as nausea,
vomiting and diarrhea/loose stools, due to higher glucose available to bacteria.

SULPHONYLUREA DERIVATIVES
SU-derivatives stimulate the release of insulin from β-cells by blocking K+/ATP channels. There are short-acting (tolbutamide,
gliclazide (first choice, because of a lower hypoglycemia risk)) and long-acting agents (glibenclamide, glimepiride).
1. Indications
In DM2, in combination with metformin if the latter is inefficient by itself.
2. Side effects
The main side effect is hypoglycemia since the release of insulin occurs independently of the level of glucose. Glibenclamide is
contraindicated in renal impairment because accumulation of active metabolites (that should be excreted by the kidney) may
contribute to the risk of hyperglycemia.
3. Interactions
Non-selective β-blockers may mask the early symptoms of hypoglycemia, and they can even delay recovery of blood glucose levels
after.
4. Hypoglycemia
It occurs in two phases. Blood glucose level <4mmol/l leads to stimulation of the adrenergic system, resulting in tachycardia,
sweating, restlessness and tremors. This glucose level starts affecting the brain, the secondary neuroglycopenic symptoms can
occur, such as dysarthria, diplopia, headache, impaired concentration and confusion.
Mild symptoms can be controlled administering carbohydrates or glucose, or if it is not possible, an intravenous glucose solution
or glucagon should be administered.

SGLT2-INHIBITORS
They selectively and reversibly block the sodium-glucose cotransporter-2 in the kidneys, which inhibits renal glucose reabsorption,
leading to excretion of glucose in the urine.
1. Indications
DM2 when neither metformin, SU-derivatives nor insulin have resulted in adequate glucose control.
2. Side effects
The most important side effect to watch out for is euglycemic diabetic ketoacidosis (EDKA). A low-carbohydrate diet can increase
the risk.

INSULIN
1. Indications
Necessary in DM1. In DM2, insulin is indicated if there is an insufficient response to oral antidiabetic agents.
2. Side effects
Hypoglycemia caused by overdose, eating too late or too little food, excessive alcohol consumption or physical exertion.
3. Interactions
Non-selective β-blockers may mask the early symptoms of hypoglycemia, and they can even delay recovery of blood glucose levels
after.
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ANTIDEPRESSANTS

ANTIDEPRESSANTS
Antidepressants Mechanism of action
Amitriptyline inhibits both the reuptake of serotonin and norepinephrine.
Tricyclic antidepressants (TCAs): amitriptyline,
Nortriptyline (metabolite of amitriptyline) inhibits mainly the reuptake of
nortriptyline
norepinephrine.
Selective serotonin reuptake inhibitors
Serotonin signaling targeted
(SSRIs): citalopram, fluoxetine, paroxetine
1. Indications
Patients with moderately severe depression. SSRIs are also indicated for a variety of anxiety disorders due to their panic and
anxiety-reducing action. A non-registered use of TCAs is for neuropathic pain.
2. Side effects
Type Pharmacological property Side effects
• Visual disturbances, reduced accommodation, worsening of glaucoma
• Dry mouth
Anticholinergic (muscarinic receptor • Micturition disorders
blockade) • Constipation
• Sexual disfunction
TCAs • Confusion, delirium
Antihistaminic (histamine H1
• Sedation, drowsiness
receptor blockade)
Antinoradrenergic (a-1 receptors
• Postural hypotension, falls
blockade)
Quinidine-like • Conduction disorders
• Hyponatremia
• Thrombocytopathy (hemorrhage)
• Gastrointestinal symptoms
SSRIs Mainly due to serotonin potentiation • Headache
• Insomnia
• Sexual dysfunction
• Serotonin syndrome
3. Interactions
Type Drug interactions Side effects
TCAs Antihypertensives and diuretics Orthostasis
Thiazide diuretics Hyponatremia
SSRIs
NSAIDs* Risk of hemorrhage
*SSRIs + NSAIDs: useful to reduce the NSAIDs dose or replace it with a selective COX2 inhibitor, with less GI effects.

LITHIUM
1. Indications and kinetics
Used in monotherapy to suppress and prevent the occurrence of mania and depression in patients with bipolar disorders. It is also
a complimentary drug in the treatment of treatment-resistant unipolar depressive disorder.
Lithium is excreted primarily through the kidneys and 75% is reabsorbed again in the proximal tubule. It has a narrow therapeutical
index. (0,4-1,2mmol/l) and should be dose-adjusted according to blood levels to prevent and overdose. Lithium interacts with
sodium, so an inadequate fluid and salt intake or excessive sweating can lead to toxic levels on blood.
2. Side effects
Lithium can cause renal dysfunction, diabetes insipidus, hypothyroidism, nausea and vomiting. Therefore, patients should be
instructed to take their medication regularly, drink plenty of water (2-3l/day) and to have their renal function checked regularly.
3. Interactions
Diuretics, NSAIDs and RAS inhibitors may cause higher lithium blood levels.

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BENZODIAZEPINES
1. Mechanism of action and pharmacokinetics
BDZs enhance the inhibitory action of GABA binding to the GABAA ion channel and prolonging the influx of chloride leading to
neuronal hyperpolarization. They have sedative, hypnotic, anxiolytic, anticonvulsant and muscle relaxing effects.
All their pharmacodynamics are the same, but they differ in their pharmacokinetics, t1/2 being shorter in temazepam and
oxazepam (t1/2 <15 hours, which makes them useful as a hypnotic) than diazepam (t1/2 40-100 hours).
In elderly patients, metabolism and excretion may be slowed down, causing a “hungover” effect.
2. Indications
The main indications include sleeping disorders (temazepam or zolpidem), generalized anxiety disorder (lorazepam) and treatment
for withdrawal symptoms. In addition, they are sometimes used as anticonvulsants for fever convulsions and seizures, especially
clonazepam, diazepam or midazolam.
3. Side effects
BDZs often alter alertness and motor skills, being able to cause muscle weakness and memory loss. Long-term use can induce
tolerance as well as dependency. BDZs overdoses lead to respiratory depression, counteracted by flumazenil (a BDZ-receptor
antagonist).
4. Prevention of adverse effects
Tolerance and dependency should be prevented by prescribing BDZs only for short periods of time (<2 weeks). Dependency can
be treated with long-acting BDZs, and doses should be lowered gradually and finally phased out.
5. Interactions
• Antihypertensives, alcohol or opiates: tendency to fall
• Opiates or alcohol: respiratory depression

ANTIBIOTICS

b-LACTAM ANTIBIOTICS
Inhibitors of bacteria cell wall synthesis.
1. Penicillins
Divided into narrow-spectrum (penicillin) and broad-spectrum (amoxicillin).
1.1. Indications
Penicillins are particularly effective against Gram+ bacteria, but 80-90% of S.
aureus strains are now resistant to benzylpenicillin and amoxicillin. In MRSA
cases, a non-β-lactam such as vancomycin is indicated.
Flucloxacillin is a β-lactamase-insensitive penicillin effective against Gram+, or it
can be combined with broader-spectrum antibiotics (amoxicillin or piperacillin),
so Gram- are also covered, even P. aeruginosa.
Penicillins can also be combined with a β-lactamase inhibitor, such as clavulanic acid or tazobactam. This overcomes the resistance
conferred by the bacterial β-lactamase production. E.g.: amoxicillin-clavulanic acid or piperacillin-tazobactam.
1.2. Side effects
The most common side effects are eruptions and diarrhea (if caused by Clostridium difficile infection, must be treated with
metronidazole). There is also risk of anaphylactic shock if there is any allergy.
2. Cephalosporins
Cephalosporin Properties
1st generation: cefazolin Narrow-spectrum and is especially effective against Gram+
2nd generation: cefuroxime Β-lactamase-insensitive and more efficient against Gram-
3rd generation: ceftazidime Broader-spectrum and IV; particularly effective against Gram- (even Pseudomonas)

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3. Carbapenems: imipenem and meropenem
Active against nearly all types of Gram+, Gram- and anaerobic bacteria. They are “last choice” antimicrobials, used in highly
resistant infections, like extended spectrum β-lactamase-producing bacteria (ESBL).

TETRACYCLINES
Tetracyclines inhibit protein synthesis. They are bacteriostatic and may inhibit bactericidal antibiotics, like penicillins or
cephalosporins. They are not to use during pregnancy and should be avoided in <8 yo children.
1. Side effects
Discoloration of the teeth in children (hence why they should not be used) and photosensitivity (avoid sunlight exposure) are their
main side effects.
2. Interactions
• Iron preparations, milk or antiacids: reduce tetracyclines’ absorption because of the formation of insoluble complexes

AMINOGLYCOSIDES
Aminoglycosides (gentamicin, tobramycin) are particularly effective against Gram- microorganisms. They have important and
serious side effects, such as irreversible deafness or reversible renal impairment; and should therefore be used for a short period
of time.
They block the interaction between mRNA and ribosomes (blocking the protein synthesis) and have a bactericidal effect. They are
especially active against Gram- rods (Escherichia, Proteus, Pseudomonas, Haemophilus).
They do not get absorbed by the intestines, so they can only be administered parenterally. Having a narrow therapeutic index,
they can cause ototoxicity and nephrotoxicity, having to regularly check blood levels if using these drugs.

MACROLIDES
Macrolides (clarithromycin, erythromycin, azithromycin) inhibit protein synthesis (bacteriostatic) and are effective against atypical
and Gram+ pathogens. The disadvantage is that they can inhibit the metabolism of many other drugs through CYP3A4 inhibition,
causing plenty of drug interactions.
They are especially effective against Gram+ bacteria, like S. aureus, pneumococcus and intracellular microorganisms (Legionella,
Chlamydia, Mycobacteria).
They should be used carefully if combined with statins or QTc-prolonging agents, given they can increase the risk of
rhabdomyolysis and torsade de pointes, respectively.

SULPHONAMIDES/TRIMETHOPRIM
This combination is called cotrimoxazole, and it is synergistic (efficacy increases 5-10x
compared to trimethoprim alone). Cotrimoxazole has bactericidal activity and has a
lower risk of developing resistance, however a higher risk of toxic effects due to a
double inhibition of folic acid synthesis.
1. Mechanism of action
Sulphonamides’ bacteriostatic action is based on the inhibition of bacterial synthesis
of dihydropteric acid by blocking the addition of para-aminobenzoic acid. On the other
hand, trimethoprim inhibits dyhidrofolic acid turning into tetrahydrofolate.
2. Interactions
Antibiotic Interaction with drug Side effects
Trimethoprim, cotrimoxazole Methotrexate Leukopenia
Cotrimoxazole Coumarins Increased INR levels

QUINOLONES
Quinolones (ciprofloxacin, levofloxacin, moxifloxacin and norfloxacin) are particularly effective against Gram- organisms. They
have bactericidal activity, affecting the DNA synthesis by inhibition of bacterial DNA gyrase.
They have the same interaction as tetracyclines. To prevent this from happening, using another antibiotic should be considered,
or if that is not possible, assuring a certain amount of time passes between both ingestions.

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